Edaravone oral sustained-release composition, preparation method and application

Abstract

The application discloses a kind of oral sustained-release composition of edaravone, preparation method and application.The application provides a kind of pharmaceutical composition, it includes tablet core and coating;The tablet core includes drug-containing layer tablet core and / or boost layer tablet core;The drug-containing layer tablet core includes edaravone pharmaceutical active ingredient and carrier;The carrier is one or more in polymer carrier, osmotic pressure regulator, swelling agent, thickening agent and lubricant;The boost layer tablet core includes one or more in osmotic pressure regulator, swelling agent, colorant and lubricant.The pharmaceutical composition of the application maintains 24 hours sustained-release, oral convenient, blood drug concentration is stable, avoids the method of 2 times intravenous drip in a day, improves patient compliance.In addition, the pharmaceutical composition, prescription and preparation process are simple, easy to industrial production.

Description

[0001] This application claims priority to Chinese Patent Application No. 202010870276.0, filed on August 26, 2020, with the China National Intellectual Property Administration, entitled "Edaravone Oral Sustained-Release Composition, Preparation Method and Application". The entire contents of that application are incorporated herein by reference.

[0002] This application is a divisional application of application number 202110989532.2, filed with the China National Intellectual Property Administration on August 26, 2021, entitled "Edaravone Oral Sustained-Release Composition, Preparation Method and Application". Technical Field

[0003] This invention relates to an oral sustained-release composition of edaravone, its preparation method, and its application. Background Technology

[0004] Edaravone is a neuroprotective agent (free radical scavenger). Clinical studies suggest that N-acetylaspartate (NAA) is a specific marker of surviving nerve cells, and its levels decrease sharply in the early stages of cerebral infarction. Administration of edaravone to patients in the acute phase of cerebral infarction can inhibit the reduction in local cerebral blood flow around the infarct, resulting in a significantly higher NAA level in the brain on day 28 after onset compared to the glycerol control group. Therefore, edaravone is used to improve neurological symptoms, activities of daily living, and functional impairments caused by acute cerebral infarction.

[0005] The marketed edaravone preparation is an injectable solution. The usual adult dosage is 30 mg twice daily, diluted with an appropriate amount of normal saline and administered via intravenous infusion over 30 minutes. Administration should begin within 24 hours of symptom onset, with a treatment course of 14 days. Patient compliance with twice-daily intravenous infusion is poor, and side effects include acute renal failure, liver dysfunction, jaundice, thrombocytopenia, disseminated intravascular coagulation (DIC), injection site rash, redness, swelling, blisters, itching, belching, fever, hot flashes, increased blood pressure, increased or decreased serum cholesterol, increased triglycerides, decreased serum total protein, decreased creatine kinase (CK) and creatine phosphokinase (CPK), and decreased serum calcium.

[0006] Therefore, it is necessary to develop an oral sustained-release formulation of edaravone to improve its bioavailability and ensure a stable release rate, thereby significantly improving patient compliance and reducing toxic side effects. Summary of the Invention

[0007] To address the aforementioned technical problems, the present invention provides a pharmaceutical composition having the following characteristics A), B), and C). A) No more than 20% of the active pharmaceutical ingredient dissolves within 1 hour; B) 20%–60% of the active pharmaceutical ingredient dissolves within 6 hours; C) At least 70% of the active pharmaceutical ingredient dissolves within 24 hours; The active pharmaceutical ingredient may be selected from one or more of edaravone, its pharmaceutically acceptable salts, hydrates and solvates.

[0008] According to embodiments of the present invention, the pharmaceutical composition preferably has the following characteristics A), B), and C): A) No more than 15% of the active pharmaceutical ingredient dissolves within 1 hour; B) 20%–55% of the active pharmaceutical ingredient dissolves within 6 hours; C) At least 75% of the active pharmaceutical ingredient dissolves within 24 hours.

[0009] According to an embodiment of the present invention, the pharmaceutical composition more preferably has the following characteristics A), B), and C): A) No more than 15% of the active pharmaceutical ingredient dissolves within 1 hour; B) 25%–55% of the active pharmaceutical ingredient dissolves within 6 hours; C) At least 80% of the active pharmaceutical ingredient dissolves within 24 hours; The term "dissolution" refers to the cumulative dissolution rate of the active pharmaceutical ingredient (such as edaravone); further, the cumulative dissolution rate is measured in a pH 6.8 phosphate buffer solution. Those skilled in the art will understand that the dissolution rate of the active pharmaceutical ingredient (such as edaravone) gradually increases over time.

[0010] According to an embodiment of the present invention, the pharmaceutical composition is a sustained-release composition, preferably a pharmaceutical composition that is continuously sustained-released for 24 hours, and more preferably an oral pharmaceutical composition that is continuously sustained-released for 24 hours.

[0011] The present invention also provides a pharmaceutical composition comprising a tablet core and a coating; said tablet core comprising a drug-containing tablet core and / or a propulsion tablet core; The drug-containing layer core contains edaravone, an active pharmaceutical ingredient, and a carrier. The carrier is one or more of the following: polymer carrier, osmotic pressure regulator, swelling agent, thickener, and lubricant; The booster core comprises one or more of the following: osmotic pressure regulator, swelling agent, colorant, and lubricant.

[0012] According to an embodiment of the present invention, the pharmaceutical composition is an orally sustained-release pharmaceutical composition.

[0013] According to an embodiment of the present invention, the pharmaceutical composition has one of the combinations of features A), B) and C) described above.

[0014] According to an embodiment of the invention, the outer surface of the core is covered with a coating. Preferably, the coating is impermeable to substances other than water. For example, the coating surface has no openings or contains one or more openings through which the coating can pass.

[0015] According to an embodiment of the present invention, in the drug-containing tablet core, the edaravone active pharmaceutical ingredient may be selected from one or more of edaravone, its pharmaceutically acceptable salts, hydrates and solvates.

[0016] According to an embodiment of the present invention, the solvent in the edaravone solvate is an organic solvent, which may be one or more of the organic solvents known in the art, such as methanol, ethanol, tetrahydrofuran and diethyl ether.

[0017] According to an embodiment of the present invention, the content of the edaravone active pharmaceutical ingredient is preferably 5.0% to 60.0%, for example 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 55.0% or 60.0%; wherein, the content refers to the percentage of the weight of the edaravone active pharmaceutical ingredient, calculated as edaravone, to the total weight of the drug-containing tablet core.

[0018] According to an embodiment of the present invention, in the drug-containing tablet core, the polymer carrier is selected from one or more of polyethylene glycol, copovidone (PVP / VA), hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate-povidone mixture, poloxamer, and carboxymethyl ethyl cellulose (CMEC). According to an embodiment of the present invention, the content of the polymer carrier is preferably 5.0% to 60.0%, for example 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 55.0% or 60.0%; wherein, the content refers to the percentage of the weight of the polymer carrier to the total weight of the drug-containing tablet core.

[0019] According to an embodiment of the present invention, in the drug-containing tablet core, the swelling agent (also known as a propellant) can be selected from substances that can absorb solvent and expand, preferably one or more of polyoxyethylene, carbomer, sodium carboxymethyl starch, crospovidone, hydroxypropyl methylcellulose, gum arabic, polyvinylpyrrolidone and sodium alginate.

[0020] According to an embodiment of the present invention, the content of the swelling agent is preferably 10.0% to 50.0%, for example 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0% or 50.0%; wherein, the content refers to the percentage of the weight of the swelling agent to the total weight of the drug-containing tablet core.

[0021] According to an embodiment of the present invention, in the drug-containing tablet core, the osmotic pressure regulator can be a substance that regulates osmosis, preferably one or more of sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose, and lactose.

[0022] According to an embodiment of the present invention, the content of the osmotic pressure regulator is preferably 0% to 50.0%, for example 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0% or 50.0%; wherein, the content refers to the percentage of the weight of the osmotic pressure regulator to the total weight of the drug-containing tablet core.

[0023] According to an embodiment of the present invention, in the drug-containing tablet core, the thickener (also referred to as a suspending agent or binder) can be an additive capable of increasing the viscosity of the dispersion medium to reduce the settling velocity of the particles or increase the hydrophilicity of the particles, preferably one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, copovidone, gum arabic, pregelatinized starch and polyvinylpyrrolidone.

[0024] According to an embodiment of the present invention, the content of the thickener is preferably 0% to 40.0%, for example 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0% or 40.0%; wherein, the content refers to the percentage of the weight of the thickener to the total weight of the drug-containing tablet core.

[0025] According to an embodiment of the present invention, in the drug-containing tablet core, the lubricant can be a substance with lubricating properties, preferably one or more of metal stearate, stearic acid, talc, stearate ester, and micronized silica gel. The metal stearate is preferably magnesium stearate and / or calcium stearate. The stearate ester is preferably glyceryl stearate.

[0026] According to an embodiment of the present invention, the content of the lubricant is preferably 0.1% to 3.0%, for example 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3.0%; wherein, the content refers to the percentage of the weight of the lubricant to the total weight of the medicated core.

[0027] According to an embodiment of the present invention, the drug-containing tablet core may include the following components: 5.0% to 60.0% of edaravone active pharmaceutical ingredient, 5.0% to 60.0% of polymer carrier, 10.0% to 50.0% of swelling agent, 10.0% to 40.0% of thickener, 0% to 50.0% of osmotic pressure regulator and 0.1% to 3.0% of lubricant; wherein the percentages refer to the percentage of each component by the total weight of the drug-containing tablet core.

[0028] According to an embodiment of the present invention, the drug-containing tablet core preferably has any of the following components by weight percentage: Component 1: 20.00% edaravone active pharmaceutical ingredient, 20.00% hydroxypropyl methylcellulose acetate succinate, 20.00% sorbitol, 10.00% sodium chloride, 10.00% hydroxypropyl methylcellulose, 10.00% copovidone, 9.00% crospovidone and 1.00% magnesium stearate; Component 2: 20.00% edaravone active pharmaceutical ingredient, 20.00% hydroxypropyl methylcellulose acetate succinate, 40.00% sorbitol, 10.00% sodium chloride, 4.00% hydroxypropyl methylcellulose, 5.00% copovidone and 1.00% magnesium stearate; Component 3: 30.03% edaravone active pharmaceutical ingredient, 30.03% hydroxypropyl methylcellulose acetate succinate, 27.02% polyvinylpyrrolidone, 6.01% mannitol, 6.01% sodium chloride and 0.90% magnesium stearate; Component 4: 30.03% edaravone active pharmaceutical ingredient, 30.03% hydroxypropyl methylcellulose acetate succinate, 30.03% sodium alginate, 9.02% sodium chloride and 0.90% magnesium stearate; Component 5: 30.03% edaravone active pharmaceutical ingredient, 30.03% hydroxypropyl methylcellulose acetate succinate, 18.02% polyoxyethylene, 6.01% hydroxypropyl methylcellulose, 15.01% sorbitol and 0.90% magnesium stearate; the percentages mentioned refer to the percentage of each component in the total weight of the drug-containing tablet core.

[0029] Unless otherwise stated, the content or proportion of edaravone as the active pharmaceutical ingredient in this invention context is expressed as edaravone.

[0030] According to an embodiment of the present invention, in the booster layer core, the osmotic pressure regulator can be a substance that regulates osmosis, preferably one or more of sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose, and lactose.

[0031] According to an embodiment of the present invention, the content of the osmotic pressure regulator is preferably 0% to 50.0%, for example 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0% or 50.0%; wherein, the content refers to the percentage of the weight of the osmotic pressure regulator to the total weight of the booster core.

[0032] According to an embodiment of the present invention, in the booster core, the swelling agent can be a substance capable of absorbing solvent and expanding, preferably one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, gum arabic, hydroxyethyl cellulose, carbomer, sodium carboxymethyl starch, copovidone, sodium alginate and polyoxyethylene.

[0033] According to an embodiment of the present invention, the content of the swelling agent is preferably 40.0% to 90.0%, for example 40.0%, 45.0%, 50.0%, 55.0%, 6.0%, 65.0%, 70.0%, 75.0%, 80.0%, 85.0% or 90.0%; wherein, the content refers to the percentage of the weight of the swelling agent to the total weight of the booster core.

[0034] According to an embodiment of the present invention, in the booster layer core, the colorant can be a substance capable of achieving the coloring purpose, preferably one or more of iron oxide red, iron oxide yellow and iron oxide black.

[0035] According to an embodiment of the present invention, the content of the colorant is preferably 0.5% to 3.0%, for example 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3.0%; wherein, the content refers to the percentage of the weight of the colorant to the total weight of the booster core.

[0036] According to an embodiment of the present invention, in the booster core, the lubricant can be a substance with lubricating properties, preferably one or more of metal stearate, stearic acid, talc, stearate ester, and micronized silica gel. The metal stearate is preferably magnesium stearate and / or calcium stearate.

[0037] According to an embodiment of the present invention, the stearate is preferably glyceryl stearate. The content of the lubricant is preferably 0.5% to 3.0%, for example 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3.0%; wherein, the content refers to the percentage of the weight of the lubricant to the total weight of the booster core.

[0038] According to an embodiment of the present invention, the booster core comprises the following components: 0% to 50.0% of an osmotic pressure regulator, 40.0% to 90.0% of a swelling agent, 0.5% to 3.0% of a colorant, and 0.5% to 3.0% of a lubricant; the percentages refer to the weight of each component as a percentage of the total weight of the booster core.

[0039] According to an embodiment of the present invention, the booster core is further preferably composed of any of the following components by weight percentage: Component 1: 73.65% polyoxyethylene, 23.95% sodium chloride, 1.20% iron oxide red and 1.20% magnesium stearate; Component 2: 73.65% polyoxyethylene, 11.98% sodium chloride, 11.97% sorbitol, 1.20% iron oxide red and 1.20% magnesium stearate; Component 3: 64.67% polyoxyethylene, 32.93% sodium chloride, 1.20% iron oxide red and 1.20% magnesium stearate.

[0040] According to an embodiment of the present invention, the coating material is preferably a semi-permeable membrane material. The semi-permeable membrane material preferably comprises one or more of a film-forming material, a plasticizer, and a pore-forming agent.

[0041] According to an embodiment of the present invention, the film-forming material can be a material that can be dispersed on a solid surface and cured to form a film, preferably one or more of cellulose acetate, ethyl cellulose, cellulose acetate phthalate and (meth)acrylic resin.

[0042] According to an embodiment of the present invention, the content of the film-forming material is preferably 5.0% to 15.0%, for example 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0% or 15.0%; wherein, the percentage refers to the percentage of the weight of the film-forming material to the total weight of the tablet core.

[0043] According to an embodiment of the present invention, the plasticizer may be a substance that can increase the plasticity of the polymer, preferably one or more of polyethylene glycol, triacetin, glyceryl citrate, glyceryl esters and phthalates.

[0044] According to an embodiment of the present invention, the content of the plasticizer is preferably 0% to 5.0%, for example 0%, 1.0%, 2.0%, 3.0%, 4.0% or 5.0%; wherein, the percentage refers to the percentage of the weight of the plasticizer to the total weight of the tablet core.

[0045] According to an embodiment of the present invention, the pore-forming agent may be a substance capable of forming pores in a material, preferably polyethylene glycol and / or hydroxypropyl cellulose.

[0046] According to an embodiment of the present invention, the content of the pore-forming agent is preferably 0.1% to 15.0%, for example 0.1%, 0.5%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 8.0%, 10.0%, 12.0% or 15.0%; wherein, the percentage refers to the percentage of the weight of the pore-forming agent to the total weight of the tablet core.

[0047] According to an embodiment of the present invention, the semi-permeable membrane material comprises the following components: 5.0% to 15.0% of film-forming material, 0% to 5.0% of plasticizer and 0.1% to 15.0% of pore-forming agent, wherein the percentages refer to the percentage of the mass of each component relative to the total mass of the tablet core; According to an embodiment of the present invention, the semi-permeable membrane material further preferably has any of the following components in weight percentage: Coating 1: 9.00% cellulose acetate and 1.00% polyethylene glycol, where the percentages refer to the mass of each component relative to the total mass of the tablet core; Coating 2: 7.20% cellulose acetate and 0.80% polyethylene glycol 4000, where the percentages refer to the mass of each component relative to the total mass of the tablet core.

[0048] The present invention also provides an edaravone pharmaceutical active ingredient dispersion, comprising the edaravone pharmaceutical active ingredient dispersed in a polymer carrier. Preferably, the polymer carrier is selected from one or more of polyethylene glycol, copovidone, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, a mixture of polyvinyl acetate and povidone, poloxamer, and carboxymethyl ethyl cellulose.

[0049] According to an embodiment of the present invention, in the edaravone drug active ingredient dispersion, the mass ratio of the edaravone drug active ingredient to the polymer carrier can be 1:1 or lower, for example 1:2, 1:3, 1:4, 1:5, 1:6 or lower.

[0050] The present invention also provides a pharmaceutical composition comprising the edaravone active pharmaceutical ingredient dispersion.

[0051] According to an embodiment of the present invention, the pharmaceutical composition is a solid dosage form, such as a tablet.

[0052] The present invention also provides a method for preparing the pharmaceutical composition, which may be a direct tableting method, a wet granulation method, or a dry granulation method, etc.

[0053] According to an embodiment of the present invention, the direct tableting method includes the following steps: Step 1: Preparation of tablet core material: Edaravone active pharmaceutical ingredient and hydroxypropyl methylcellulose acetate succinate are dissolved in methanol / water solution and spray-dried to obtain edaravone active pharmaceutical ingredient solid dispersion; The solid dispersion of edaravone active pharmaceutical ingredient is mixed with a swelling agent, an osmotic pressure regulator, and a thickener, and then a lubricant is added and mixed to obtain a drug-containing tablet core material. The swelling agent, osmotic pressure regulator and colorant are mixed, and then a lubricant is added and mixed to obtain the core material of the booster layer. Step 2 Tableting: The drug-containing tablet core material and the propulsion layer tablet core material obtained in Step 1 are compressed into tablet cores using a tablet press. Step 3 Coating: Dissolve the film-forming material, plasticizer and pore-forming agent in a solvent to prepare a coating solution, coat the core obtained in Step 2 and age it to obtain a coated sheet; Step 4: Punching holes in the drug-containing side of the coated tablets obtained in Step 3 to obtain the drug composition. In step 3, the coating is preferably performed until the weight of the coated sheet increases by 2% to 20%. The weight increase refers to (weight of the coated sheet after coating - weight of the core before coating) / weight of the core before coating.

[0054] In step 3, the aging time is preferably 1 hour to 24 hours, more preferably 8 hours to 16 hours, for example 12 hours. The aging temperature is preferably 20℃ to 60℃, more preferably 30℃ to 50℃, for example 40℃.

[0055] In step 4, the hole diameter is preferably 0~1000μm; the number of holes can be 0, 1 or more.

[0056] According to an embodiment of the present invention, the wet granulation includes the following steps: Step ① Preparation of tablet core material: Edaravone active pharmaceutical ingredient and hydroxypropyl methylcellulose acetate succinate are dissolved in methanol / water solution and spray-dried to obtain edaravone active pharmaceutical ingredient solid dispersion; The solid dispersion of edaravone active pharmaceutical ingredient is mixed with a swelling agent, an osmotic pressure regulator, and a thickener, then wet granulated, dried, and granulated. Finally, a lubricant is added and mixed to obtain a drug-containing tablet core material. The swelling agent, osmotic pressure regulator and colorant are mixed, wet granulated, dried and sized, and then a lubricant is added and mixed to obtain the core material of the booster layer. Step ② Tableting: The drug-containing tablet core material and the propulsion layer tablet core material obtained in step ① are compressed into tablet cores using a tablet press. Step 3 Coating: Dissolve the film-forming material, plasticizer and pore-forming agent in a solvent to prepare a coating solution, coat the core obtained in step 2 and age it to obtain a coated sheet; Step 4: Punching holes in the drug-containing surface of the coated tablets obtained in step 3 to obtain the drug composition. In step ③, the coating is preferably applied until the weight of the coated sheet increases by 2% to 20%. The weight increase refers to (weight of the coated sheet after coating - weight of the core before coating) / weight of the core before coating.

[0057] The aging time in step ③ is preferably 1 hour to 24 hours, more preferably 8 hours to 16 hours, for example 12 hours. The aging temperature is preferably 20℃ to 60℃, more preferably 30℃ to 50℃, for example 40℃.

[0058] In step ④, the hole diameter is preferably 0~1000μm; the number of holes can be 0, 1 or more.

[0059] According to an embodiment of the present invention, the dry granulation method mainly includes the following steps: Step (1) Preparation of tablet core material: Edaravone active pharmaceutical ingredient and hydroxypropyl methylcellulose acetate succinate are dissolved in methanol / water solution and spray dried to obtain edaravone active pharmaceutical ingredient solid dispersion; The solid dispersion of edaravone active pharmaceutical ingredient is mixed with a swelling agent, an osmotic pressure regulator, a thickener, and a lubricant, then dry-granulated and sized. The lubricant is then added and mixed again to obtain a drug-containing tablet core material. The swelling agent, osmotic pressure regulator, lubricant and colorant are mixed, dry granulated, sized, and then the lubricant is added and mixed to obtain the core material of the booster layer. Step (2) Tableting: The drug-containing tablet core material and the booster tablet core material obtained in step (1) are pressed into tablet cores using a tablet press. Step (3) Coating: Dissolve the film-forming material, plasticizer and pore-forming agent in a solvent to prepare a coating solution, coat the core obtained in step (2) and age it to obtain a coated sheet; Step (4) Punching: Punch holes in the drug-containing surface of the coated tablets obtained in step (3) to obtain the drug composition.

[0060] According to an embodiment of the present invention, in step (3), the coating is preferably performed such that the weight of the coated sheet increases by 2% to 20% after coating, and the weight increase refers to (weight of the coated sheet after coating - weight of the core sheet before coating) / weight of the core sheet before coating.

[0061] According to an embodiment of the present invention, in step (3), the aging time is preferably 1 hour to 24 hours, more preferably 8 hours to 16 hours, for example 12 hours. The aging temperature is preferably 20°C to 60°C, more preferably 30°C to 50°C, for example 40°C.

[0062] According to an embodiment of the present invention, in step (4), the hole diameter is preferably 0~1000μm; the number of holes can be 0, 1 or more.

[0063] According to an embodiment of the present invention, the drug-containing layer may or may not have drug release pores on one side.

[0064] According to an embodiment of the present invention, the pharmaceutical composition is preferably an osmotic pump tablet.

[0065] The present invention also provides the use of the pharmaceutical composition in the preparation of medicaments for treating and / or preventing oxidative stress-related diseases.

[0066] The present invention also provides a method for treating and / or preventing oxidative stress-related diseases, comprising administering the pharmaceutical composition to a patient (e.g., a person) in need.

[0067] According to an embodiment of the present invention, the oxidative stress-related diseases are selected from Alzheimer's disease, ALS (amyotrophic lateral sclerosis), Parkinson's disease, ischemic heart disease, cerebral infarction / stroke, thrombophlebitis, COPD (chronic obstructive pulmonary disease), HIV / AIDS (human immune system disease / acquired immune system syndrome), and diabetes.

[0068] The significant advantages of this invention are as follows: After administration, the gastrointestinal fluid of the pharmaceutical composition permeates through the semi-permeable membrane into the patient's body. The drug-containing tablet core absorbs water, forming a drug-containing suspension. The propulsion tablet core expands and swells, propelling the drug out uniformly through the pores, thus achieving sustained-release and controlled-release effects. The pharmaceutical composition of this invention maintains continuous release for 24 hours, is convenient for oral administration, avoids the need for twice-daily intravenous infusions, and improves patient compliance. Furthermore, the formulation and preparation process of this pharmaceutical composition are simple, making it easy for industrial production. Detailed Implementation

[0069] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0070] Unless otherwise stated, the raw materials and reagents used in the examples below are commercially available or can be prepared by those skilled in the art using known methods.

[0071] Examples 1-2

[0072] Preparation process: Step 1: Add edaravone and HPMCAS from the above formulation to the solvent (methanol:water = 9:1), place the sample in a constant temperature water bath and stir, set the heating temperature to 50℃, and dissolve; Step 2: Spray dry the solution from Step 1 using a spray dryer to obtain edaravone solid dispersion, and then pass the edaravone solid dispersion through a 40-mesh sieve. Step 3: Place the edaravone solid dispersion and the pneumatic excipients in the above formulation, except for magnesium stearate, into a mixing pot, set the mixing speed to 18 r / min, mix for 20 minutes, then add the internally added magnesium stearate, set the mixing speed to 18 r / min, and mix for 5 minutes; to obtain the drug-containing mixture. Step 4: Place the mixture obtained in Step 3 into a dry granulator, adjust the equipment parameters to compress it into large tablets with a certain hardness, and then granulate it using a 1.0mm sieve; then mix it with magnesium stearate, set the mixing speed to 18r / min, and mix for 5 minutes; then place it on a rotary tablet press and compress it into shallow arc-shaped tablet cores. Step 5: Prepare the sustained-release coating solution according to the following steps: Add purified water to a beaker and stir with a magnetic stirrer. Add acetone while stirring. After all the acetone has been added, stir for 5 minutes to mix it evenly. Then slowly add Opadry®CA and continue stirring for 30 to 120 minutes to completely dissolve it to obtain the sustained-release coating solution. The tablet cores obtained in step 4 are coated with the above-mentioned sustained-release coating solution using a coating pan rotating at 8-15 rpm, with the air intake volume controlled at 30 m³ / h. 3 / h~120m 3 The tablet bed temperature is controlled at 25℃~35℃, and the spraying speed is set at 5rpm~20rpm. The coating is continued until the coating weight gain is 7.86% and 8.14% respectively. The spraying is then stopped, and the tablets are dried at a tablet bed temperature of 30℃~35℃ for 5 to 10 minutes. The tablets are then removed and placed in a forced-air drying oven at a set temperature of 45℃ for aging. The coated tablets are obtained after 24 hours. Step 6: The coated tablets obtained in Step 5 are laser-drilled to obtain edaravone sustained-release tablets with a hole size of 0.4~0.6mm.

[0073] Examples 3-4

[0074] Preparation process: Step 1: Add edaravone and HPMCAS from the above formulation to the solvent (methanol:water = 9:1), place the sample in a constant temperature water bath and stir, set the heating temperature to 50℃, and dissolve; Step 2: Spray dry the solution from Step 1 using a spray dryer to obtain edaravone solid dispersion, and then pass the edaravone solid dispersion through a 40-mesh sieve. Step 3: Place the edaravone solid dispersion and the drug-containing excipients (except magnesium stearate) in a mixing pot, set the mixing speed to 18 r / min, and mix for 20 minutes; then add the drug-containing magnesium stearate, set the mixing speed to 18 r / min, and mix for 5 minutes to obtain the drug-containing mixture; Place the polyoxyethylene, sodium chloride, sorbitol, and iron oxide red of the booster layer in a mixing pot, set the mixing speed to 18 r / min, and mix for 10 minutes; then add the magnesium stearate of the booster layer, set the mixing speed to 18 r / min, and mix for 5 minutes to obtain the booster layer mixture. Step 4: Place the drug-containing layer mixture and the booster layer mixture obtained in Step 3 on a rotary tablet press, adjust the equipment parameters so that the tablet weight of the drug-containing layer is 333mg, the tablet weight of the booster layer is 167mg, the total tablet weight is 500mg, and the tablet core is a shallow arc-shaped drug-containing tablet with a hardness of 100N~180N. Step 5: Prepare the sustained-release coating solution according to the following steps: Add purified water to a beaker and stir with a magnetic stirrer. Add acetone while stirring. After all the acetone is added, stir for 5 minutes to mix it evenly. Then slowly add Opadry® CA and continue stirring for 30 to 90 minutes to completely dissolve it to obtain the sustained-release coating solution. The drug-containing tablet cores obtained in step 4 are coated with the above-mentioned sustained-release coating solution. The coating pan speed is 8 rpm to 15 rpm, the tablet bed temperature is controlled at 25℃ to 35℃, and the spraying speed is set to 5 rpm to 20 rpm. The coating is continued until the coating weight gain is 9.87% and 9.94%, then the spraying is stopped. The tablets are then dried at a tablet bed temperature of 30℃ to 35℃ for 5 to 10 minutes, and then the tablets are removed. They are then placed in a forced-air drying oven at a set temperature of 45℃ for aging. After 24 hours, the coated tablets are obtained. Step 5: Laser-drill holes in the coated tablets obtained in Step 4. The drilled surface should be the drug-containing layer (the white side). The hole size should be 0.4~0.6mm to obtain edaravone sustained-release tablets.

[0075] Example 5

[0076] Preparation process: Step 1: Add edaravone and HPMCAS from the above formulation to the solvent (methanol:water = 9:1), place the sample in a constant temperature water bath and stir, set the heating temperature to 50℃, and dissolve; Step 2: Spray dry the solution from Step 1 using a spray dryer to obtain edaravone solid dispersion, and then pass the edaravone solid dispersion through a 40-mesh sieve. Step 3: Place the drug-containing edaravone solid dispersion, polyoxyethylene, hydroxypropyl methylcellulose, and sorbitol into a mixing pot, set the mixing speed to 18 r / min, and mix for 20 minutes; then add the drug-containing magnesium stearate, set the mixing speed to 18 r / min, and mix for 5 minutes to obtain the drug-containing mixture; Place the polyoxyethylene, sodium chloride, and iron oxide red of the booster layer in a mixing pot, set the mixing speed to 18 r / min, and mix for 10 minutes; then add the magnesium stearate of the booster layer, set the mixing speed to 18 r / min, and mix for 5 minutes to obtain the booster layer mixture. Step 4: Place the drug-containing layer mixture and the booster layer mixture obtained in Step 3 on a rotary tablet press, adjust the equipment parameters so that the tablet weight of the drug-containing layer is 333mg, the tablet weight of the booster layer is 167mg, the total tablet weight is 500mg, and the tablet core is a shallow arc-shaped drug-containing tablet with a hardness of 100N~180N. Step 5: Prepare the sustained-release coating solution according to the following steps: Add 95% ethanol to a beaker and stir with a magnetic stirrer. Slowly add Opadry® EC while stirring, and continue stirring for 60 to 120 minutes to completely dissolve it to obtain the sustained-release coating solution. The drug-containing tablet cores obtained in step 4 are coated with the above-mentioned sustained-release coating solution. The coating pan speed is 8 rpm to 15 rpm, the tablet bed temperature is controlled at 25℃ to 35℃, and the spraying speed is set to 5 rpm to 20 rpm. The coating is continued until the coating weight gain is 8.06% and 8.12%, then the spraying is stopped. The tablets are then dried at a tablet bed temperature of 30℃ to 35℃ for 5 to 10 minutes, and then the tablets are removed. They are then placed in a forced-air drying oven at a set temperature of 45℃ for aging. After 24 hours, the coated tablets are obtained. Step 5: Laser-drill holes in the coated tablets obtained in Step 4. The drilled surface should be the drug-containing layer (the white side). The hole size should be 0.4~0.6mm to obtain edaravone sustained-release tablets.

[0077] The release rate of the edaravone sustained-release tablets prepared above was determined. The method for determining the release rate is as follows: Take 12 sustained-release tablets, and dissolve them according to Method II, Appendix XC, Part II of the Chinese Pharmacopoeia 2020, using 900 ml of pH 6.8 phosphate buffer solution as the dissolution medium, at a rotation speed of 50 r / min. Collect 1.5 ml of the solution at 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours, filter through a 10 μm microporous membrane, and detect the cumulative drug release rate using high-performance liquid chromatography (HPLC). The dissolution results are as follows:

[0078] Example 6 Edaravone exhibits low solubility (less than 1 mg / ml) in aqueous solutions at various pH values, resulting in low bioavailability. Therefore, a polymer carrier was used in this example to prepare edaravone into a solid dispersion. The solubility results are as follows:

[0079] The results showed that the solubility of edaravone was increased by 6 to 25 times after it was prepared into a solid dispersion with hydroxypropyl methylcellulose acetate succinate (HPMCAS). Therefore, preparing edaravone into an amorphous solid dispersion in this invention is beneficial to improving its solubility and bioavailability. Preparing it into a sustained-release formulation can keep the blood drug concentration stable and reduce toxic side effects.

Claims

1. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises a tablet core and a coating; the tablet core comprises a drug-containing tablet core and / or a propulsion tablet core. The drug-containing layer core contains edaravone, an active pharmaceutical ingredient, and a carrier. The carrier is one or more of the following: polymer carrier, osmotic pressure regulator, swelling agent, thickener, and lubricant; The booster core comprises one or more of the following: osmotic pressure regulator, swelling agent, colorant, and lubricant; The edaravone active pharmaceutical ingredient is selected from one or more of edaravone, its pharmaceutically acceptable salts, hydrates and solvates; Preferably, the pharmaceutical composition has one of the following defined features A), B), and C); A) No more than 20% of the active pharmaceutical ingredient dissolves within 1 hour; B) 20%–60% of the active pharmaceutical ingredient dissolves within 6 hours; C) At least 70% of the active pharmaceutical ingredient dissolves within 24 hours; The active pharmaceutical ingredient may be selected from one or more of edaravone, its pharmaceutically acceptable salts, hydrates and solvates; Preferably, the pharmaceutical composition has the following characteristics A), B), and C): A) No more than 15% of the active pharmaceutical ingredient dissolves within 1 hour; B) 20%–55% of the active pharmaceutical ingredient dissolves within 6 hours; C) At least 75% of the active pharmaceutical ingredient dissolves within 24 hours; More preferably, the pharmaceutical composition has the following characteristics A), B), and C): A) No more than 15% of the active pharmaceutical ingredient dissolves within 1 hour; B) 25%–55% of the active pharmaceutical ingredient dissolves within 6 hours; C) No less than 80% of the active pharmaceutical ingredient dissolves within 24 hours.

2. The pharmaceutical composition according to claim 1, characterized in that: The coating is impermeable to substances other than water; Preferably, the coating surface has no or contains one or more openings through which the coating can pass.

3. The pharmaceutical composition according to claim 1, characterized in that: In the drug-containing tablet core, the polymer carrier is selected from one or more of polyethylene glycol, copovidone, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate-povidone mixture, poloxamer, and carboxymethyl ethyl cellulose. And / or, In the drug-containing tablet core, the swelling agent is selected from one or more of polyoxyethylene, carbomer, sodium carboxymethyl starch, crospovidone, hydroxypropyl methylcellulose, gum arabic, polyvinylpyrrolidone, and sodium alginate. And / or, In the drug-containing tablet core, the osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose, and lactose; And / or, in the drug-containing tablet core, the thickener is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, copovidone, gum arabic, pregelatinized starch, and polyvinylpyrrolidone; And / or, In the drug-containing tablet core, the lubricant is selected from one or more of metal stearate, stearic acid, talc, stearate esters, and micronized silica gel.

4. The pharmaceutical composition according to claim 1, characterized in that: In the drug-containing tablet core, the content of the edaravone active pharmaceutical ingredient is 5.0% to 60.0%, and the content refers to the percentage of the weight of the edaravone active pharmaceutical ingredient to the total weight of the drug-containing tablet core, calculated as edaravone. And / or, In the drug-containing tablet core, the content of the polymer carrier is 5.0% to 60.0%, where the content refers to the percentage of the weight of the polymer carrier to the total weight of the drug-containing tablet core; And / or, In the drug-containing tablet core, the content of the swelling agent is 10.0% to 50.0%, where the content refers to the percentage of the weight of the swelling agent to the total weight of the drug-containing tablet core; And / or, In the drug-containing tablet core, the content of the osmotic pressure regulator is 0% to 50.0%, where the content refers to the percentage of the weight of the osmotic pressure regulator to the total weight of the drug-containing tablet core; And / or, In the drug-containing tablet core, the content of the thickener is 0% to 40.0%, where the content refers to the percentage of the weight of the thickener to the total weight of the drug-containing tablet core; And / or, In the medicated tablet core, the content of the lubricant is 0.1% to 3.0%, and the content refers to the percentage of the weight of the lubricant to the total weight of the medicated tablet core.

5. The pharmaceutical composition according to claim 1, characterized in that: The drug-containing tablet core comprises the following components: 5.0%~60.0% edaravone active pharmaceutical ingredient, 5.0%~60.0% polymer carrier, 10.0%~50.0% swelling agent, 10.0%~40.0% thickener, 0%~50.0% osmotic pressure regulator, and 0.1%~3.0% lubricant; the percentages refer to the percentage of each component by the total weight of the drug-containing tablet core; Preferably, the drug-containing tablet core is selected from any of the following components having the following weight percentages: Component 1: 20.00% edaravone active pharmaceutical ingredient, 20.00% hydroxypropyl methylcellulose acetate succinate, 20.00% sorbitol, 10.00% sodium chloride, 10.00% hydroxypropyl methylcellulose, 10.00% copovidone, 9.00% crospovidone, 1.00% magnesium stearate; Component 2: 20.00% edaravone active pharmaceutical ingredient, 20.00% hydroxypropyl methylcellulose acetate succinate, 40.00% sorbitol, 10.00% sodium chloride, 4.00% hydroxypropyl methylcellulose, 5.00% copovidone, 1.00% magnesium stearate; Component 3: 30.03% edaravone active pharmaceutical ingredient, 30.03% hydroxypropyl methylcellulose acetate succinate, 27.02% polyvinylpyrrolidone, 6.01% mannitol, 6.01% sodium chloride, 0.90% magnesium stearate; Component 4: 30.03% edaravone active pharmaceutical ingredient, 30.03% hydroxypropyl methylcellulose acetate succinate, 30.03% sodium alginate, 9.02% sodium chloride, 0.90% magnesium stearate; Component 5: 30.03% edaravone active pharmaceutical ingredient, 30.03% hydroxypropyl methylcellulose acetate succinate, 18.02% polyoxyethylene, 6.01% hydroxypropyl methylcellulose, 15.01% sorbitol, 0.90% magnesium stearate; the percentages mentioned refer to the percentage of each component in the total weight of the drug-containing tablet core.

6. The pharmaceutical composition according to claim 1, characterized in that: In the aforementioned booster layer core, the osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose, and lactose; And / or, In the aforementioned booster core, the swelling agent is selected from one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose, gum arabic, hydroxyethyl cellulose, carbomer, sodium carboxymethyl starch, copovidone, sodium alginate, and polyoxyethylene. And / or, In the aforementioned booster layer core, the colorant is selected from one or more of iron oxide red, iron oxide yellow, and iron oxide black; And / or, In the aforementioned booster core, the lubricant is selected from one or more of metal stearate, stearic acid, talc, stearate ester, and micronized silica gel. Preferably, the content of the osmotic pressure regulator is 0% to 50.0%, where the content refers to the percentage of the weight of the osmotic pressure regulator to the total weight of the booster core. And / or, The content of the swelling agent is 40.0% to 90.0%, and the content refers to the percentage of the weight of the swelling agent to the total weight of the booster core. And / or, The content of the colorant is 0.5% to 3.0%, and the content refers to the percentage of the weight of the colorant to the total weight of the booster core. And / or, The content of the lubricant is 0.5% to 3.0%, and the content refers to the percentage of the weight of the lubricant to the total weight of the booster core.

7. The pharmaceutical composition according to claim 1, characterized in that: The booster core comprises the following components: 0%~50.0% osmotic pressure regulator, 40.0%~90.0% swelling agent, 0.5%~3.0% colorant and 0.5%~3.0% lubricant, wherein the percentages refer to the weight of each component as a percentage of the total weight of the booster core. Preferably, the booster core is selected from any of the following components having the following weight percentages: Component 1: 73.65% polyoxyethylene, 23.95% sodium chloride, 1.20% iron oxide red, 1.20% magnesium stearate; Component 2: 73.65% polyoxyethylene, 11.98% sodium chloride, 11.97% sorbitol, 1.20% iron oxide red, 1.20% magnesium stearate; Component 3: 64.67% polyoxyethylene, 32.93% sodium chloride, 1.20% iron oxide red, 1.20% magnesium stearate.

8. The pharmaceutical composition according to claim 1, characterized in that: The coating material is a semi-permeable membrane material; Preferably, the semi-permeable membrane material includes one or more of a film-forming material, a plasticizer, and a pore-forming agent; Preferably, the film-forming material is one or more selected from cellulose acetate, ethyl cellulose, cellulose acetate phthalate, and (meth)acrylic resin; And / or, The plasticizer is selected from one or more of polyethylene glycol, triacetin, glyceryl citrate, glyceryl esters, and phthalates; And / or, The pore-forming agent is selected from polyethylene glycol and / or hydroxypropyl cellulose. More preferably, the content of the film-forming material is 5.0% to 15.0%, and the percentage refers to the percentage of the weight of the film-forming material to the total weight of the tablet core; And / or, The content of the plasticizer is 0% to 5.0%, and the percentage refers to the percentage of the weight of the plasticizer to the total weight of the tablet core; And / or, The content of the pore-forming agent is 0.1% to 15.0%, and the percentage refers to the percentage of the weight of the pore-forming agent to the total weight of the tablet core; More preferably, the semipermeable membrane material comprises the following components: 5.0% to 15.0% of film-forming material, 0% to 5.0% of plasticizer, and 0.1% to 15.0% of pore-forming agent; More preferably, the semipermeable membrane material is selected from any of the components having the following percentages: Coating 1: 9.00% cellulose acetate and 1.00% polyethylene glycol, where the percentages refer to the mass of each component relative to the total mass of the tablet core; Coating 2: 7.20% cellulose acetate and 0.80% polyethylene glycol 4000, where the percentages refer to the mass of each component relative to the total mass of the tablet core.

9. The method for preparing the pharmaceutical composition according to any one of claims 1-8, characterized in that: The pharmaceutical composition is prepared by direct compression, wet granulation, or dry granulation.

10. The use of the pharmaceutical composition according to any one of claims 1-8 in the preparation of a medicament for treating and / or preventing oxidative stress-related diseases; Preferably, the oxidative stress-related diseases are selected from Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, ischemic heart disease, cerebral infarction / stroke, thrombophlebitis, chronic obstructive pulmonary disease, human immune system diseases / acquired immune system syndromes, and diabetes.

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