Medical treatment comprising enteral administration of edaravone

Abstract

The invention relates to a solid water-dispersible pharmaceutical composition for use in the treatment of a disease, said treatment comprising dispersing said pharmaceutical composition into an aqueous liquid to produce an enteraliy administrable liquid containing at least 0.5 gram of said pharmaceutical composition and at least 0.3 g / 1 of edaravone, followed by enteral administration of said enteraliy administrable liquid to a human patient in an amount to provide a dose of 30-300 mg of edaravone, said pharmaceutical composition comprising: 2-50 weight % of 3-methyl-l-phenyl-2-pyrazolin-5-one (edaravone); and 3-50 weight % of a water-soluble alkalizing agent. This solid composition containing edaravone can be easily dispersed in an aqueous liquid to prepare an aqueous solution of edaravone that can be ingested by a patient. The solid composition of the invention provides the advantage that when the composition is introduced into water the edaravone dissolves very rapidly and the enteraliy administrable liquid thus obtained has a high oral bioavailability.

Description

Technical Field

[0001] This invention relates to a solid pharmaceutical composition containing 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) for medical treatment, said treatment comprising dispersing the solid pharmaceutical composition in an aqueous liquid to produce an enterically administerable liquid, and subsequently administering the enterically administerable liquid into a human patient.

[0002] The solid edaravone composition of the present invention is very stable and is readily ingested once dissolved in an aqueous liquid, providing edaravone with high oral bioavailability.

[0003] Examples of diseases that can be treated by oral administration of the compositions of the present invention include neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease; cerebral amyloid angiopathy (CAA); autoimmune diseases such as multiple sclerosis (MS); myocardial infarction and cerebrovascular diseases such as ischemic stroke. Background Technology

[0004] ALS is a neurodegenerative disease that affects the upper motor neurons in the brain and the lower motor neurons in the spinal cord and brainstem. Degeneration of the upper motor neurons usually leads to muscle spasms, while degeneration of the lower motor neurons leads to muscle weakness, muscle atrophy, and convulsions.

[0005] Early symptoms of ALS typically include muscle weakness in the hands, arms, legs, or feet, causing weakness or spasms in these areas. The disease itself can also affect the muscles that control speech or swallowing, leading to difficulty chewing, speaking, swallowing, and breathing. As the disease progresses, it spreads to other parts of the body, causing progressive muscle weakness and paralysis. ALS patients eventually lose the ability to initiate and control all voluntary movements, and neuromuscular respiratory failure makes breathing increasingly difficult. The early symptoms and progression of the disease vary from person to person.

[0006] The sensory and autonomic nervous systems remain unaffected, keeping hearing, vision, touch, smell, and taste, as well as involuntary muscles such as those controlling heartbeat, gastrointestinal tract, bowel, and bladder function intact. Cognitive function is also generally unaffected.

[0007] Most people develop ALS between the ages of 40 and 70, but the disease can also occur at a younger age. The prevalence has been found to increase with age. Although ALS is classified as a rare disease, it is the most common motor neuron disorder. Approximately one or two people out of every 100,000 develop ALS each year, and the prevalence of ALS is estimated at about two cases per 100,000 people, with the number of cases increasing due to an aging population.

[0008] Riluzole is currently the only approved drug for ALS. It is believed to work by its potential to reduce glutamate signaling, a neurotransmitter found at high levels in people with ALS. The drug has been shown to have limited beneficial effects on ALS symptoms and disease progression. It will improve survival rates, but to a limited extent.

[0009] Other medications prescribed for ALS patients aim to improve their quality of life and alleviate ALS symptoms such as muscle cramps and spasms, constipation, fatigue, excessive salivation and phlegm, pain, depression, and sleep problems.

[0010] Edaravone is a nootropic and neuroprotective agent used to aid in neurological recovery after acute cerebral ischemia and subsequent cerebral infarction. It acts as a potent antioxidant and powerfully scavenge free radicals, thereby preventing oxidative stress and neuronal apoptosis.

[0011] European Patent A1 405 637 describes the use of edaravone in the treatment of motor neuron diseases, including ALS.

[0012] European Patent A1 714 960 relates to the use of edaravone in the treatment of ALS, wherein there are one or more drug holidays during treatment.

[0013] European Patent A2 754 440 describes the use of edaravone for the treatment of ALS in a specific patient population, wherein the agent is administered by repeating a 14-day administration period and a 14-day drug holiday, or by establishing an initial 14-day administration period and an initial 14-day drug holiday, followed by repeating the administration period for 10 days and a 14-day drug holiday.

[0014] CN 1449754 describes the preparation of a pharmaceutical composition by mixing edaravone with a pharmacologically acceptable alkaline substance and water to prepare a clear solution, followed by freeze-drying to produce a lyophilized powder that can be used to prepare an injectable liquid formulation.

[0015] CN 103251554 relates to a stable edaravone injection and a method for preparing the same. The edaravone injection contains an osmotic pressure regulator, a pH regulator, a dissolving adjuvant, and an antioxidant, comprising sodium chloride, phosphoric acid, phosphate, citric acid monohydrate, and sodium bisulfite. Sodium hydroxide not only acts as a pH regulator but also as a dissolving adjuvant, thus significantly shortening the dissolution time of the active pharmaceutical ingredient.

[0016] It is generally accepted in the prior art that edaravone has low oral bioavailability, and studies have been conducted to provide oral formulations of edaravone with improved oral bioavailability.

[0017] Rong et al.羟丙基-磺丁基-β-环糊精通过调节肠细胞药物外排泵提高依达拉奉的口服 生物利用度 A study described in the *Journal of Pharmaceutical Sciences (2013), DOI 10.1002 / jps.23807, 1-13* investigated the effects of hydroxypropyl-sulfobutyl-β-cyclodextrin on the bioavailability and intestinal absorption of edaravone. The study found that the inclusion complex of edaravone and cyclodextrin improved the water solubility of edaravone and increased its bioavailability in rats. Table 2 of the article shows the absolute bioavailability (F) of orally administered “raw” edaravone (suspended in 0.5% CMC-Na). abs The bioavailability of edaravone was only 5.23% (in contrast, the bioavailability of intravenously administered edaravone was 100%). Table 2 further shows that by complexing edaravone with cyclodextrin, the oral bioavailability of edaravone can be increased by more than 10 times.

[0018] Parikh et al. 一种用于提高生物利用度的依达拉奉新型口服给药系统的研发 (依达拉奉的脂质纳米系统:研发、 The development of an oral delivery system for edaravone was discussed in the *International Journal of Pharmaceutics* (515(2016) 490–500). The authors described a novel oral delivery system for edaravone (NODS) consisting of a mixture of Labrasol and an acidic aqueous system optimized based on solubility and stability studies. The NODS delivery system contains 30 mg / mL edaravone. The in vivo oral bioavailability of the NODS delivery system was investigated in adult rats using an equivalent dose of 30 mg / kg edaravone. The oral bioavailability of the NODS delivery system was found to be 5.7 times that of an edaravone suspension containing 30 mg / mL edaravone and 0.5% sodium carboxymethyl cellulose (see Table 2).

[0019] Parikh et al. 优化、表征及体外 / 体内评价 ExamplesDrug Delivery 24(1); (2017), 962-978) describes a study aimed at achieving oral administration of edaravone through the development of lipid-based nanosystems (LNS). LNS were selected based on their components (including oil, surfactant, and co-surfactant) for maximizing solubility in gastrointestinal (GI) fluids, minimizing glucuronidation, and improving transmembrane permeability. A liquid LNS (L-LNS) was prepared in the form of a microemulsion containing Capryol™ PGMC (oil), Cremophor® RH40:Labrasol® :TPGS 1000 (1:0.8:0.2) (surfactant), and Transcutol® P (co-surfactant). The oral bioavailability of L-LNS was found to be nearly 11 times that of an edaravone suspension containing 30 mg / mL edaravone and 0.5% sodium carboxymethyl cellulose (see Table 3).

[0020] WO 2012 / 019381 describes an oral pharmaceutical composition containing edaravone and cyclodextrin, wherein the weight ratio of edaravone to cyclodextrin is 1:6-100. The preparation method includes the following steps: Mix β-cyclodextrin or a mixture of cyclodextrins containing β-cyclodextrin with 1-5 times their weight of water. Add edaravone or a solution thereof in an organic solvent to the cyclodextrin solution. Grinding or stirring, and Evaporate moisture at a temperature not exceeding 60°C and dry under reduced pressure.

[0021] CN 101 953 832 describes an oral pharmaceutical composition comprising the cyclodextrin combination edaravone. Examples of Chinese patent applications describe tablets, capsules, and granules containing cyclodextrin-edaravone complexes.

[0022] CN 105 816 423 describes various drug delivery systems containing edaravone. Examples of this Chinese patent application describe the oral administration of edaravone (30 mg / kg) to rats using a self-microemulsifying drug delivery system (SMEDDS).

[0023] Currently, edaravone is administered intravenously via ampoules, with the ampoule contents diluted with physiological fluid. However, intravenous injection is a less appealing route of administration because it requires a physician's presence and therefore does not allow for self-administration. Furthermore, many patients dislike receiving medication by injection.

[0024] Edaravone is unstable in aqueous solution because it is readily oxidized and decomposes, exhibiting decreasing stability with increasing concentration. Aqueous solutions of edaravone, such as injectable formulations, are difficult to prepare because edaravone is only slightly soluble in water (approximately 1.85 mg / mL at 25°C) and dissolves very slowly. Summary of the Invention

[0025] Of the various methods of drug delivery, oral delivery remains the most attractive and acceptable route of administration for active pharmaceutical ingredients. The oral route is preferred because it is convenient, produces high levels of patient acceptance and long-term adherence, which in turn increases the therapeutic value of the drug. In most cases, it allows patients to administer the medication themselves without the assistance of a physician.

[0026] Therefore, there is a desire to provide edaravone formulations that can be administered orally. However, traditional oral formulations (such as tablets and capsules) pose problems for patients with swallowing difficulties. This is often the case for patients with ALS, for example.

[0027] The inventors have designed a solid composition containing edaravone that can be readily dispersed in an aqueous liquid to prepare an edaravone aqueous solution, which can be ingested by a patient immediately after preparation. The advantage of the solid composition of this invention is that edaravone dissolves very rapidly when the composition is introduced into water.

[0028] The inventors unexpectedly discovered that the dissolution rate of edaravone in water significantly increased in the presence of an alkalizing agent. While the inventors did not wish to be bound by theory, it is believed that when edaravone is added to water at a concentration of 0.3 g / L or higher, this results in a significant decrease in pH due to edaravone's weak acidity. Because edaravone dissolves more slowly at lower pH levels, its dissolution rate decreases rapidly with increasing dosage when introduced into water. The inventors have found that solid dosage forms containing edaravone combined with an alkalizing agent achieve high edaravone dissolution rates, especially when added to water at concentrations equivalent to at least 0.3 g edaravone per liter.

[0029] The inventors have further discovered that the edaravone aqueous solution prepared using the solid pharmaceutical formulation of the present invention has a surprisingly high oral bioavailability. Although the aforementioned article by Rong et al. reported an absolute bioavailability of only 5.23% for orally administered "unprocessed" edaravone, the inventors have observed an absolute bioavailability of approximately 35% for the edaravone aqueous solution prepared using the solid pharmaceutical composition of the present invention.

[0030] Therefore, one aspect of the present invention relates to a solid aqueous dispersible pharmaceutical composition for treating a disease, said treatment comprising dispersing said pharmaceutical composition in an aqueous liquid to produce an enterically administerable liquid containing at least 0.5 g of said pharmaceutical composition and at least 0.3 g / L edaravone, and subsequently administering said enterically administerable liquid into a human patient in an amount providing a dose of 30-300 mg edaravone, said pharmaceutical composition comprising: ● 2-50% by weight of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone); and ● 3-50% by weight of water-soluble alkalizing agent; When the composition is added to softened water at 25°C at a concentration equivalent to 1.4 g / L of edaravone, the edaravone in the pharmaceutical composition is completely dissolved, and the solution at 25°C has a pH at 25°C that is at least 0.5 pH units higher than that of a solution having the same edaravone concentration and consisting only of edaravone and softened water.

[0031] The solid edaravone compositions of the present invention offer additional advantages, particularly their stability when packaged in sealed pouches or containers. Examples of possible enteral administration methods include oral and gastric administration. Gastric administration involves the use of a tube administered through a nasal passage (NG tube) or a tube that extends directly into the stomach in the abdomen (PEG tube). Invention Details

[0032] A first aspect of the invention relates to a solid aqueous dispersible pharmaceutical composition for treating a disease, the treatment comprising dispersing the pharmaceutical composition in an aqueous liquid to produce an enterically administerable liquid containing at least 0.5 g of the pharmaceutical composition and at least 0.3 g / L edaravone, and subsequently administering the enterically administerable liquid into a human patient in an amount providing a dose of 30-300 mg edaravone, the pharmaceutical composition comprising: ● 2-50% by weight of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone); and ● 3-50% by weight of water-soluble alkalizing agent; When the composition is added to softened water at 25°C at a concentration equivalent to 1.4 g / L of edaravone, the edaravone in the pharmaceutical composition is completely dissolved, and the solution at 25°C has a pH at 25°C that is at least 0.5 pH units higher than that of a solution having the same edaravone concentration and consisting only of edaravone and softened water.

[0033] As used in this article, the term "edaravone" refers to the substance 3-methyl-1-phenyl-2-pyrazolin-5-one.

[0034] Unless otherwise stated, the term "water-soluble" as used herein refers to a material having a solubility greater than 20 g / l in softened water at 25°C.

[0035] Unless otherwise stated, the term "water insoluble" as used herein refers to a material having a solubility of less than 1 g / L in softened water at 25°C.

[0036] As used in this article, the term "treatment" encompasses both therapeutic and conservative treatments.

[0037] As used herein, the term "filler" refers to a pharmaceutically acceptable inert material that provides the desired volume, flow, and / or compressibility properties. Examples of suitable fillers include monosaccharides, disaccharides, and oligosaccharides such as glucose, fructose, sucrose, lactose, raffinose, trehalose, and dextrose; and sugar alcohols such as mannitol, sorbitol, maltitol, xylitol, and lactitol; and combinations thereof.

[0038] As used herein, the term "disintegrant" refers to a pharmaceutically acceptable material that exhibits wicking and / or swelling properties upon contact with water. Examples of suitable disintegrants include povidone, crospovidone, starch, pregelatinized starch, sodium glycolate starch, hydroxypropyl starch, microcrystalline cellulose, sodium or calcium carboxymethyl cellulose, crospovidone carboxymethyl cellulose, polacrilin potassium, low-substituted hydroxypropyl cellulose, sodium or calcium alginate, sodium docusate, methylcellulose, agar, guar gum, chitosan, alginate, sodium bicarbonate, and combinations thereof.

[0039] As used herein, the term "effervescent agent" refers to a pharmaceutically acceptable component that produces gas upon contact with water. Suitable examples of effervescent agents are combinations of basic carbonates and organic acids, such as sodium bicarbonate and citric acid.

[0040] As used herein, the term "binder" refers to a pharmaceutically acceptable component capable of causing adhesion between powder particles within granules. Examples of suitable (wet) binders include maltodextrin, dextrin, ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and hydrocolloids such as gum arabic, alginate, carrageenan, dextran, furcellaran, pectin, gelatin, gum agar, locust bean gum, Indian gum, guar gum, tragacanth gum, xanthan gum, karaya gum, tara gum, cellulose derivatives, starch derivatives, polyvinyl alcohol / polyethylene glycol graft copolymers, and combinations thereof.

[0041] According to a particularly preferred embodiment, when the pharmaceutical composition is added to softened water at 25°C at a concentration equivalent to 1.4 g / L edaravone, a solution having a pH of at least 6.0, more preferably at least 6.5, and even more preferably at least 6.8 is produced. The pH of the solution produced in the above manner generally does not exceed 9.0, more preferably not more than 8.8, and most preferably not more than 8.5. The pharmaceutical composition of the present invention is preferably a powder or tablet. The term "powder" here also includes granules.

[0042] If the pharmaceutical composition is a powder, edaravone is preferably present at a concentration of 3-25% by weight, more preferably 4-20% by weight, and most preferably 6-18% by weight.

[0043] If the pharmaceutical composition is a tablet, edaravone is preferably present at a concentration of 4-40% by weight, more preferably 8-35% by weight, and most preferably 10-30% by weight.

[0044] According to a particularly preferred embodiment, the composition is a powder. Typically, the mass-weighted average particle size of the powder is 30 to 1000 µm, more preferably 40 to 950 µm, and most preferably 50 to 900 µm. The mass-weighted average particle size can be suitably determined using a set of sieves with different aperture sizes.

[0045] In a preferred embodiment, the pharmaceutical composition is a powder in granular form. Preferably, the mass-weighted average particle size is 100 to 1000 µm, more preferably 150 to 950 µm, and most preferably 200 to 900 µm.

[0046] The water-soluble alkalizing agent is preferably present in the pharmaceutical composition at a concentration of 4-45% by weight, more preferably 5-40% by weight, and most preferably 6-35% by weight.

[0047] The pharmaceutical composition preferably contains less than 5% by weight, more preferably less than 3% by weight, and most preferably less than 1% by weight of water-insoluble substances.

[0048] Preferably, the pharmaceutical composition further comprises 25-95% by weight of an excipient selected from fillers, disintegrants, effervescent agents, binders, and combinations thereof. More preferably, the pharmaceutical composition comprises 40-85% by weight of such excipients.

[0049] According to a particularly preferred embodiment, the pharmaceutical composition contains at least 30% by weight, more preferably at least 35% by weight, and most preferably at least 40% by weight of a water-soluble filler.

[0050] According to a particularly preferred embodiment, the pharmaceutical composition contains at least 30% by weight of one or more polyols, more preferably at least 30% by weight of one or more polyols selected from mannitol, sorbitol, xylitol, maltitol, lactitol, and combinations thereof. Most preferably, the pharmaceutical composition contains at least 30% by weight of mannitol.

[0051] The pharmaceutical composition of the present invention preferably contains 0.5-15% by weight, more preferably 0.8-12% by weight, and most preferably 1-10% by weight of a surfactant. More preferably, the composition contains at least 0.5% by weight, more preferably at least 0.8% by weight, and most preferably at least 1% by weight of a nonionic surfactant.

[0052] The nonionic surfactant is preferably selected from poloxamer, polysorbate, and combinations thereof. Poloxamer is a nonionic triblock copolymer composed of a central hydrophobic polyoxypropylene chain flanked by two hydrophilic polyoxyethylene chains.

[0053] The surfactant is preferably present in the pharmaceutical composition at a concentration of 5-100% by weight of edaravone, more preferably at a concentration of 8-70% by weight of edaravone, and most preferably at a concentration of 15-50% by weight of edaravone.

[0054] The pharmaceutical compositions of the present invention preferably comprise edaravone in a micronized form. Typically, at least 90% by volume of edaravone is present in the form of micronized particles with a particle size of less than 100 μm, more preferably in the form of micronized particles with a particle size of 0.1 to 60 μm, and most preferably in the form of micronized particles with a particle size of 0.2 to 50 μm. The particle size distribution of the micronized edaravone particles can be determined using a MALVERN 3000 particle size analyzer and AERO S dry powder dispersant (sample amount: 200-300 mg; analytical model: general; scattering model: Fraunhofer; venturi tube type: standard; pressure: 1 bar; feed rate: 40) by laser powder diffraction.

[0055] Micronized edaravone particles may be present in the pharmaceutical composition as discrete particles and / or as part of an aggregate of micronized edaravone particles or as part of an aggregate of micronized edaravone particles and other pharmaceutically acceptable particulate components.

[0056] The water-soluble alkalizing agent in the pharmaceutical composition is preferably selected from oxides and hydroxides of alkali metals; oxides and hydroxides of alkaline earth metals; Al(OH)3; Fe2O3; salts of weak organic and weak inorganic acids; basic amines; basic amino acids; and combinations thereof. The oxides and hydroxides of alkali metals are preferably selected from NaOH, KOH, LiOH, and combinations thereof. The oxides and hydroxides of alkaline earth metals are preferably selected from Ca(OH)2, CaO, Mg(OH)2, MgO, and combinations thereof. The salts of weak organic and weak inorganic acids are preferably selected from carbonates, bicarbonates, borates, carboxylates (e.g., lactates, citrates, acetates, formates, and oxalates), phosphates, sulfates, and combinations thereof. The basic amines are preferably selected from tris(hydroxymethyl)aminomethane, ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, glucosamine, ethylenediamine, diethylamine, triethylamine, isopropylamine, diisopropylamine, ammonia, and combinations thereof. The basic amino acids are preferably selected from arginine, histidine, lysine, and combinations thereof.

[0057] The present invention also covers the use of the above-mentioned water-soluble alkalizing agents in the form of pharmaceutically acceptable salts and hydrates.

[0058] According to a preferred embodiment, the water-soluble basifying agent is a base with a pKa of at least 7, more preferably 7.5 to 12, and most preferably 7.7 to 11 at 20°C. If the water-soluble basifying agent is a polybasic acid capable of losing an i-proton, then the agent has at least one pKa within the above-mentioned range. ai .

[0059] According to a particularly preferred embodiment, the water-soluble alkalizing agent is selected from tris(hydroxymethyl)aminomethane, phosphates (e.g., Na3PO4), and combinations thereof.

[0060] According to a particularly preferred embodiment, the pharmaceutical composition of the present invention comprises edaravone and a water-soluble alkalizing agent in particulate form. The pharmaceutical composition may be a simple blend of these particulate components. Alternatively, the pharmaceutical composition may comprise particles containing both particulate components, or it may comprise a combination of two different particles, such as particles containing edaravone and particles containing a water-soluble alkalizing agent.

[0061] According to a preferred embodiment, the pharmaceutical composition comprises a mixture of at least three different powders, including: 2-50% by weight of edaravone particles, wherein the edaravone content is at least 50% by weight and the particle size is 2-120µm; 3-50% by weight of alkalized particles, said alkalized particles containing at least 50% by weight of alkalizing agent and having a particle size of 10-750 µm; 25-95% by weight of filler particles, containing at least 90% by weight of water-soluble filler and having a particle size of 10-750 μm.

[0062] According to another preferred embodiment, the pharmaceutical composition contains at least 10% by weight, more preferably at least 30% by weight, and most preferably at least 50% by weight, of particles with a diameter of 80 to 1200 μm, said particles comprising: 2-50% by weight of edaravone; and 3-50% by weight of water-soluble alkalizing agent; 25-95% by weight of water-soluble filler.

[0063] Preferably, the combination of edaravone, a water-soluble alkalizing agent, and a water-soluble filler constitutes at least 80% by weight of the aforementioned particles, more preferably at least 85% by weight, and most preferably at least 90% by weight.

[0064] According to an alternative preferred embodiment, the pharmaceutical composition comprises a combination of at least two different particles, said particles comprising: ● At least 5% by weight of edaravone particles having a diameter of 80 to 1200 μm, said edaravone particles containing: - 3-70% by weight of edaravone; - 0-5% by weight, preferably 0% by weight, of water-soluble alkalizing agent and - 30-97% by weight of water-soluble fillers; ● At least 5% by weight of alkalized particles with a diameter of 80 to 1200 μm, wherein the edaravone particles contain: - 7-80% by weight of water-soluble alkalizing agent; - 0-5% by weight, preferably 0% by weight of edaravone; and - 20-93% by weight of water-soluble fillers.

[0065] Preferably, the combination of edaravone, a water-soluble alkalizing agent, and a water-soluble filler constitutes at least 80% by weight of the aforementioned particle combination, more preferably at least 85% by weight, and most preferably at least 90% by weight.

[0066] The treatment of the present invention preferably comprises an oral or gastric administration of a liquid that can be administered enterally. Most preferably, the treatment comprises oral administration of the liquid.

[0067] According to a particularly preferred embodiment, the pharmaceutical composition according to the invention is used to treat neurodegenerative diseases; cerebral amyloid angiopathy (CAA); autoimmune diseases; myocardial infarction; or cerebrovascular diseases. More preferably, the composition is used to treat neurodegenerative diseases or cerebrovascular diseases.

[0068] Examples of neurodegenerative diseases that can be treated according to the present invention include amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. The pharmaceutical compositions of the present invention are particularly suitable for the treatment of ALS.

[0069] According to the particularly preferred implementation scheme, the current treatment for the disease includes conservative treatment.

[0070] Aqueous liquids used to prepare enterally administered edaravone-containing liquids typically contain at least 80% by weight water, more preferably at least 90% by weight water. Examples of suitable aqueous liquids include mineral water, tap water, cold drinks (including milk), and hot drinks. Most preferably, the aqueous liquid is mineral water or tap water.

[0071] According to a particularly preferred embodiment, the aforementioned treatment includes administering the enterally applicable liquid into the intestine at a dose of 10 to 300 ml, more preferably at a dose of 20 to 250 ml, and most preferably at a dose of 30 to 200 ml.

[0072] Treatment according to the invention generally comprises dispersing 1 part by weight of the pharmaceutical composition in 20 to 200 parts by weight of an aqueous liquid, more preferably 30 to 150 parts by weight of an aqueous liquid, and most preferably 40 to 100 parts by weight of an aqueous liquid.

[0073] The enteric liquid prepared for treatment in this invention typically contains 0.5-6 g, more preferably 0.8-5 g, and most preferably 1-4 g of a pharmaceutical composition.

[0074] The enteric liquid used for treatment according to the present invention preferably contains at least 500 mg / L, more preferably 800-3,000 mg / L of edaravone, even more preferably 900-2,000 mg / L of edaravone, and most preferably 1,000-1,500 mg / L of edaravone.

[0075] The enteral fluid is preferably administered to human patients at a dose sufficient to provide 30-300 mg of edaravone, more preferably 60-240 mg of edaravone, and most preferably 90-180 mg of edaravone.

[0076] The enterically administered liquid used in the treatment of this invention preferably contains edaravone in an aqueous solution form. Even more preferably, the enterically administered liquid is a monophase solution. Here, the term "monophase" means that it does not contain a liquid composition with two or more different phases. Therefore, the monophase enterically administered liquid is not an emulsion (e.g., a microemulsion, nanoemulsion, or micellar suspension / solution).

[0077] According to another preferred embodiment, edaravone present in the enterally administered liquid is not contained in a clathrate (e.g., a complex with cyclodextrin).

[0078] According to another preferred embodiment, the enterally applicable liquid contains less than 3% by weight, preferably less than 1% by weight, of a water-soluble organic solvent selected from polyethylene glycol (e.g., PEG200-10,000), propylene glycol, diethylene glycol monoethyl ether (e.g., Transcutol HP, Transcuto lP), polyoxyethylene castor oil (e.g., Cremophor RH40, Cremophor EL), polyoxyethylene glycerol esters (e.g., Labrasol), polyoxyethylene sorbitan fatty acid esters (e.g., Tween 20, Tween 80), water-soluble forms of vitamin E (e.g., TPGS 1000), and ethanol.

[0079] The liquid that can be administered into the intestine preferably contains no more than 3% by weight, or even more preferably no more than 1% by weight, of organic matter other than edaravone and organic water-soluble alkalizing agents.

[0080] Enterally administered liquids are typically administered in an amount sufficient to provide a daily dose of 0.4-8 mg edaravone / kg body weight. More preferably, the enterally administered liquid provides a daily dose of 0.6-4 mg edaravone / kg body weight, and most preferably, a daily dose of 1-3 mg edaravone / kg body weight.

[0081] In another preferred embodiment of the treatment of the present invention, the patient fasts for at least 1 hour before oral administration of the enteral liquid.

[0082] The treatment according to the invention preferably includes administering the enterosorbable liquid into the patient's intestine at least once a day for at least 2 weeks, more preferably for at least 4 weeks.

[0083] The invention is further illustrated by the following non-limiting embodiments.

[0084] ​

[0085] Example 1

[0086] Water-dispersible particles were prepared based on the formulations shown in Table 1.

[0087] Table 1

[0088] 1 Pearlitol® 200, provided by Roquette

[0089] The micronized edaravone used has the following particle size distribution (volume distribution, measured by laser diffraction):

[0090] Dv(10): 1.60 µm

[0091] Dv(50): 12.6 µm

[0092] Dv(90): 72.6 µm

[0093] Weigh edaravone and the excipients, sieve them through a 1,000 µm sieve, add them to a Kenwood shredder mixer, and dry-mix for 60 seconds. While mixing, slowly add purified water (dropwise) to 40 g batches using a needle and syringe. Formulations containing 2%, 5%, and 8% poloxamer require 6 mL, 5 mL, and 4 mL of water, respectively, to obtain suitable wet granules.

[0094] The obtained wet granules were placed in a tray and dried in an oven at 60°C for 2 hours. Finally, the granules were passed through a 1,000µm sieve, and the sieved product was stored in amber vials.

[0095] The dissolution behavior of the granules was evaluated by adding 1.5 g of granules to 100 ml of tap water to provide 140 mg edaravone per 100 ml of water. The granules were added to a 100 mL volumetric flask containing approximately 80 mL of purified water and mixed on a vortex mixer for 15 seconds, repeated three times. The solution was then brought to a final volume of 100 mL.

[0096] All three types of particles were found to dissolve rapidly, producing a clear solution.

[0097] Example 2

[0098] Prepare powder mixtures based on the formulations shown in Table 2.

[0099] Table 2

[0100] 1 Unmicronized. Particle size distribution (volume distribution, measured by laser diffraction): Dv(10): 36.7 µm Dv(50): 240 µm Dv(90): 425 µm Weigh edaravone and the excipient and add them to a separate weighing boat, where they are gently mixed with a spatula. Add the blend to a 100 mL volumetric flask containing approximately 80 mL of purified water and vortex for 15 seconds, repeating three times. Then bring the solution to 100 mL. Observe the dissolution status after sample preparation, and observe again at 1 hour and 8 hours.

[0101] All the powder was found to produce a suspension that rapidly formed deposits (edaravone particles). After 8 hours, no changes were observed by visual inspection.

[0102] Example 3

[0103] Using the procedure described in Example 2, powder mixtures were prepared based on the formulations shown in Table 3.

[0104] Table 3

[0105] 1 Unmicronized. Particle size distribution (volume distribution, measured by laser diffraction): Dv(10): 36.7 µm Dv(50): 240 µm Dv(90): 425 µm The dissolution behavior of the blend was studied in the same manner as described in Example 2.

[0106] Both powders were found to produce a suspension that rapidly formed deposits (edaravone particles). After 8 hours, no changes were observed visually.

[0107] Example 4

[0108] Edaravone was wet-granulated using an aqueous suspension of sodium dodecyl sulfate (SLS) as the granulation liquid. Edaravone was weighed and added to the mortar. Then, SLS was weighed and dissolved in purified water to form a white suspension. The mass of SLS used was calculated, yielding granules containing 35 parts by weight of edaravone and 6 parts by weight of SLS.

[0109] The SLS suspension was added to edaravone via a nebulizer while being mixed in a pestle and mortar to form a slurry. The slurry was then passed through a 500 μm sieve and dried at 60°C for 2 hours.

[0110] The dried particles were then ground using a pestle and mortar, and the finer powder was passed through a 75 μm sieve. The resulting fine powder (edaravone / SLS) was stored in a snap cap vile under dark conditions.

[0111] Using the procedure described in Example 2, powder mixtures were prepared based on the formulations shown in Table 4.

[0112] Table 4

[0113] The dissolution behavior of these blends was studied in the same manner as described in Example 2.

[0114] Blend 4.1 produced a turbid suspension with a pH of 4.7, which remained turbid after 8 hours.

[0115] Mixtures 4.2 and 4.3 produced clear solutions. Blend 4.2 was found to dissolve slightly faster than blend 4.3. The solution prepared with blend 4.2 had a pH of 7.5.

[0116] Example 5

[0117] Water-dispersible particles were prepared based on the formulations shown in Tables 5a and 5b.

[0118] Table 5a

[0119] Table 5b

[0120] The following study was conducted in which these particles 5a and 5b were dissolved in water and administered orally to dogs. The bioavailability of orally administered edaravone was compared with that of intravenously administered edaravone. In each case, a single dose of 60 mg edaravone was administered.

[0121] This study was conducted in a group of four male beagle dogs. Animals were given a single oral administration of an aqueous solution of each of the aforementioned edaravone granules (1000 mg granule 5a dissolved in 50 mL or 750 mg granule 5b dissolved in 50 mL) or a single intravenous administration of two Radicut® ampoules of edaravone (each ampoule containing 30 mg edaravone / 20 mL solution).

[0122] Blood samples were collected periodically before and after administration, and the edaravone plasma concentration in each sample was determined. The average results of these measurements are shown in Table 6. Average parameters indicating relative bioavailability are provided in Table 7.

[0123] Table 6

[0124] nd.: Not determined

[0125] Table 7

[0126] 1 Median

[0127] 2 AUC last The area under the plasma concentration-time curve from the time of administration to the last measurable plasma concentration.

[0128] 3 AUC 0-inf The area under the plasma concentration-time curve from the time of administration to (extrapolated) infinity.

[0129] These results indicate that orally administered edaravone exhibits rapid absorption, reaching peak concentrations approximately 5 minutes after administration. Furthermore, the results show that edaravone aqueous solutions prepared using the particles according to the invention possess unexpectedly high systemic oral bioavailability.

Claims

1. Use of a solid aqueous dispersible pharmaceutical composition in the preparation of a medicament for treating a disease, said treatment comprising dispersing said pharmaceutical composition in an aqueous liquid to produce an enterically administered single-phase liquid containing at least 0.5 g of said pharmaceutical composition and at least 0.3 g / L edaravone, followed by enteral administration of said enterically administered liquid to a human patient in an amount providing a dose of 30-180 mg edaravone, said pharmaceutical composition comprising: 2-50% by weight of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone); and 3-50% by weight of water-soluble alkalizing agent; When the composition is added to softened water at 25°C at a concentration equivalent to 1.4 g / L of edaravone, the edaravone in the pharmaceutical composition is completely dissolved, and the pH of such a solution at 25°C is at least 0.5 pH units higher than that of a solution having the same edaravone concentration and consisting only of edaravone and softened water; and the edaravone present in the enterally administered liquid is not contained in the composition.

2. The use according to claim 1, wherein the pharmaceutical composition is a powder or tablet.

3. The use according to claim 1 or 2, wherein the composition further comprises 25-95% by weight of an excipient selected from fillers, disintegrants, effervescent agents, binders, and combinations thereof.

4. The use according to claim 3, wherein the composition contains at least 30% by weight of one or more polyols selected from mannitol, sorbitol, xylitol, maltitol, lactitol, and combinations thereof.

5. The use according to any one of the preceding claims, wherein the composition further comprises 0.5-15% by weight of a surfactant.

6. The use according to claim 5, wherein the composition contains at least 0.5% by weight of a nonionic surfactant.

7. The use according to any one of the preceding claims, wherein at least 90% by volume of the edaravone is present in the form of micronized particles with a particle size of less than 100 micrometers.

8. The use according to any one of the preceding claims, wherein the composition contains less than 1% by weight of a water-insoluble substance.

9. The use according to any one of the preceding claims, wherein the water-soluble alkalizing agent is selected from oxides and hydroxides of alkali metals; oxides and hydroxides of alkaline earth metals; Al(OH)₂ )3 Fe2O3; salts of weak organic and weak inorganic acids, basic amines; basic amino acids; and combinations thereof.

10. The use according to any one of the preceding claims, wherein the pKa value of the water-soluble alkalizing agent is at least 7.

11. The use according to any one of the preceding claims, wherein the enteric composition contains less than 3% by weight, preferably less than 1% by weight, of a water-soluble organic solvent selected from polyethylene glycol, propylene glycol, diethylene glycol monoethyl ether, polyoxyethylene castor oil, polyoxyethylene glycerol ester, polyoxyethylene sorbitan fatty acid ester, water-soluble form of vitamin E, and ethanol.

12. The use according to any one of the preceding claims, wherein the enterally applicable liquid is a single-phase solution.

13. The use according to any one of the preceding claims, wherein 1 part by weight of the pharmaceutical composition is dispersed in 20 to 200 parts by weight of the aqueous liquid.

14. The product for use according to any one of the preceding claims, wherein the enteric liquid contains at least 500 mg / L, more preferably 800-3,000 mg / L of edaravone.

15. The use according to any one of the preceding claims, wherein the composition is used to treat neurodegenerative diseases; cerebral amyloid angiopathy (CAA); autoimmune diseases; myocardial infarction or cerebrovascular diseases.

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