WO2022042645A1 - Oral sustained release composition of edaravone, preparation method, and application - Google Patents

Oral sustained release composition of edaravone, preparation method, and application Download PDF

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Publication number
WO2022042645A1
WO2022042645A1 PCT/CN2021/114758 CN2021114758W WO2022042645A1 WO 2022042645 A1 WO2022042645 A1 WO 2022042645A1 CN 2021114758 W CN2021114758 W CN 2021114758W WO 2022042645 A1 WO2022042645 A1 WO 2022042645A1
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Prior art keywords
tablet core
drug
edaravone
percentage
containing layer
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PCT/CN2021/114758
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French (fr)
Chinese (zh)
Inventor
郭桢
陈丽娜
谢文凤
王婷婷
应述欢
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上海博志研新药物技术有限公司
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Publication of WO2022042645A1 publication Critical patent/WO2022042645A1/en

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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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    • A61K47/02—Inorganic compounds
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Definitions

  • the present invention relates to an oral sustained release composition of edaravone, a preparation method and application.
  • Edaravone is a brain protectant (free radical scavenger).
  • N-acetylaspartic acid NAA
  • Edaravone given to patients in the acute stage of cerebral infarction can inhibit the reduction of local cerebral blood flow around the infarction, and the NAA content in the brain on the 28th day after the onset of the disease is significantly higher than that of the glycerol control group. Therefore, edaravone is used to improve acute cerebral infarction. Neurological symptoms, activities of daily living, and functional impairment due to infarction.
  • the marketed edaravone preparation is an injection, usually 30 mg of edaravone for adults, 2 times a day, diluted with an appropriate amount of normal saline, and intravenously infused within 30 minutes. Dosing was started within 24 hours of onset, and the course of treatment was 14 days.
  • Patients with twice-daily intravenous infusion have poor compliance, and toxic side effects include acute renal failure, liver dysfunction, jaundice, thrombocytopenia, disseminated intravascular coagulation (DIC), injection site rash, redness, herpes, Itching, belching, fever, heat, increased blood pressure, increased serum cholesterol, decreased serum cholesterol, increased triglycerides, decreased serum total protein, decreased creatine kinase (CK), creatine phosphokinase (CPK), serum Low calcium.
  • DIC disseminated intravascular coagulation
  • DIC disseminated intravascular coagulation
  • injection site rash redness
  • herpes Itching, belching, fever, heat, increased blood pressure, increased serum cholesterol, decreased serum cholesterol, increased triglycerides, decreased serum total protein, decreased creatine kinase (CK), creatine phosphokinase (CPK), serum Low calcium.
  • the present invention provides a pharmaceutical composition, which has the following features A), B) and C):
  • the pharmaceutical active ingredient can be selected from one or more of edaravone, its pharmaceutically acceptable salts, hydrates and solvates.
  • the pharmaceutical composition preferably has the following characteristics A), B) and C):
  • the pharmaceutical composition more preferably has the following characteristics A), B) and C):
  • the “dissolution” refers to the cumulative dissolution rate of a pharmaceutical active ingredient (such as edaravone); further, the cumulative dissolution rate is measured in pH 6.8 phosphate buffer.
  • a pharmaceutical active ingredient such as edaravone
  • the dissolution rate of the active pharmaceutical ingredient gradually increases with time.
  • the pharmaceutical composition is a sustained-release composition, preferably a sustained-release pharmaceutical composition within 24 hours, more preferably an oral pharmaceutical composition with sustained sustained-release within 24 hours.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a tablet core and a coating;
  • the tablet core includes a drug-containing layer tablet core and/or a booster layer tablet core;
  • the described drug-containing layer tablet core comprises edaravone pharmaceutical active ingredient and carrier
  • the carrier is one or more of a polymer carrier, an osmotic pressure regulator, a swelling agent, a thickener and a lubricant;
  • the booster layer core includes one or more of an osmotic pressure regulator, a swelling agent, a coloring agent and a lubricant.
  • the pharmaceutical composition is an oral sustained release pharmaceutical composition.
  • the pharmaceutical composition has one of the combinations of features A), B) and C) described above.
  • the outer surface of the tablet core is covered with a coating.
  • the coating is impermeable to substances other than water.
  • the coating surface is free of or contains one or more openings through which the coating can pass.
  • the edaravone pharmaceutical active ingredient in the drug-containing layer tablet core, can be selected from edaravone, its pharmaceutically acceptable salts, hydrates and solvates one or more of.
  • the solvent in the edaravone solvate is an organic solvent
  • the organic solvent can be an organic solvent known in the art, such as one of methanol, ethanol, tetrahydrofuran and diethyl ether, etc. one or more.
  • the content of the edaravone pharmaceutical active ingredient is preferably 5.0% to 60.0%, such as 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 Edaravone Calculated as a percentage of the weight of the active ingredient of the edaravone drug in the total weight of the drug-containing layer tablet core.
  • the polymer carrier is selected from polyethylene glycol, copovidone (PVP/VA), hypromellose, and hypromellose acetate One of hydroxypropyl succinate (HPMCAS), hypromellose phthalate (HPMCP), polyvinyl acetate povidone mixture, poloxamer, carboxymethyl ethyl cellulose (CMEC) one or more;
  • the content of the polymer carrier is preferably 5.0% to 60.0%, such as 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 weight of the polymer carrier in the drug-containing layer Percentage of total core weight.
  • the swelling agent in the drug-containing layer tablet core, can be selected from substances that can absorb a solvent and swell, preferably polyoxyethylene, carbomer , one or more of sodium starch glycolate, crospovidone, hydroxypropyl methylcellulose, gum arabic, polyvinylpyrrolidone and sodium alginate.
  • the content of the swelling agent is preferably 10.0% to 50.0%, such as 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 layer tablet core.
  • the osmotic pressure regulator in the drug-containing layer tablet core, can be a substance that regulates osmotic action, preferably sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, One or more of magnesium sulfate, glucose, fructose, sucrose, and lactose.
  • the content of the osmotic pressure regulator is preferably 0% to 50.0%, such as 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 in the total weight of the drug-containing layer tablet core.
  • the thickening agent in the drug-containing layer tablet core, may be capable of increasing the viscosity of the dispersion medium to reduce the settling of particles Additives that speed or increase the hydrophilicity of the microparticles, preferably among hypromellose, hypromellose, hydroxyethyl cellulose, ethyl cellulose, copovidone, acacia, pregelatinized starch and polyvinylpyrrolidone one or more of.
  • the content of the thickener is preferably 0% to 40.0%, such as 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 in the total weight of the drug-containing layer tablet core.
  • the lubricant in the drug-containing layer tablet core, can be a substance with lubricating effect, preferably metal stearate, stearic acid, talc, stearate and micropowder One or more of silica gels.
  • the metal stearate is preferably magnesium stearate and/or calcium stearate.
  • the stearate is preferably glyceryl stearate.
  • the content of the lubricant is preferably 0.1% to 3.0%, such as 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3.0%; wherein, the content refers to the lubricant
  • the weight of the drug-containing layer is the percentage of the total weight of the tablet core.
  • the drug-containing layer tablet core may include the following components: 5.0%-60.0% of the active pharmaceutical ingredient of edaravone, 5.0%-60.0% of a polymer carrier, 10.0%-50.0% 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 proportion of each component in the drug-containing layer tablet Percentage of total core weight.
  • the drug-containing layer tablet core further preferably has any of the following weight percentages:
  • Component 1 20.00% edaravone active ingredient, 20.00% hypromellose acetate succinate, 20.00% sorbitol, 10.00% sodium chloride, 10.00% hypromellose, 10.00% copovidone , 9.00% crospovidone and 1.00% magnesium stearate;
  • Component 2 20.00% edaravone active ingredient, 20.00% hypromellose acetate succinate, 40.00% sorbitol, 10.00% sodium chloride, 4.00% hypromellose, 5.00% copovidone and 1.00% magnesium stearate;
  • Component three 30.03% edaravone pharmaceutical active ingredients, 30.03% hypromellose acetate succinate, 27.02% polyvinylpyrrolidone, 6.01% mannitol, 6.01% sodium chloride and 0.90% magnesium stearate;
  • Component four 30.03% edaravone active ingredient, 30.03% hypromellose acetate succinate, 30.03% sodium alginate, 9.02% sodium chloride and 0.90% magnesium stearate;
  • Component Five 30.03% Edaravone Pharmaceutical Active Ingredient, 30.03% Hypromellose Acetate Succinate, 18.02% Polyoxyethylene, 6.01% Hypromellose, 15.01% Sorbitol and 0.90% Magnesium Stearate ; The percentage refers to the percentage of each component in the total weight of the drug-containing layer tablet core.
  • the content or ratio of edaravone pharmaceutically active ingredient in the context of the present invention is based on edaravone.
  • the osmotic pressure regulator in the booster layer core, can be a substance that regulates osmotic action, preferably sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, One or more of magnesium sulfate, glucose, fructose, sucrose, and lactose.
  • the content of the osmotic pressure regulator is preferably 0% to 50.0%, such as 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 layer core.
  • the swelling agent in the core of the booster layer, can be a substance that can absorb a solvent and swell, preferably polyvinylpyrrolidone, hydroxypropyl methylcellulose, gum arabic, hydroxyethyl alcohol
  • a solvent and swell preferably polyvinylpyrrolidone, hydroxypropyl methylcellulose, gum arabic, hydroxyethyl alcohol
  • base cellulose carbomer, sodium starch glycolate, copovidone, sodium alginate and polyoxyethylene.
  • the content of the swelling agent is preferably 40.0% to 90.0%, such as 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 in the total weight of the booster layer core.
  • the colorant in the booster layer core, can be a substance that can achieve the purpose of coloring, preferably one or more of red iron oxide, yellow iron oxide and black iron oxide .
  • the content of the colorant is preferably 0.5% to 3.0%, such as 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3.0%; wherein, the content refers to the colorant
  • the weight of the booster layer as a percentage of the total core weight.
  • the lubricant in the booster layer core, can be a substance with lubricating effect, preferably metal stearate, stearic acid, talc, stearate and micropowder One or more of silica gels.
  • the metal stearate is preferably magnesium stearate and/or calcium stearate.
  • the stearate is preferably glyceryl stearate.
  • the content of the lubricant is preferably 0.5% to 3.0%, such as 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3.0%; wherein, the content refers to the weight of the lubricant in the booster layer sheet Percentage of total core weight.
  • the booster layer 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% % to 3.0% of lubricant; the percentages refer to the percentage of the weight of each component in the total weight of the booster layer core.
  • the booster layer core further preferably has any of the following components by weight:
  • Component 1 73.65% polyoxyethylene, 23.95% sodium chloride, 1.20% red iron oxide and 1.20% magnesium stearate;
  • Component 2 73.65% polyoxyethylene, 11.98% sodium chloride, 11.97% sorbitol, 1.20% red iron oxide and 1.20% magnesium stearate;
  • Component three 64.67% polyoxyethylene, 32.93% sodium chloride, 1.20% red iron oxide and 1.20% magnesium stearate.
  • the coating material is preferably a semi-permeable membrane material.
  • the semipermeable membrane material preferably includes one or more of a membrane-forming material, a plasticizer and a porogen.
  • the film-forming material may be a material that can be dispersed on a solid surface and cured to form a film, preferably cellulose acetate, ethyl cellulose, cellulose acetate phthalate and (meth)acrylic resin one or more of.
  • the content of the film-forming material is preferably 5.0% to 15.0%, such as 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 in the total weight of the tablet core.
  • the plasticizer can be a substance that can increase the plasticity of the polymer, preferably among polyethylene glycol, triacetin, citric acid, glyceride and phthalate. one or more of.
  • the content of the plasticizer is preferably 0% to 5.0%, such as 0%, 1.0%, 2.0%, 3.0%, 4.0% or 5.0%; wherein, the percentage refers to the increase The weight of the plasticizer as a percentage of the total weight of the tablet core.
  • the porogen may be a substance capable of pore-forming the material, preferably polyethylene glycol and/or hydroxypropyl cellulose.
  • the content of the porogen is preferably 0.1% to 15.0%, such as 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 porogen in the total weight of the tablet core.
  • the semipermeable membrane material includes the following components: 5.0%-15.0% of film-forming material, 0%-5.0% of plasticizer and 0.1%-15.0% of porogen, so The stated percentage refers to the percentage of the mass of each component in the total mass of the tablet core;
  • the semipermeable membrane material further preferably has any of the following weight percentages:
  • Coating 1 9.00% cellulose acetate and 1.00% polyethylene glycol, the percentage refers to the percentage of the mass of each component in the total mass of the tablet core;
  • Coating II 7.20% cellulose acetate and 0.80% polyethylene glycol 4000, the percentages refer to the percentage of the mass of each component in the total mass of the tablet core.
  • the present invention also provides an edaravone pharmaceutical active ingredient dispersion, comprising the edaravone pharmaceutical active ingredient dispersed in a polymer carrier.
  • the polymer carrier is selected from polyethylene glycol, copovidone, hypromellose, hypromellose acetate succinate, hypromellose phthalate, polyacetate One or more of vinyl ester povidone mixture, poloxamer and carboxymethyl ethyl cellulose.
  • the mass ratio of the active pharmaceutical ingredient of edaravone to the polymer carrier may be 1:1 or lower, such as 1:2, 1 :3, 1:4, 1:5, 1:6 or lower.
  • the pharmaceutical composition is a solid formulation, such as a tablet.
  • the present invention also provides a preparation method of the pharmaceutical composition, which can be a direct compression method, a wet granulation method, or a dry granulation method, and the like.
  • the described direct compression method comprises the following steps:
  • Step 1 Preparation of tablet core material: Edaravone active ingredient and hypromellose acetate succinate are dissolved in methanol/water solution, and spray-dried to obtain Edaravone active ingredient solid dispersion;
  • Step 2 tableting: use a tablet press to press the drug-containing layer tablet core material and the booster layer tablet core material obtained in step 1 into tablet cores;
  • Step 3 coating dissolve the film-forming material, plasticizer and pore-forming agent with a solvent, prepare a coating solution, and coat and age the tablet core obtained in step 2 to obtain a coated tablet;
  • Step 4 Punch holes: Punch holes on the drug-containing surface of the coated tablet obtained in Step 3 to obtain the pharmaceutical composition
  • the coating is preferably such that the weight gain of the coated tablet after coating is 2% to 20%, and the weight gain refers to (the weight of the coated tablet after coating - the weight of the tablet core before coating)/ Front core weight.
  • 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.
  • the pore size of the punched holes is preferably 0-1000 ⁇ m; the number of the punched holes can be 0, 1 or more.
  • the wet granulation comprises the following steps:
  • Step 1 Preparation of tablet core material: Dissolve the active ingredients of Edaravone and hypromellose acetate succinate in methanol/water solution, and spray-dry to obtain the solid dispersion of active ingredients of Edaravone;
  • Step (2) Tabletting use a tablet press to press the drug-containing layer tablet core material and booster layer tablet core material obtained in step (1) into tablet cores;
  • Step 3 coating: dissolve the film-forming material, the plasticizer and the pore-forming agent with a solvent, prepare a coating solution, and coat and age the tablet core obtained in step 2 to obtain a coated tablet;
  • Step 4. punching: the coated tablet obtained in step 3. is punched on the drug-containing surface to obtain the pharmaceutical composition
  • the coating is preferably to a weight gain of 2% to 20% of the coated tablet after the coating, and the weight gain refers to (the weight of the coated tablet after the coating - the weight of the tablet core before the coating)/package. Front core weight.
  • 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°C to 60°C, more preferably 30°C to 50°C, for example 40°C.
  • the hole diameter of the punched hole is preferably 0-1000 ⁇ m; the number of the punched hole can be 0, 1 or more.
  • the dry granulation method mainly comprises the following steps:
  • Step (1) Preparation of tablet core material: Edaravone medicinal active ingredient and hypromellose acetate succinate are dissolved in methanol/water solution, and the edaravone medicinal active ingredient solid dispersion is obtained by spray drying;
  • Step (2) tableting using a tablet press to press the drug-containing layer tablet core material and the booster layer tablet core material obtained in step (1) into tablet cores;
  • Step (3) coating dissolve the film-forming material, the plasticizer and the porogen with a solvent, prepare a coating solution, and coat and age the tablet core obtained in the step (2) to obtain a coated tablet;
  • Step (4) perforating perforating the drug-containing surface of the coated tablet obtained in step (3), the pharmaceutical composition can be obtained.
  • the coating is preferably such that the weight gain of the coated tablet after coating is 2% to 20%, and the weight gain refers to (the weight of the coated tablet after coating - Tablet core weight before coating) / Tablet core weight before coating.
  • 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.
  • the pore size of the punched holes is preferably 0-1000 ⁇ m; the number of the punched holes can be 0, 1 or more.
  • the drug-containing layer sheet may or may not have drug-release apertures.
  • the pharmaceutical composition is preferably an osmotic pump tablet.
  • the present invention also provides the application of the pharmaceutical composition in preparing a medicine for treating and/or preventing oxidative stress-related diseases.
  • the present invention also provides a method of treating and/or preventing oxidative stress-related diseases, comprising administering the pharmaceutical composition to a patient (eg, a human) in need thereof.
  • the oxidative stress-related disease is selected from the group consisting of Alzheimer's disease (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.
  • Alzheimer's disease Alzheimer's disease
  • ALS Amyotrophic lateral sclerosis
  • Parkinson's disease ischemic heart disease
  • Cerebral infarction/stroke Cerebral infarction/stroke
  • thrombophlebitis chronic obstructive pulmonary disease
  • HIV/AIDS human immune system disease/acquired immune system syndrome
  • the positive improvement effect of the present invention is that: after taking the pharmaceutical composition of the present invention, the gastrointestinal fluid enters the membrane through the semi-permeable membrane, the core of the drug-containing layer absorbs water to form a drug-containing suspension, and the core of the booster layer absorbs water and swells It promotes the release of the drug from the pores at a uniform speed, so as to achieve the effect of sustained and controlled release.
  • the pharmaceutical composition of the invention maintains continuous release for 24 hours, is convenient for oral administration, avoids the method of intravenous drip twice a day, and improves patient compliance.
  • the pharmaceutical composition, the prescription and the preparation process are simple, and the industrial production is easy.
  • Step 2 The solution in step 1 is spray-dried with a spray dryer to obtain the edaravone solid dispersion, and the edaravone solid dispersion is passed through a 40-mesh sieve;
  • Step 3 Put the edaravone solid dispersion and the air pressure auxiliary materials other than magnesium stearate in the above prescription in the mixing pot, set the mixing speed to 18r/min, mix for 20 minutes, and then add the magnesium stearate inside. , set the mixing speed to 18r/min, and mix for 5 minutes; obtain a drug-containing layer mixture;
  • Step 4 place the mixture obtained in step 3 in a dry granulator, adjust the equipment parameters so that it can be compressed into large pieces with a certain hardness, and then use a 1.0mm screen to granulate; and then mix with magnesium stearate, Set the mixing speed to 18r/min, and mix for 5 minutes; then place it on a rotary tablet press, and press it into a shallow arc circular tablet core;
  • a sustained-release coating solution is obtained
  • the drug-containing tablet cores obtained in step 4 are coated with the above-mentioned sustained-release coating solution, and the rotation speed of the coating pan is used to rotate at 8 rpm to 15 rpm.
  • the spraying speed is set in the range of 5rpm ⁇ 20rpm to spray the liquid, and the coating weight gain is 7.86% and 8.14% respectively.
  • Step 6 The coated tablet obtained in step 5 is subjected to laser drilling, and the size of the small hole is 0.4-0.6 mm to obtain Edaravone sustained-release tablet.
  • Step 2 The solution in step 1 is spray-dried with a spray dryer to obtain the edaravone solid dispersion, and the edaravone solid dispersion is passed through a 40-mesh sieve;
  • Step 3 Place the edaravone solid dispersion and the auxiliary materials of the drug-containing layer (except magnesium stearate) in the mixing pot, set the mixing speed to 18r/min, and mix for 20 minutes; then add the stearic acid of the drug-containing layer.
  • Magnesium set the mixing speed to 18r/min, and mix for 5 minutes to obtain a drug-containing layer mixture;
  • Step 4 Place the drug-containing layer mixture and the booster layer mixture obtained in step 3 on a rotary tableting machine, and adjust the equipment parameters so that the tablet weight of the drug-containing layer is 333 mg, the tablet weight of the booster layer is 167 mg, and the total tablet weight is 500mg, shallow arc circular tablet core with hardness 100N ⁇ 180N;
  • Step 5 Prepare the slow-release coating solution according to the following steps: add purified water to the beaker, stir with a magnetic stirrer, add acetone during the stirring process, and stir for 5 minutes after all addition to make it evenly mixed; then slowly add CA, stirring continuously for 30 to 90 minutes to make it completely dissolved to obtain a sustained-release coating solution;
  • the drug-containing tablet cores obtained in step 4 are coated with the above-mentioned sustained-release coating solution, the rotating speed of the coating pan is 8 rpm to 15 rpm, the temperature of the tablet bed is controlled at 25 ° C to 35 ° C, and the spraying speed is set in the range of 5 rpm to 20 rpm for spraying. liquid, continue coating to make the coating weight gain by 9.87% and 9.94%, stop spraying liquid, and then dry for 5 minutes to 10 minutes at a tablet bed temperature of 30 ° C ⁇ 35 ° C, and take out tablets; then place it in a set temperature of 45 ° C In a blast drying oven, aging is performed, and coated tablets are obtained after 24 hours;
  • Step 5 The coated tablet obtained in step 4 is subjected to laser drilling, and the punched surface should be the drug-containing layer (white corresponding surface) with a small hole size of 0.4-0.6 mm to obtain Edaravone sustained-release tablets.
  • Step 2 The solution in step 1 is spray-dried with a spray dryer to obtain the edaravone solid dispersion, and the edaravone solid dispersion is passed through a 40-mesh sieve;
  • Step 3 Place the edaravone solid dispersion, polyoxyethylene, hypromellose, sorbitol in the drug-containing layer in a mixing pot, set the mixing speed to 18r/min, and mix for 20 minutes; then add the drug-containing layer layer of magnesium stearate, set a mixing speed of 18r/min, and mix for 5 minutes to obtain a drug-containing layer mixture;
  • the mixing pot Put the polyoxyethylene, sodium chloride and red iron oxide of the booster layer in the above-mentioned prescription in the mixing pot, set the mixing speed to 18r/min, and mix for 10 minutes; then add the magnesium stearate of the booster layer, and set the mixing speed 18r/min, mixing for 5 minutes to obtain a booster layer mixture;
  • Step 4 Place the drug-containing layer mixture and the booster layer mixture obtained in step 3 on a rotary tableting machine, and adjust the equipment parameters so that the tablet weight of the drug-containing layer is 333 mg, the tablet weight of the booster layer is 167 mg, and the total tablet weight is 500mg, shallow arc circular tablet core with hardness 100N ⁇ 180N;
  • Step 5 Prepare the sustained-release coating solution according to the following steps: add 95% ethanol to the beaker, stir with a magnetic stirrer, add slowly during stirring Continue stirring for 60 to 120 minutes to completely dissolve to obtain a sustained-release coating solution;
  • the drug-containing tablet cores obtained in step 4 are coated with the above-mentioned sustained-release coating solution, the rotating speed of the coating pan is 8 rpm to 15 rpm, the temperature of the tablet bed is controlled at 25 ° C to 35 ° C, and the spraying speed is set in the range of 5 rpm to 20 rpm for spraying. liquid, continue coating to make the coating weight gain 8.06% and 8.12%, stop spraying liquid, and then dry for 5 minutes to 10 minutes at a tablet bed temperature of 30 ° C ⁇ 35 ° C, and take out tablets; then place it in a set temperature of 45 ° C In a blast drying oven, aging is performed, and coated tablets are obtained after 24 hours;
  • Step 5 The coated tablet obtained in step 4 is subjected to laser drilling, and the punched surface should be the drug-containing layer (white corresponding surface) with a small hole size of 0.4-0.6 mm to obtain Edaravone sustained-release tablets.
  • HPLC high performance liquid phase
  • edaravone is prepared as amorphous
  • the solid dispersion is beneficial to improve its solubility and bioavailability; it is prepared into a sustained-release dosage form, which can stabilize the blood drug concentration in the body and reduce the toxic and side effects.

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Abstract

An oral sustained release composition of edaravone, a preparation method, and an application. The composition comprises a core and a coating; the core comprises a drug-containing-layer core and/or a boost-layer core; the drug-containing-layer core comprises active ingredients of edaravone and a carrier; the carrier is one or more of a polymer carrier, an osmotic pressure regulator, a swelling agent, a thickener, and a lubricant; and the boost-layer core comprises one or more of an osmotic pressure regulator, a swelling agent, a colorant, and a lubricant.

Description

依达拉奉口服持续释放组合物、制备方法及应用Edaravone oral sustained release composition, preparation method and application
本申请要求享有2020年8月26日向中国国家知识产权局提交的申请号为202010870276.0，名称为“依达拉奉口服持续释放组合物、制备方法及应用”的发明专利申请的优先权。该申请的全文以引用的方式并入本文。This application claims the priority of the invention patent application with the application number 202010870276.0 submitted to the State Intellectual Property Office of China on August 26, 2020 and entitled "Edaravone oral sustained release composition, preparation method and application". The entirety of this application is incorporated herein by reference.
技术领域technical field
本发明涉及一种依达拉奉口服持续释放组合物、制备方法及应用。The present invention relates to an oral sustained release composition of edaravone, a preparation method and application.
背景技术Background technique
依达拉奉是一种脑保护剂(自由基清除剂)。临床研究提示N-乙酰门冬氨酸(NAA)是特异性的存活神经细胞的标志，脑梗塞发病初期含量急剧减少。脑梗塞急性期患者给予依达拉奉，可抑制梗塞周围局部脑血流量的减少，使发病后第28天脑中NAA含量较甘油对照组明显升高，因此依达拉奉用于改善急性脑梗塞所致的神经症状、日常生活活动能力和功能障碍。Edaravone is a brain protectant (free radical scavenger). Clinical studies suggest that N-acetylaspartic acid (NAA) is a specific marker of surviving nerve cells, and its content is sharply reduced in the early stage of cerebral infarction. Edaravone given to patients in the acute stage of cerebral infarction can inhibit the reduction of local cerebral blood flow around the infarction, and the NAA content in the brain on the 28th day after the onset of the disease is significantly higher than that of the glycerol control group. Therefore, edaravone is used to improve acute cerebral infarction. Neurological symptoms, activities of daily living, and functional impairment due to infarction.
上市依达拉奉制剂为注射液，通常成人依达拉奉30mg，一日2次，用时以适量的生理盐水稀释，30min内静脉滴注完。发病后24小时内开始给药，疗程为14天。一日2次静脉滴注患者的顺应性较差，且毒副作用包括急性肾功能衰竭、肝功能障碍、黄疸、血小板减少、弥散性血管内凝血(DIC)，注射部位发疹、红肿，疱疹，瘙痒感，嗳气，发热，热感，血压上升，血清胆固醇升高，血清胆固醇降低，三酰甘油升高，血清总蛋白减少，肌酸激酶(CK)、肌酸磷酸激酶(CPK)降低，血清钙低下。The marketed edaravone preparation is an injection, usually 30 mg of edaravone for adults, 2 times a day, diluted with an appropriate amount of normal saline, and intravenously infused within 30 minutes. Dosing was started within 24 hours of onset, and the course of treatment was 14 days. Patients with twice-daily intravenous infusion have poor compliance, and toxic side effects include acute renal failure, liver dysfunction, jaundice, thrombocytopenia, disseminated intravascular coagulation (DIC), injection site rash, redness, herpes, Itching, belching, fever, heat, increased blood pressure, increased serum cholesterol, decreased serum cholesterol, increased triglycerides, decreased serum total protein, decreased creatine kinase (CK), creatine phosphokinase (CPK), serum Low calcium.
因此，有必要开发一种依达拉奉口服缓释制剂，以提高其生物利用度、并使释药速度平稳，从而显著提高患者用药顺应性及降低毒副作用。Therefore, it is necessary to develop an oral sustained-release formulation of edaravone to improve its bioavailability and stabilize the drug release rate, thereby significantly improving the patient's medication compliance and reducing toxic and side effects.
发明内容SUMMARY OF THE INVENTION
为改善上述技术问题，本发明提供一种药物组合物，所述药物组合物 具有以下特征A)、B)和C)：In order to improve the above-mentioned technical problems, the present invention provides a pharmaceutical composition, which has the following features A), B) and C):
A)在1小时内溶出不超过20％的药物活性成分；A) Dissolve no more than 20% of the active pharmaceutical ingredients within 1 hour;
B)在6小时内溶出20％～60％的药物活性成分；B) Dissolve 20% to 60% of active pharmaceutical ingredients within 6 hours;
C)在24小时内溶出不低于70％的药物活性成分；C) Dissolve not less than 70% of active pharmaceutical ingredients within 24 hours;
其中，所述的药物活性成分可以选自依达拉奉、其药学上可接受的盐、水合物和溶剂合物中的一种或多种。Wherein, the pharmaceutical active ingredient can be selected from one or more of edaravone, its pharmaceutically acceptable salts, hydrates and solvates.
根据本发明的实施方案，所述药物组合物优选具有以下特征A)、B)和C)：According to an embodiment of the present invention, the pharmaceutical composition preferably has the following characteristics A), B) and C):
A)在1小时内溶出不超过15％的药物活性成分；A) Dissolve no more than 15% of active pharmaceutical ingredients within 1 hour;
B)在6小时内溶出20％～55％的药物活性成分；B) Dissolve 20% to 55% of active pharmaceutical ingredients within 6 hours;
C)在24小时内溶出不低于75％的药物活性成分。C) Dissolve not less than 75% of the active pharmaceutical ingredients within 24 hours.
根据本发明的实施方案，所述药物组合物更优选具有以下特征A)、B)和C)：According to an embodiment of the present invention, the pharmaceutical composition more preferably has the following characteristics A), B) and C):
A)在1小时内溶出不超过15％的药物活性成分；A) Dissolve no more than 15% of active pharmaceutical ingredients within 1 hour;
B)在6小时内溶出25％～55％的药物活性成分；B) Dissolve 25% to 55% of active pharmaceutical ingredients within 6 hours;
C)在24小时内溶出不低于80％的药物活性成分；C) Dissolve not less than 80% of active pharmaceutical ingredients within 24 hours;
其中，所述“溶出”指药物活性成分(如依达拉奉)的累积溶出度；进一步地，所述累积溶出度在pH 6.8磷酸盐缓冲液中测得。本领域技术人员能够理解，随着时间增加，所述药物活性成分(如依达拉奉)的溶出度逐渐增加。Wherein, the "dissolution" refers to the cumulative dissolution rate of a pharmaceutical active ingredient (such as edaravone); further, the cumulative dissolution rate is measured in pH 6.8 phosphate buffer. Those skilled in the art can understand that the dissolution rate of the active pharmaceutical ingredient (eg, edaravone) gradually increases with time.
根据本发明的实施方案，所述药物组合物为缓释组合物，优选为24小时内持续缓释的药物组合物，更优选为24小时内持续缓释的口服药物组合物。According to an embodiment of the present invention, the pharmaceutical composition is a sustained-release composition, preferably a sustained-release pharmaceutical composition within 24 hours, more preferably an oral pharmaceutical composition with sustained sustained-release within 24 hours.
本发明还提供一种药物组合物，其包括片芯和包衣；所述的片芯包括含药层片芯和/或助推层片芯；The present invention also provides a pharmaceutical composition comprising a tablet core and a coating; the tablet core includes a drug-containing layer tablet core and/or a booster layer tablet core;
其中，所述的含药层片芯包含依达拉奉药物活性成分以及载体；Wherein, the described drug-containing layer tablet core comprises edaravone pharmaceutical active ingredient and carrier;
所述的载体为聚合物载体、渗透压调节剂、溶胀剂、增稠剂和润滑剂中的一种或多种；The carrier is one or more of a polymer carrier, an osmotic pressure regulator, a swelling agent, a thickener and a lubricant;
所述的助推层片芯包括渗透压调节剂、溶胀剂、着色剂和润滑剂中的一种或多种。The booster layer core includes one or more of an osmotic pressure regulator, a swelling agent, a coloring agent and a lubricant.
根据本发明的实施方案，所述药物组合物为口服持续释放的药物组合物。According to an embodiment of the present invention, the pharmaceutical composition is an oral sustained release pharmaceutical composition.
根据本发明的实施方案，所述药物组合物具有上文所述的特征A)、B)和C)的组合中的一种。According to an embodiment of the invention, the pharmaceutical composition has one of the combinations of features A), B) and C) described above.
根据本发明的实施方案，所述的片芯的外表面被包衣覆盖。优选地，所述的包衣不可渗透除水以外的物质。例如，所述的包衣表面没有或含有一个或多个能穿过所述的包衣的开口形式。According to an embodiment of the present invention, the outer surface of the tablet core is covered with a coating. Preferably, the coating is impermeable to substances other than water. For example, the coating surface is free of or contains one or more openings through which the coating can pass.
根据本发明的实施方案，所述的含药层片芯中，所述的依达拉奉药物活性成分可以选自依达拉奉、其药学上可接受的盐、水合物和溶剂合物中的一种或多种。According to an embodiment of the present invention, in the drug-containing layer tablet core, the edaravone pharmaceutical active ingredient can be selected from edaravone, its pharmaceutically acceptable salts, hydrates and solvates one or more of.
根据本发明的实施方案，所述的依达拉奉溶剂合物中的溶剂为有机溶剂，所述有机溶剂可以为本领域已知的有机溶剂，例如甲醇、乙醇、四氢呋喃和乙醚等中的一种或多种。According to an embodiment of the present invention, the solvent in the edaravone solvate is an organic solvent, and the organic solvent can be an organic solvent known in the art, such as one of methanol, ethanol, tetrahydrofuran and diethyl ether, etc. one or more.
根据本发明的实施方案，所述的依达拉奉药物活性成分的含量优选5.0％～60.0％，例如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％或60.0％；其中，所述的含量是指以依达拉奉计，依达拉奉药物活性成分的重量占含药层片芯总重量的百分比。According to an embodiment of the present invention, the content of the edaravone pharmaceutical active ingredient is preferably 5.0% to 60.0%, such as 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 Edaravone Calculated as a percentage of the weight of the active ingredient of the edaravone drug in the total weight of the drug-containing layer tablet core.
根据本发明的实施方案，所述的含药层片芯中，所述的聚合物载体选自聚乙二醇、共聚维酮(PVP/VA)、羟丙甲纤维素、醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)、羟丙甲纤维素邻苯二甲酸酯(HPMCP)、聚醋酸乙烯酯聚维酮混合物、泊洛沙姆、羧甲基乙基纤维素(CMEC)中的一种或多种；According to an embodiment of the present invention, in the drug-containing layer tablet core, the polymer carrier is selected from polyethylene glycol, copovidone (PVP/VA), hypromellose, and hypromellose acetate One of hydroxypropyl succinate (HPMCAS), hypromellose phthalate (HPMCP), polyvinyl acetate povidone mixture, poloxamer, carboxymethyl ethyl cellulose (CMEC) one or more;
根据本发明的实施方案，所述的聚合物载体的含量优选5.0％～60.0％，例如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％或60.0％；其中，所述的含量是指聚合物载体的重量占含药层片芯总重量的百分比。According to an embodiment of the present invention, the content of the polymer carrier is preferably 5.0% to 60.0%, such as 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 weight of the polymer carrier in the drug-containing layer Percentage of total core weight.
根据本发明的实施方案，所述的含药层片芯中，所述的溶胀剂(也可以称为推动剂)可以选自能够吸收溶剂而发生膨胀的物质，优选聚氧乙烯、卡波姆、羧甲淀粉钠、交联聚维酮、羟丙甲基纤维素、阿拉伯胶、聚乙烯吡咯烷酮和海藻酸钠中的一种或多种。According to an embodiment of the present invention, in the drug-containing layer tablet core, the swelling agent (also referred to as a propellant) can be selected from substances that can absorb a solvent and swell, preferably polyoxyethylene, carbomer , one or more of sodium starch glycolate, crospovidone, hydroxypropyl methylcellulose, gum arabic, polyvinylpyrrolidone and sodium alginate.
根据本发明的实施方案，所述的溶胀剂的含量优选10.0％～50.0％，例如10.0％、15.0％、20.0％、25.0％、30.0％、35.0％、40.0％、45.0％或50.0％；其中，所述的含量是指溶胀剂的重量占含药层片芯总重量的百分比。According to an embodiment of the present invention, the content of the swelling agent is preferably 10.0% to 50.0%, such as 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 layer tablet core.
根据本发明的实施方案，所述的含药层片芯中，所述的渗透压调节剂可以为调节渗透作用的物质，优选氯化钠、氯化钾、甘露醇、山梨醇、硫酸钠、硫酸镁、葡萄糖、果糖、蔗糖和乳糖中的一种或多种。According to an embodiment of the present invention, in the drug-containing layer tablet core, the osmotic pressure regulator can be a substance that regulates osmotic action, preferably sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, One or more of magnesium sulfate, glucose, fructose, sucrose, and lactose.
根据本发明的实施方案，所述的渗透压调节剂的含量优选0％～50.0％，例如1.0％、5.0％、10.0％、15.0％、20.0％、25.0％、30.0％、35.0％、40.0％、45.0％或50.0％；其中，所述的含量是指渗透压调节剂的重量占含药层片芯总重量的百分比。According to an embodiment of the present invention, the content of the osmotic pressure regulator is preferably 0% to 50.0%, such as 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 in the total weight of the drug-containing layer tablet core.
根据本发明的实施方案，所述的含药层片芯中，所述的增稠剂(也可以称为混悬剂或粘合剂)可以为能够增加分散介质的黏度，以降低微粒的沉降速度或增加微粒亲水性的附加剂，优选羟丙甲纤维素、羟丙纤维素、羟乙基纤维素、乙基纤维素、共聚维酮、阿拉伯胶、预胶化淀粉和聚乙烯吡咯烷酮中的一种或多种。According to an embodiment of the present invention, in the drug-containing layer tablet core, the thickening agent (also referred to as a suspending agent or a binder) may be capable of increasing the viscosity of the dispersion medium to reduce the settling of particles Additives that speed or increase the hydrophilicity of the microparticles, preferably among hypromellose, hypromellose, hydroxyethyl cellulose, ethyl cellulose, copovidone, acacia, pregelatinized starch and polyvinylpyrrolidone one or more of.
根据本发明的实施方案，所述的增稠剂的含量优选0％～40.0％，例如1.0％、5.0％、10.0％、15.0％、20.0％、25.0％、30.0％、35.0％或40.0％；其中，所述的含量是指增稠剂的重量占含药层片芯总重量的百分比。According to an embodiment of the present invention, the content of the thickener is preferably 0% to 40.0%, such as 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 in the total weight of the drug-containing layer tablet core.
根据本发明的实施方案，所述的含药层片芯中，所述的润滑剂可以为具有润滑作用的物质，优选硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯和微粉硅胶中的一种或多种。所述的硬脂酸金属盐优选硬脂酸镁和/或硬脂酸钙。所述的硬脂酸酯优选硬脂酸甘油酯。According to an embodiment of the present invention, in the drug-containing layer tablet core, the lubricant can be a substance with lubricating effect, preferably metal stearate, stearic acid, talc, stearate and micropowder One or more of silica gels. The metal stearate is preferably magnesium stearate and/or calcium stearate. The stearate is preferably glyceryl stearate.
根据本发明的实施方案，所述的润滑剂的含量优选0.1％～3.0％，例如 0.5％、1.0％、1.5％、2.0％、2.5％或3.0％；其中，所述的含量是指润滑剂的重量占含药层片芯总重量的百分比。According to an embodiment of the present invention, the content of the lubricant is preferably 0.1% to 3.0%, such as 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3.0%; wherein, the content refers to the lubricant The weight of the drug-containing layer is the percentage of the total weight of the tablet core.
根据本发明的实施方案，所述的含药层片芯可以包括以下组分：5.0％～60.0％的依达拉奉药物活性成分，5.0％～60.0％的聚合物载体，10.0％～50.0％的溶胀剂，10.0％～40.0％的增稠剂，0％～50.0％的渗透压调节剂和0.1％～3.0％的润滑剂；其中，所述的百分比是指各组分占含药层片芯总重量的百分比。According to an embodiment of the present invention, the drug-containing layer tablet core may include the following components: 5.0%-60.0% of the active pharmaceutical ingredient of edaravone, 5.0%-60.0% of a polymer carrier, 10.0%-50.0% 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 proportion of each component in the drug-containing layer tablet Percentage of total core weight.
根据本发明的实施方案，所述的含药层片芯进一步优选具有以下重量百分比的任一组分：According to an embodiment of the present invention, the drug-containing layer tablet core further preferably has any of the following weight percentages:
组分一：20.00％依达拉奉药物活性成分，20.00％醋酸羟丙甲纤维素琥珀酸酯，20.00％山梨醇，10.00％氯化钠，10.00％羟丙甲纤维素，10.00％共聚维酮，9.00％交联聚维酮和1.00％硬脂酸镁；Component 1: 20.00% edaravone active ingredient, 20.00% hypromellose acetate succinate, 20.00% sorbitol, 10.00% sodium chloride, 10.00% hypromellose, 10.00% copovidone , 9.00% crospovidone and 1.00% magnesium stearate;
组分二：20.00％依达拉奉药物活性成分，20.00％醋酸羟丙甲纤维素琥珀酸酯，40.00％山梨醇，10.00％氯化钠，4.00％羟丙甲纤维素，5.00％共聚维酮和1.00％硬脂酸镁；Component 2: 20.00% edaravone active ingredient, 20.00% hypromellose acetate succinate, 40.00% sorbitol, 10.00% sodium chloride, 4.00% hypromellose, 5.00% copovidone and 1.00% magnesium stearate;
组分三：30.03％依达拉奉药物活性成分，30.03％醋酸羟丙甲纤维素琥珀酸酯，27.02％聚乙烯吡咯烷酮，6.01％甘露醇，6.01％氯化钠和0.90％硬脂酸镁；Component three: 30.03% edaravone pharmaceutical active ingredients, 30.03% hypromellose acetate succinate, 27.02% polyvinylpyrrolidone, 6.01% mannitol, 6.01% sodium chloride and 0.90% magnesium stearate;
组分四：30.03％依达拉奉药物活性成分，30.03％醋酸羟丙甲纤维素琥珀酸酯，30.03％海藻酸钠，9.02％氯化钠和0.90％硬脂酸镁；Component four: 30.03% edaravone active ingredient, 30.03% hypromellose acetate succinate, 30.03% sodium alginate, 9.02% sodium chloride and 0.90% magnesium stearate;
组分五：30.03％依达拉奉药物活性成分，30.03％醋酸羟丙甲纤维素琥珀酸酯，18.02％聚氧乙烯，6.01％羟丙甲纤维素，15.01％山梨醇和0.90％硬脂酸镁；所述的百分比是指各组分占含药层片芯总重量的百分比。Component Five: 30.03% Edaravone Pharmaceutical Active Ingredient, 30.03% Hypromellose Acetate Succinate, 18.02% Polyoxyethylene, 6.01% Hypromellose, 15.01% Sorbitol and 0.90% Magnesium Stearate ; The percentage refers to the percentage of each component in the total weight of the drug-containing layer tablet core.
除非另有说明，本发明上下文中依达拉奉药物活性成分的含量或比例以依达拉奉计。Unless otherwise stated, the content or ratio of edaravone pharmaceutically active ingredient in the context of the present invention is based on edaravone.
根据本发明的实施方案，所述的助推层片芯中，所述的渗透压调节剂可以为调节渗透作用的物质，优选氯化钠、氯化钾、甘露醇、山梨醇、硫酸钠、 硫酸镁、葡萄糖、果糖、蔗糖和乳糖中的一种或多种。According to an embodiment of the present invention, in the booster layer core, the osmotic pressure regulator can be a substance that regulates osmotic action, preferably sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, One or more of magnesium sulfate, glucose, fructose, sucrose, and lactose.
根据本发明的实施方案，所述的渗透压调节剂的含量优选0％～50.0％，例如1.0％、5.0％、10.0％、15.0％、20.0％、25.0％、30.0％、35.0％、40.0％、45.0％或50.0％；其中，所述的含量是指渗透压调节剂重量占的助推层片芯总重量的百分比。According to an embodiment of the present invention, the content of the osmotic pressure regulator is preferably 0% to 50.0%, such as 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 layer core.
根据本发明的实施方案，所述的助推层片芯中，所述的溶胀剂可以为能够吸收溶剂而发生膨胀的物质，优选聚乙烯吡咯烷酮、羟丙甲基纤维素、阿拉伯胶、羟乙基纤维素、卡波姆、羧甲淀粉钠、共聚维酮、海藻酸钠和聚氧乙烯中的一种或多种。According to an embodiment of the present invention, in the core of the booster layer, the swelling agent can be a substance that can absorb a solvent and swell, preferably polyvinylpyrrolidone, hydroxypropyl methylcellulose, gum arabic, hydroxyethyl alcohol One or more of base cellulose, carbomer, sodium starch glycolate, copovidone, sodium alginate and polyoxyethylene.
根据本发明的实施方案，所述的溶胀剂的含量优选40.0％～90.0％，例如40.0％、45.0％、50.0％、55.0％、6.0％、65.0％、70.0％、75.0％、80.0％、85.0％或90.0％；其中，所述的含量是指溶胀剂的重量占助推层片芯总重量的百分比。According to an embodiment of the present invention, the content of the swelling agent is preferably 40.0% to 90.0%, such as 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 in the total weight of the booster layer core.
根据本发明的实施方案，所述的助推层片芯中，所述的着色剂可以为能够达到着色目的的物质，优选氧化铁红、氧化铁黄和氧化铁黑中的一种或多种。According to an embodiment of the present invention, in the booster layer core, the colorant can be a substance that can achieve the purpose of coloring, preferably one or more of red iron oxide, yellow iron oxide and black iron oxide .
根据本发明的实施方案，所述的着色剂的含量优选0.5％～3.0％，例如0.5％、1.0％、1.5％、2.0％、2.5％或3.0％；其中，所述的含量是指着色剂的重量占助推层片芯总重量的百分比。According to an embodiment of the present invention, the content of the colorant is preferably 0.5% to 3.0%, such as 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3.0%; wherein, the content refers to the colorant The weight of the booster layer as a percentage of the total core weight.
根据本发明的实施方案，所述的助推层片芯中，所述的润滑剂可以为具有润滑作用的物质，优选硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯和微粉硅胶中的一种或多种。所述的硬脂酸金属盐优选硬脂酸镁和/或硬脂酸钙。According to an embodiment of the present invention, in the booster layer core, the lubricant can be a substance with lubricating effect, preferably metal stearate, stearic acid, talc, stearate and micropowder One or more of silica gels. The metal stearate is preferably magnesium stearate and/or calcium stearate.
根据本发明的实施方案，所述的硬脂酸酯优选硬脂酸甘油酯。所述的润滑剂的含量优选0.5％～3.0％，例如0.5％、1.0％、1.5％、2.0％、2.5％或3.0％；其中，所述的含量是指润滑剂的重量占助推层片芯总重量的百分比。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%, such as 0.5%, 1.0%, 1.5%, 2.0%, 2.5% or 3.0%; wherein, the content refers to the weight of the lubricant in the booster layer sheet Percentage of total core weight.
根据本发明的实施方案，所述的助推层片芯包括以下组分：0％～50.0％的渗透压调节剂，40.0％～90.0％的溶胀剂，0.5％～3.0％的着色剂和0.5％～3.0％ 的润滑剂；所述的百分比是指各组分的重量占助推层片芯总重量的百分比。According to an embodiment of the present invention, the booster layer 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% % to 3.0% of lubricant; the percentages refer to the percentage of the weight of each component in the total weight of the booster layer core.
根据本发明的实施方案，所述的助推层片芯进一步优选具有以下重量百分比的任一组分：According to an embodiment of the present invention, the booster layer core further preferably has any of the following components by weight:
组分一：73.65％聚氧乙烯，23.95％氯化钠，1.20％氧化铁红和1.20％硬脂酸镁；Component 1: 73.65% polyoxyethylene, 23.95% sodium chloride, 1.20% red iron oxide and 1.20% magnesium stearate;
组分二：73.65％聚氧乙烯，11.98％氯化钠，11.97％山梨醇，1.20％氧化铁红和1.20％硬脂酸镁；Component 2: 73.65% polyoxyethylene, 11.98% sodium chloride, 11.97% sorbitol, 1.20% red iron oxide and 1.20% magnesium stearate;
组分三：64.67％聚氧乙烯，32.93％氯化钠，1.20％氧化铁红和1.20％硬脂酸镁。Component three: 64.67% polyoxyethylene, 32.93% sodium chloride, 1.20% red iron oxide and 1.20% magnesium stearate.
根据本发明的实施方案，所述的包衣材料优选半透膜材料。所述的半透膜材料优选包括成膜材料、增塑剂和致孔剂中的一种或多种。According to an embodiment of the present invention, the coating material is preferably a semi-permeable membrane material. The semipermeable membrane material preferably includes one or more of a membrane-forming material, a plasticizer and a porogen.
根据本发明的实施方案，所述的成膜材料可以为能够分散在固体表面固化成膜的材料，优选醋酸纤维素、乙基纤维素、邻苯二甲酸醋酸纤维素和(甲基)丙烯酸树脂中的一种或多种。According to an embodiment of the present invention, the film-forming material may be a material that can be dispersed on a solid surface and cured to form a film, preferably cellulose acetate, ethyl cellulose, cellulose acetate phthalate and (meth)acrylic resin one or more of.
根据本发明的实施方案，所述的成膜材料的含量优选5.0％～15.0％，例如5.0％、6.0％、7.0％、8.0％、9.0％、10.0％、11.0％、12.0％、13.0％、14.0％或15.0％；其中，所述的百分比是指成膜材料的重量占药片片芯总重量的百分比。According to an embodiment of the present invention, the content of the film-forming material is preferably 5.0% to 15.0%, such as 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 in the total weight of the tablet core.
根据本发明的实施方案，所述的增塑剂可以为能使聚合物塑性增加的物质，优选聚乙二醇、三醋酸甘油酯、柠檬酸甘油酯、甘油酯和邻苯二甲酸酯中的一种或多种。According to an embodiment of the present invention, the plasticizer can be a substance that can increase the plasticity of the polymer, preferably among polyethylene glycol, triacetin, citric acid, glyceride and phthalate. one or more of.
根据本发明的实施方案，所述的增塑剂的含量优选0％～5.0％，例如0％、1.0％、2.0％、3.0％、4.0％或5.0％；其中，所述的百分比是指增塑剂的重量占药片片芯总重量的百分比。According to an embodiment of the present invention, the content of the plasticizer is preferably 0% to 5.0%, such as 0%, 1.0%, 2.0%, 3.0%, 4.0% or 5.0%; wherein, the percentage refers to the increase The weight of the plasticizer as a percentage of the total weight of the tablet core.
根据本发明的实施方案，所述的致孔剂可以为能够使材料成孔的物质，优选聚乙二醇和/或羟丙基纤维素。According to an embodiment of the present invention, the porogen may be a substance capable of pore-forming the material, preferably polyethylene glycol and/or hydroxypropyl cellulose.
根据本发明的实施方案，所述的致孔剂的含量优选0.1％～15.0％，例如 0.1％、0.5％、1.0％、2.0％、3.0％、4.0％、5.0％、8.0％、10.0％、12.0％或15.0％；其中，所述的百分比是指致孔剂的重量占药片片芯总重量的百分比。According to an embodiment of the present invention, the content of the porogen is preferably 0.1% to 15.0%, such as 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 porogen in the total weight of the tablet core.
根据本发明的实施方案，所述的半透膜材料包括以下组分：5.0％～15.0％的成膜材料、0％～5.0％的增塑剂和0.1％～15.0％的致孔剂，所述的百分比是指各组分的质量占药片片芯总质量的百分比；According to an embodiment of the present invention, the semipermeable membrane material includes the following components: 5.0%-15.0% of film-forming material, 0%-5.0% of plasticizer and 0.1%-15.0% of porogen, so The stated percentage refers to the percentage of the mass of each component in the total mass of the tablet core;
根据本发明的实施方案，所述的半透膜材料进一步优选具有如下重量百分比的任一组分：According to an embodiment of the present invention, the semipermeable membrane material further preferably has any of the following weight percentages:
包衣一：9.00％醋酸纤维素和1.00％聚乙二醇，所述的百分比是指各组分的质量占药片片芯总质量的百分比；Coating 1: 9.00% cellulose acetate and 1.00% polyethylene glycol, the percentage refers to the percentage of the mass of each component in the total mass of the tablet core;
包衣二：7.20％醋酸纤维素和0.80％聚乙二醇4000，所述的百分比是指各组分的质量占药片片芯总质量的百分比。Coating II: 7.20% cellulose acetate and 0.80% polyethylene glycol 4000, the percentages refer to the percentage of the mass of each component in the total mass of the tablet core.
本发明还提供一种依达拉奉药物活性成分分散体，包括分散于聚合物载体中的依达拉奉药物活性成分。优选地，所述的聚合物载体选自聚乙二醇、共聚维酮、羟丙甲纤维素、醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素邻苯二甲酸酯、聚醋酸乙烯酯聚维酮混合物、泊洛沙姆和羧甲基乙基纤维素中的一种或多种。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 polyethylene glycol, copovidone, hypromellose, hypromellose acetate succinate, hypromellose phthalate, polyacetate One or more of vinyl ester povidone mixture, poloxamer and carboxymethyl ethyl cellulose.
根据本发明的实施方案，在所述依达拉奉药物活性成分分散体中，依达拉奉药物活性成分与聚合物载体的质量比可以为1:1或更低，例如1:2、1:3、1:4、1:5、1:6或更低。According to an embodiment of the present invention, in the edaravone active pharmaceutical ingredient dispersion, the mass ratio of the active pharmaceutical ingredient of edaravone to the polymer carrier may be 1:1 or lower, such as 1:2, 1 :3, 1:4, 1:5, 1:6 or lower.
本发明还提供一种药物组合物，其中所述药物组合物包含所述依达拉奉药物活性成分分散体。The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the edaravone pharmaceutical active ingredient dispersion.
根据本发明的实施方案，所述药物组合物为固体制剂，如片剂。According to an embodiment of the present invention, the pharmaceutical composition is a solid formulation, such as a tablet.
本发明还提供了所述药物组合物的制备方法，其可为直接压片法、湿法制粒法或干法制粒法等。The present invention also provides a preparation method of the pharmaceutical composition, which can be a direct compression method, a wet granulation method, or a dry granulation method, and the like.
根据本发明的实施方案，所述的直接压片法包括以下步骤：According to an embodiment of the present invention, the described direct compression method comprises the following steps:
步骤1片芯物料制备：将依达拉奉药物活性成分和醋酸羟丙甲纤维素琥珀酸酯溶解于甲醇/水溶液中，经喷雾干燥得依达拉奉药物活性成分固体分散 体；Step 1: Preparation of tablet core material: Edaravone active ingredient and hypromellose acetate succinate are dissolved in methanol/water solution, and spray-dried to obtain Edaravone active ingredient solid dispersion;
将依达拉奉药物活性成分固体分散体与溶胀剂、渗透压调节剂、增稠剂混合，然后加入润滑剂，混合，得含药层片芯物料；Mixing the edaravone pharmaceutical active ingredient solid dispersion with a swelling agent, an osmotic pressure regulator and a thickening agent, then adding a lubricant and mixing to obtain a drug-containing layer tablet core material;
将溶胀剂、渗透压调节剂和着色剂混合，然后加入润滑剂，混合，得助推层片芯物料；Mix the swelling agent, the osmotic pressure regulator and the colorant, then add the lubricant, and mix to obtain the core material of the booster layer;
步骤2压片：采用压片机将步骤1制得的含药层片芯物料和助推层片芯物料压制成片芯；Step 2: tableting: use a tablet press to press the drug-containing layer tablet core material and the booster layer tablet core material obtained in step 1 into tablet cores;
步骤3包衣：用溶剂溶解成膜材料、增塑剂和致孔剂，配制包衣液，对步骤2得到的片芯进行包衣、老化，得到包衣片；Step 3 coating: dissolve the film-forming material, plasticizer and pore-forming agent with a solvent, prepare a coating solution, and coat and age the tablet core obtained in step 2 to obtain a coated tablet;
步骤4打孔：将步骤3得到的包衣片在含药面打孔，即可得到所述的药物组合物；Step 4: Punch holes: Punch holes on the drug-containing surface of the coated tablet obtained in Step 3 to obtain the pharmaceutical composition;
步骤3中，所述的包衣优选至包衣后包衣片增重2％～20％，所述的增重是指(包衣后包衣片重量-包衣前片芯重量)/包衣前片芯重量。In step 3, the coating is preferably such that the weight gain of the coated tablet after coating is 2% to 20%, and the weight gain refers to (the weight of the coated tablet after coating - the weight of the tablet core before coating)/ Front core weight.
步骤3中，所述的老化的时间优选1小时～24小时，进一步优选8小时～16小时，例如12小时。所述的老化的温度优选20℃～60℃，进一步优选30℃～50℃，例如40℃。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.
步骤4中，所述的打孔的孔径优选0～1000μm；所述的打孔的数量可为0、1个或多个。In step 4, the pore size of the punched holes is preferably 0-1000 μm; the number of the punched holes can be 0, 1 or more.
根据本发明的实施方案，所述的湿法制粒包括以下步骤：According to an embodiment of the present invention, the wet granulation comprises the following steps:
步骤①片芯物料制备：将依达拉奉药物活性成分和醋酸羟丙甲纤维素琥珀酸酯溶解于甲醇/水溶液中，经喷雾干燥得依达拉奉药物活性成分固体分散体；Step 1: Preparation of tablet core material: Dissolve the active ingredients of Edaravone and hypromellose acetate succinate in methanol/water solution, and spray-dry to obtain the solid dispersion of active ingredients of Edaravone;
将依达拉奉药物活性成分固体分散体与溶胀剂、渗透压调节剂、增稠剂混合，进行湿法制粒，干燥，整粒，然后加入润滑剂，混合，得含药层片芯物料；Mixing the edaravone active ingredient solid dispersion with a swelling agent, an osmotic pressure regulator and a thickening agent, wet granulation, drying, and granulation, then adding a lubricant and mixing to obtain a drug-containing layer tablet core material;
将溶胀剂、渗透压调节剂和着色剂混合，进行湿法制粒，干燥，整粒，然后加入润滑剂，混合，得助推层片芯物料；Mix swelling agent, osmotic pressure regulator and colorant, carry out wet granulation, dry, granulate, then add lubricant and mix to obtain booster layer tablet core material;
步骤②压片：采用压片机将步骤①制得的含药层片芯物料和助推层片芯物料压制成片芯；Step (2) Tabletting: use a tablet press to press the drug-containing layer tablet core material and booster layer tablet core material obtained in step (1) into tablet cores;
步骤③包衣：用溶剂溶解成膜材料、增塑剂和致孔剂，配制包衣液，对步骤②得到的片芯进行包衣、老化，得到包衣片；Step 3. coating: dissolve the film-forming material, the plasticizer and the pore-forming agent with a solvent, prepare a coating solution, and coat and age the tablet core obtained in step 2 to obtain a coated tablet;
步骤④打孔：将步骤③得到的包衣片在含药面打孔，即可得到所述的药物组合物；Step 4. punching: the coated tablet obtained in step 3. is punched on the drug-containing surface to obtain the pharmaceutical composition;
步骤③中，所述的包衣优选至包衣后包衣片增重2％～20％，所述的增重是指(包衣后包衣片重量-包衣前片芯重量)/包衣前片芯重量。In step 3., the coating is preferably to a weight gain of 2% to 20% of the coated tablet after the coating, and the weight gain refers to (the weight of the coated tablet after the coating - the weight of the tablet core before the coating)/package. Front core weight.
步骤③所述的老化的时间优选1小时～24小时，进一步优选8小时～16小时，例如12小时。所述的老化的温度优选20℃～60℃，进一步优选30℃～50℃，例如40℃。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°C to 60°C, more preferably 30°C to 50°C, for example 40°C.
步骤④中，所述的打孔的孔径优选0～1000μm；所述的打孔的数量可为0、1个或多个。In step ④, the hole diameter of the punched hole is preferably 0-1000 μm; the number of the punched hole can be 0, 1 or more.
根据本发明的实施方案，所述的干法制粒法主要包括以下步骤：According to an embodiment of the present invention, the dry granulation method mainly comprises the following steps:
步骤(1)片芯物料制备：将依达拉奉药物活性成分和醋酸羟丙甲纤维素琥珀酸酯溶解于甲醇/水溶液中，经喷雾干燥得依达拉奉药物活性成分固体分散体；Step (1) Preparation of tablet core material: Edaravone medicinal active ingredient and hypromellose acetate succinate are dissolved in methanol/water solution, and the edaravone medicinal active ingredient solid dispersion is obtained by spray drying;
将依达拉奉药物活性成分固体分散体与溶胀剂、渗透压调节剂、增稠剂、润滑剂混合，干法制粒，整粒，然后再加入润滑剂，混合，得含药层片芯物料；Mix the solid dispersion of edaravone pharmaceutical active ingredient with swelling agent, osmotic pressure regulator, thickener and lubricant, dry granulation, granulate, then add lubricant and mix to obtain drug-containing layer tablet core material ;
将溶胀剂、渗透压调节剂、润滑剂和着色剂混合，干法制粒，整粒，然后再加入润滑剂，混合，得助推层片芯物料；Mix swelling agent, osmotic pressure regulator, lubricant and colorant, dry granulate, granulate, then add lubricant and mix to obtain booster layer tablet core material;
步骤(2)压片：采用压片机将步骤(1)制得的含药层片芯物料和助推层片芯物料压制成片芯；Step (2) tableting: using a tablet press to press the drug-containing layer tablet core material and the booster layer tablet core material obtained in step (1) into tablet cores;
步骤(3)包衣：用溶剂溶解成膜材料、增塑剂和致孔剂，配制包衣液，对步骤(2)得到的片芯进行包衣、老化，得到包衣片；Step (3) coating: dissolve the film-forming material, the plasticizer and the porogen with a solvent, prepare a coating solution, and coat and age the tablet core obtained in the step (2) to obtain a coated tablet;
步骤(4)打孔：将步骤(3)得到的包衣片含药面打孔，即可得到所述 的药物组合物。Step (4) perforating: perforating the drug-containing surface of the coated tablet obtained in step (3), the pharmaceutical composition can be obtained.
根据本发明的实施方案，步骤(3)中，所述的包衣优选至包衣后包衣片增重2％～20％，所述的增重是指(包衣后包衣片重量-包衣前片芯重量)/包衣前片芯重量。According to an embodiment of the present invention, in step (3), the coating is preferably such that the weight gain of the coated tablet after coating is 2% to 20%, and the weight gain refers to (the weight of the coated tablet after coating - Tablet core weight before coating) / Tablet core weight before coating.
根据本发明的实施方案，步骤(3)中，所述的老化的时间优选1小时～24小时，进一步优选8小时～16小时，例如12小时。所述的老化的温度优选20℃～60℃，进一步优选30℃～50℃，例如40℃。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.
根据本发明的实施方案，步骤(4)中，所述的打孔的孔径优选0～1000μm；所述的打孔的数量可为0、1个或多个。According to an embodiment of the present invention, in step (4), the pore size of the punched holes is preferably 0-1000 μm; the number of the punched holes can be 0, 1 or more.
根据本发明的实施方案，含药层片面含有或没有释药孔。According to embodiments of the present invention, the drug-containing layer sheet may or may not have drug-release apertures.
根据本发明的实施方案，所述的药物组合物优选为渗透泵片。According to an embodiment of the present invention, the pharmaceutical composition is preferably an osmotic pump tablet.
本发明还提供了所述药物组合物在制备治疗和/或预防氧化性应激相关疾病的药物中的应用。The present invention also provides the application of the pharmaceutical composition in preparing a medicine for treating and/or preventing oxidative stress-related diseases.
本发明还提供一种治疗和/或预防氧化性应激相关疾病的方法，包括向有需要的患者(例如人)给予所述药物组合物。The present invention also provides a method of treating and/or preventing oxidative stress-related diseases, comprising administering the pharmaceutical composition to a patient (eg, a human) in need thereof.
根据本发明的实施方案，所述的氧化性应激相关疾病选自老年痴呆症(阿尔茨海默症)、ALS(肌萎缩侧索硬化症)、帕金森氏病、缺血性心脏病、脑梗/中风、血栓性静脉炎、COPD(慢性阻塞性肺疾病)、HIV/AIDS(人类免疫系统病/获得性免疫系统综合症)和糖尿病。According to an embodiment of the present invention, the oxidative stress-related disease is selected from the group consisting of Alzheimer's disease (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.
本发明的积极进步效果在于：本发明的药物组合物，患者服用后，胃肠液透过半透膜进入膜内，含药层片芯吸水形成含药混悬液，助推层片芯吸水膨胀推动药物从小孔中匀速释放，从而达到缓释和控释效果。本发明的药物组合物维持24小时持续释放，口服方便，避免了一天两次静脉滴注的方法，提高了患者顺应性。此外，该药物组合物，处方及制备工艺简单，易于工业化生产。The positive improvement effect of the present invention is that: after taking the pharmaceutical composition of the present invention, the gastrointestinal fluid enters the membrane through the semi-permeable membrane, the core of the drug-containing layer absorbs water to form a drug-containing suspension, and the core of the booster layer absorbs water and swells It promotes the release of the drug from the pores at a uniform speed, so as to achieve the effect of sustained and controlled release. The pharmaceutical composition of the invention maintains continuous release for 24 hours, is convenient for oral administration, avoids the method of intravenous drip twice a day, and improves patient compliance. In addition, the pharmaceutical composition, the prescription and the preparation process are simple, and the industrial production is easy.
具体实施方式detailed description
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
除非另有说明，下文实施例所使用的原料和试剂是可商购的或可由本领域技术人员通过已知的方法制备。Unless otherwise indicated, the starting materials and reagents used in the examples below are either commercially available or can be prepared by methods known to those skilled in the art.
实施例1-2Example 1-2
Figure PCTCN2021114758-appb-000001
Figure PCTCN2021114758-appb-000001
制备工艺：Preparation Process:
步骤1：将上述处方中的依达拉奉和HPMCAS加入到溶剂中(甲醇：水＝9:1)，将样品置于恒温水浴锅中搅拌，设置加热温度50℃，进行溶解；Step 1: add Edaravone and HPMCAS in the above recipe into a solvent (methanol:water=9:1), place the sample in a constant temperature water bath and stir, set the heating temperature to 50°C, and dissolve;
步骤2：将步骤1中的溶液使用喷雾干燥机进行喷雾干燥，得依达拉奉固体分散体，将依达拉奉固体分散体过40目筛网；Step 2: The solution in step 1 is spray-dried with a spray dryer to obtain the edaravone solid dispersion, and the edaravone solid dispersion is passed through a 40-mesh sieve;
步骤3：将依达拉奉固体分散体及上述处方中的除硬脂酸镁外的气压辅料置于混合锅中，设置混合速度18r/min，混合20分钟，再加入内加硬脂酸镁，设置混合速度18r/min，混合5分钟；得到含药层混合物；Step 3: Put the edaravone solid dispersion and the air pressure auxiliary materials other than magnesium stearate in the above prescription in the mixing pot, set the mixing speed to 18r/min, mix for 20 minutes, and then add the magnesium stearate inside. , set the mixing speed to 18r/min, and mix for 5 minutes; obtain a drug-containing layer mixture;
步骤4：将步骤3得到的混合物置于干法制粒机中，调节设备参数，使之能压制成有一定硬度的大片，再用1.0mm筛网进行整粒；再与硬脂酸镁混合，设置混合速度18r/min，混合5分钟；然后再置于旋转压片机上，压制成浅弧圆形片芯；Step 4: place the mixture obtained in step 3 in a dry granulator, adjust the equipment parameters so that it can be compressed into large pieces with a certain hardness, and then use a 1.0mm screen to granulate; and then mix with magnesium stearate, Set the mixing speed to 18r/min, and mix for 5 minutes; then place it on a rotary tablet press, and press it into a shallow arc circular tablet core;
步骤5：Step 5:
根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2021114758-appb-000002
CA，持续搅拌30分钟～120分钟使之完全溶解， Prepare the sustained-release coating solution according to the following steps: add purified water to a beaker, stir with a magnetic stirrer, add acetone during the stirring process, and stir for 5 minutes after all additions to make it evenly mixed; then slowly add
Figure PCTCN2021114758-appb-000002
CA, continue to stir for 30 minutes to 120 minutes to completely dissolve,
得到缓释包衣溶液；A sustained-release coating solution is obtained;
对步骤4得到的含药片芯用上述缓释包衣溶液进行包衣，使用8rpm～15rpm的包衣锅转速进行转动，进风风量控制在30m 3/h～120m 3/h，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重分别为7.86％和8.14％停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中， The drug-containing tablet cores obtained in step 4 are coated with the above-mentioned sustained-release coating solution, and the rotation speed of the coating pan is used to rotate at 8 rpm to 15 rpm. At 25℃～35℃, the spraying speed is set in the range of 5rpm～20rpm to spray the liquid, and the coating weight gain is 7.86% and 8.14% respectively. ℃ to dry for 5 minutes to 10 minutes, and then put in a blast drying oven with a set temperature of 45 ℃,
进行老化，24小时后得到包衣片；Aging was performed to obtain coated tablets after 24 hours;
步骤6：将步骤5得到的包衣片，进行激光打孔，小孔尺寸0.4～0.6mm得到依达拉奉缓释片。Step 6: The coated tablet obtained in step 5 is subjected to laser drilling, and the size of the small hole is 0.4-0.6 mm to obtain Edaravone sustained-release tablet.
实施例3-4Example 3-4
Figure PCTCN2021114758-appb-000003
Figure PCTCN2021114758-appb-000003
Figure PCTCN2021114758-appb-000004
Figure PCTCN2021114758-appb-000004
制备工艺：Preparation Process:
步骤1：将上述处方中的依达拉奉和HPMCAS加入到溶剂中(甲醇：水＝9:1)，将样品置于恒温水浴锅中搅拌，设置加热温度50℃，进行溶解；Step 1: add Edaravone and HPMCAS in the above recipe into a solvent (methanol:water=9:1), place the sample in a constant temperature water bath and stir, set the heating temperature to 50°C, and dissolve;
步骤2：将步骤1中的溶液使用喷雾干燥机进行喷雾干燥，得依达拉奉固体分散体，将依达拉奉固体分散体过40目筛网；Step 2: The solution in step 1 is spray-dried with a spray dryer to obtain the edaravone solid dispersion, and the edaravone solid dispersion is passed through a 40-mesh sieve;
步骤3：将依达拉奉固体分散体和含药层的辅料(除硬脂酸镁)置于混合锅中，设置混合速度18r/min，混合20分钟；再加入含药层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到含药层混合物；Step 3: Place the edaravone solid dispersion and the auxiliary materials of the drug-containing layer (except magnesium stearate) in the mixing pot, set the mixing speed to 18r/min, and mix for 20 minutes; then add the stearic acid of the drug-containing layer. Magnesium, set the mixing speed to 18r/min, and mix for 5 minutes to obtain a drug-containing layer mixture;
将上述处方中助推层的聚氧乙烯、氯化钠、山梨醇、氧化铁红置于混合锅中，设置混合速度18r/min，混合10分钟；再加入助推层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到助推层混合物；Place the polyoxyethylene, sodium chloride, sorbitol and red iron oxide of the booster layer in the above-mentioned prescription in a mixing pot, set a mixing speed of 18r/min, and mix for 10 minutes; then add the magnesium stearate of the booster layer, Set the mixing speed to 18r/min, and mix for 5 minutes to obtain a booster layer mixture;
步骤4：将步骤3得到的含药层混合物和助推层混合物置于旋转压片机上，调节设备参数，使含药层的片重为333mg，助推层的片重为167mg，总片重为500mg，硬度100N～180N的浅弧圆形含药片芯；Step 4: Place the drug-containing layer mixture and the booster layer mixture obtained in step 3 on a rotary tableting machine, and adjust the equipment parameters so that the tablet weight of the drug-containing layer is 333 mg, the tablet weight of the booster layer is 167 mg, and the total tablet weight is 500mg, shallow arc circular tablet core with hardness 100N～180N;
步骤5：根据以下步骤配制缓释包衣溶液：将纯化水加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中加入丙酮，全部加入后搅拌5分钟，使之混合均匀；再缓慢加入
Figure PCTCN2021114758-appb-000005
CA，持续搅拌30分钟～90分钟使之完全溶解，得到缓释包衣溶液； Step 5: Prepare the slow-release coating solution according to the following steps: add purified water to the beaker, stir with a magnetic stirrer, add acetone during the stirring process, and stir for 5 minutes after all addition to make it evenly mixed; then slowly add
Figure PCTCN2021114758-appb-000005
CA, stirring continuously for 30 to 90 minutes to make it completely dissolved to obtain a sustained-release coating solution;
对步骤4得到的含药片芯用上述缓释包衣溶液进行包衣，包衣锅转速8rpm～15rpm，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重9.87％和9.94％停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后得到包衣片；The drug-containing tablet cores obtained in step 4 are coated with the above-mentioned sustained-release coating solution, the rotating speed of the coating pan is 8 rpm to 15 rpm, the temperature of the tablet bed is controlled at 25 ° C to 35 ° C, and the spraying speed is set in the range of 5 rpm to 20 rpm for spraying. liquid, continue coating to make the coating weight gain by 9.87% and 9.94%, stop spraying liquid, and then dry for 5 minutes to 10 minutes at a tablet bed temperature of 30 ° C ~ 35 ° C, and take out tablets; then place it in a set temperature of 45 ° C In a blast drying oven, aging is performed, and coated tablets are obtained after 24 hours;
步骤5：将步骤4得到的包衣片，进行激光打孔，打孔面应为含药层(白色对应面)小孔尺寸0.4～0.6mm得到依达拉奉缓释片。Step 5: The coated tablet obtained in step 4 is subjected to laser drilling, and the punched surface should be the drug-containing layer (white corresponding surface) with a small hole size of 0.4-0.6 mm to obtain Edaravone sustained-release tablets.
实施例5Example 5
Figure PCTCN2021114758-appb-000006
Figure PCTCN2021114758-appb-000006
Figure PCTCN2021114758-appb-000007
Figure PCTCN2021114758-appb-000007
制备工艺：Preparation Process:
步骤1：将上述处方中的依达拉奉和HPMCAS加入到溶剂中(甲醇：水＝9:1)，将样品置于恒温水浴锅中搅拌，设置加热温度50℃，进行溶解；Step 1: add Edaravone and HPMCAS in the above recipe into a solvent (methanol:water=9:1), place the sample in a constant temperature water bath and stir, set the heating temperature to 50°C, and dissolve;
步骤2：将步骤1中的溶液使用喷雾干燥机进行喷雾干燥，得依达拉奉固体分散体，将依达拉奉固体分散体过40目筛网；Step 2: The solution in step 1 is spray-dried with a spray dryer to obtain the edaravone solid dispersion, and the edaravone solid dispersion is passed through a 40-mesh sieve;
步骤3：将含药层的依达拉奉固体分散体、聚氧乙烯、羟丙甲纤维素、山梨醇、置于混合锅中，设置混合速度18r/min，混合20分钟；再加入含药层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到含药层混合物；Step 3: Place the edaravone solid dispersion, polyoxyethylene, hypromellose, sorbitol in the drug-containing layer in a mixing pot, set the mixing speed to 18r/min, and mix for 20 minutes; then add the drug-containing layer layer of magnesium stearate, set a mixing speed of 18r/min, and mix for 5 minutes to obtain a drug-containing layer mixture;
将上述处方中助推层的聚氧乙烯、氯化钠、氧化铁红置于混合锅中，设 置混合速度18r/min，混合10分钟；再加入助推层的硬脂酸镁，设置混合速度18r/min，混合5分钟，得到助推层混合物；Put the polyoxyethylene, sodium chloride and red iron oxide of the booster layer in the above-mentioned prescription in the mixing pot, set the mixing speed to 18r/min, and mix for 10 minutes; then add the magnesium stearate of the booster layer, and set the mixing speed 18r/min, mixing for 5 minutes to obtain a booster layer mixture;
步骤4：将步骤3得到的含药层混合物和助推层混合物置于旋转压片机上，调节设备参数，使含药层的片重为333mg，助推层的片重为167mg，总片重为500mg，硬度100N～180N的浅弧圆形含药片芯；Step 4: Place the drug-containing layer mixture and the booster layer mixture obtained in step 3 on a rotary tableting machine, and adjust the equipment parameters so that the tablet weight of the drug-containing layer is 333 mg, the tablet weight of the booster layer is 167 mg, and the total tablet weight is 500mg, shallow arc circular tablet core with hardness 100N～180N;
步骤5：根据以下步骤配制缓释包衣溶液：将95％乙醇加入烧杯中，使用磁力搅拌器进行搅拌，在搅拌过程中缓慢加入
Figure PCTCN2021114758-appb-000008
持续搅拌60分钟～120分钟使之完全溶解，得到缓释包衣溶液； Step 5: Prepare the sustained-release coating solution according to the following steps: add 95% ethanol to the beaker, stir with a magnetic stirrer, add slowly during stirring
Figure PCTCN2021114758-appb-000008
Continue stirring for 60 to 120 minutes to completely dissolve to obtain a sustained-release coating solution;
对步骤4得到的含药片芯用上述缓释包衣溶液进行包衣，包衣锅转速8rpm～15rpm，片床温度控制在25℃～35℃，喷液速度设定在5rpm～20rpm范围进行喷液，持续包衣使之包衣增重8.06％和8.12％停止喷液，再以片床温度30℃～35℃进行干燥5分钟～10分钟，出片；然后放置于设定温度45℃的鼓风干燥箱中，进行老化，24小时后得到包衣片；The drug-containing tablet cores obtained in step 4 are coated with the above-mentioned sustained-release coating solution, the rotating speed of the coating pan is 8 rpm to 15 rpm, the temperature of the tablet bed is controlled at 25 ° C to 35 ° C, and the spraying speed is set in the range of 5 rpm to 20 rpm for spraying. liquid, continue coating to make the coating weight gain 8.06% and 8.12%, stop spraying liquid, and then dry for 5 minutes to 10 minutes at a tablet bed temperature of 30 ° C ~ 35 ° C, and take out tablets; then place it in a set temperature of 45 ° C In a blast drying oven, aging is performed, and coated tablets are obtained after 24 hours;
步骤5：将步骤4得到的包衣片，进行激光打孔，打孔面应为含药层(白色对应面)小孔尺寸0.4～0.6mm得到依达拉奉缓释片。Step 5: The coated tablet obtained in step 4 is subjected to laser drilling, and the punched surface should be the drug-containing layer (white corresponding surface) with a small hole size of 0.4-0.6 mm to obtain Edaravone sustained-release tablets.
对以上所制得的依达拉奉缓释片进行释放度测定，所述释放度的测定方法如下：取缓释片剂(n＝12)，照中国药典2020版二部附录XC第二法，以pH6.8磷酸盐缓冲溶液900ml为溶出介质，转速为50r/min，于1，2，4，6，8，12，16，20，24小时取溶液1.5ml，经10μm的微孔滤膜滤过，采用高效液相(HPLC)方法检测药物累积释放度。溶出结果如下：The edaravone sustained-release tablet prepared above is subjected to release measurement, and the method for measuring the release is as follows: take the sustained-release tablet (n=12), according to the second method of the second appendix XC of the Chinese Pharmacopoeia 2020 edition , take 900ml of pH6.8 phosphate buffer solution as the dissolution medium, the speed is 50r/min, take 1.5ml of the solution at 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours, and filter it through a 10 μm microporous filter. Membrane filtration, using high performance liquid phase (HPLC) method to detect the cumulative drug release. The dissolution results are as follows:
Figure PCTCN2021114758-appb-000009
Figure PCTCN2021114758-appb-000009
Figure PCTCN2021114758-appb-000010
Figure PCTCN2021114758-appb-000010
实施例6Example 6
依达拉奉在各pH水溶液中的溶解度均较低，小于1mg/ml，生物利用度低，因此本实施例中使用了聚合物载体，将依达拉奉制备成固体分散体后，溶解度结果如下：The solubility of Edaravone in various pH aqueous solutions is low, less than 1 mg/ml, and the bioavailability is low. Therefore, a polymer carrier is used in this example. After Edaravone is prepared into a solid dispersion, the solubility results as follows:
样品sample 溶解度(mg/ml)Solubility (mg/ml)
依达拉奉Edaravone 0.400.40
依达拉奉：HPMCAS＝1:1(质量比)Edaravone: HPMCAS=1:1 (mass ratio) 2.482.48
依达拉奉：HPMCAS＝1:3(质量比)Edaravone: HPMCAS=1:3 (mass ratio) 6..286..28
依达拉奉：HPMCAS＝1:5(质量比)Edaravone: HPMCAS=1:5 (mass ratio) 10.2510.25
结果表明，依达拉奉与醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)制备成固体分散体后，其溶解度提高了6～25倍，因此本发明中将依达拉奉制备成无定形的固体分散体，有利于提高其溶解度，可提高生物利用度；制备成缓释剂型，可使体内血药浓度平稳，降低毒副作用。The results show that the solubility of edaravone and hypromellose acetate succinate (HPMCAS) is increased by 6 to 25 times after the solid dispersion is prepared. Therefore, in the present invention, edaravone is prepared as amorphous The solid dispersion is beneficial to improve its solubility and bioavailability; it is prepared into a sustained-release dosage form, which can stabilize the blood drug concentration in the body and reduce the toxic and side effects.

Claims (12)

  1. 一种药物组合物，所述药物组合物具有以下特征A)、B)和C)：A pharmaceutical composition having the following characteristics A), B) and C):
    A)在1小时内溶出不超过20％的药物活性成分；A) Dissolve no more than 20% of the active pharmaceutical ingredients within 1 hour;
    B)在6小时内溶出20％～60％的药物活性成分；B) Dissolve 20% to 60% of active pharmaceutical ingredients within 6 hours;
    C)在24小时内溶出不低于70％的药物活性成分；C) Dissolve not less than 70% of active pharmaceutical ingredients within 24 hours;
    其中，所述的药物活性成分可以选自依达拉奉、其药学上可接受的盐、水合物和溶剂合物中的一种或多种；Wherein, the pharmaceutical active ingredient can be selected from one or more of Edaravone, its pharmaceutically acceptable salts, hydrates and solvates;
    优选地，所述药物组合物具有以下特征A)、B)和C)：Preferably, the pharmaceutical composition has the following characteristics A), B) and C):
    A)在1小时内溶出不超过15％的药物活性成分；A) Dissolve no more than 15% of active pharmaceutical ingredients within 1 hour;
    B)在6小时内溶出20％～55％的药物活性成分；B) Dissolve 20% to 55% of active pharmaceutical ingredients within 6 hours;
    C)在24小时内溶出不低于75％的药物活性成分；C) Dissolve not less than 75% of active pharmaceutical ingredients within 24 hours;
    更优选地，所述药物组合物具有以下特征A)、B)和C)：More preferably, the pharmaceutical composition has the following characteristics A), B) and C):
    A)在1小时内溶出不超过15％的药物活性成分；A) Dissolve no more than 15% of active pharmaceutical ingredients within 1 hour;
    B)在6小时内溶出25％～55％的药物活性成分；B) Dissolve 25% to 55% of active pharmaceutical ingredients within 6 hours;
    C)在24小时内溶出不低于80％的药物活性成分。C) Dissolve not less than 80% of the active pharmaceutical ingredients within 24 hours.
  2. 一种药物组合物，其特征在于：所述药物组合物包括片芯和包衣；所述的片芯包括含药层片芯和/或助推层片芯；A pharmaceutical composition, characterized in that: the pharmaceutical composition comprises a tablet core and a coating; the tablet core comprises a drug-containing layer tablet core and/or a booster layer tablet core;
    其中，所述的含药层片芯包含依达拉奉药物活性成分以及载体；Wherein, the described drug-containing layer tablet core comprises edaravone pharmaceutical active ingredient and carrier;
    所述的载体为聚合物载体、渗透压调节剂、溶胀剂、增稠剂和润滑剂中的一种或多种；The carrier is one or more of a polymer carrier, an osmotic pressure regulator, a swelling agent, a thickener and a lubricant;
    所述的助推层片芯包括渗透压调节剂、溶胀剂、着色剂和润滑剂中的一种或多种；The booster layer core comprises one or more of an osmotic pressure regulator, a swelling agent, a colorant and a lubricant;
    所述的依达拉奉药物活性成分选自依达拉奉、其药学上可接受的盐、水合物和溶剂合物中的一种或多种；The Edaravone pharmaceutical active ingredient is selected from one or more of Edaravone, its pharmaceutically acceptable salts, hydrates and solvates;
    优选地，所述药物组合物具有如权利要求1限定的特征A)、B)和C)的组合中的一种。Preferably, the pharmaceutical composition has one of the combinations of features A), B) and C) as defined in claim 1 .
  3. 如权利要求2所述的药物组合物，其特征在于：所述的包衣不可渗透除水以外的物质；The pharmaceutical composition of claim 2, wherein the coating is impermeable to substances other than water;
    优选地，所述的包衣表面没有或含有一个或多个能穿过所述的包衣的开口形式。Preferably, the coating surface is free of or contains one or more openings through which the coating can pass.
  4. 如权利要求3所述的药物组合物，其特征在于：The pharmaceutical composition of claim 3, wherein:
    所述的含药层片芯中，所述的聚合物载体选自聚乙二醇、共聚维酮、羟丙甲纤维素、醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素邻苯二甲酸酯、聚醋酸乙烯酯聚维酮混合物、泊洛沙姆和羧甲基乙基纤维素中的一种或多种；In the described drug-containing layer tablet core, the polymer carrier is selected from polyethylene glycol, copovidone, hypromellose, hypromellose acetate succinate, and hypromellose o-phthalate. One or more of diformate, polyvinyl acetate-povidone mixture, poloxamer and carboxymethyl ethyl cellulose;
    和/或，and / or,
    所述的含药层片芯中，所述的溶胀剂选自聚氧乙烯、卡波姆、羧甲淀粉钠、交联聚维酮、羟丙甲基纤维素、阿拉伯胶、聚乙烯吡咯烷酮和海藻酸钠中的一种或多种；In the drug-containing layer tablet core, the swelling agent is selected from polyoxyethylene, carbomer, sodium starch glycolate, crospovidone, hydroxypropyl methylcellulose, gum arabic, polyvinylpyrrolidone and one or more of sodium alginate;
    和/或，and / or,
    所述的含药层片芯中，所述的渗透压调节剂选自氯化钠、氯化钾、甘露醇、山梨醇、硫酸钠、硫酸镁、葡萄糖、果糖、蔗糖和乳糖中的一种或多种；In the described drug-containing layer tablet core, the osmotic pressure regulator is selected from a kind of sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose and lactose or more;
    和/或，所述的含药层片芯中，所述的增稠剂选自羟丙甲基纤维素、羟丙纤维素、羟乙基纤维素、乙基纤维素、共聚维酮、阿拉伯胶、预胶化淀粉和聚乙烯吡咯烷酮中的一种或多种；And/or, in the described drug-containing layer core, the thickening agent is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, copovidone, Arabidopsis One or more of glue, pregelatinized starch and polyvinylpyrrolidone;
    和/或，and / or,
    所述的含药层片芯中，所述的润滑剂选自硬脂酸金属盐、硬脂酸、滑石粉和硬脂酸酯和微粉硅胶中的一种或多种。In the drug-containing layer tablet core, the lubricant is selected from one or more of metal stearate, stearic acid, talc and stearate, and micropowder silica gel.
  5. 如权利要求4所述的药物组合物，其特征在于：The pharmaceutical composition of claim 4, wherein:
    所述的含药层片芯中，所述的依达拉奉药物活性成分的含量为5.0％～ 60.0％，所述的含量是指以依达拉奉计，依达拉奉药物活性成分的重量占含药层片芯总重量的百分比；In the drug-containing layer tablet core, the content of the edaravone pharmaceutical active ingredient is 5.0% to 60.0%, and the content refers to the amount of the edaravone pharmaceutical active ingredient in terms of edaravone. Weight as a percentage of the total weight of the drug-containing layer tablet core;
    和/或，and / or,
    所述的含药层片芯中，所述的聚合物载体的含量为5.0％～60.0％，所述的含量是指聚合物载体的重量占含药层片芯总重量的百分比；In the drug-containing layer tablet core, the content of the polymer carrier is 5.0% to 60.0%, and the content refers to the percentage of the weight of the polymer carrier to the total weight of the drug-containing layer tablet core;
    和/或，and / or,
    所述的含药层片芯中，所述的溶胀剂的含量为10.0％～50.0％，所述的含量是指溶胀剂的重量占含药层片芯总重量的百分比；In the drug-containing layer tablet core, the content of the swelling agent is 10.0% to 50.0%, and the content refers to the percentage of the weight of the swelling agent to the total weight of the drug-containing layer tablet core;
    和/或，and / or,
    所述的含药层片芯中，所述的渗透压调节剂的含量为0％～50.0％，所述的含量是指渗透压调节剂的重量占含药层片芯总重量的百分比；In the drug-containing layer tablet core, the content of the osmotic pressure regulator is 0% to 50.0%, and the content refers to the percentage of the weight of the osmotic pressure regulator to the total weight of the drug-containing layer tablet core;
    和/或，and / or,
    所述的含药层片芯中，所述的增稠剂的含量为0％～40.0％，所述的含量是指增稠剂的重量占含药层片芯总重量的百分比；In the drug-containing layer tablet core, the content of the thickener is 0% to 40.0%, and the content refers to the percentage of the weight of the thickener in the total weight of the drug-containing layer tablet core;
    和/或，and / or,
    所述的含药层片芯中，所述的润滑剂的含量为0.1％～3.0％，所述的含量是指润滑剂的重量占含药层片芯总重量的百分比。In the drug-containing layer 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 drug-containing layer tablet core.
  6. 如权利要求5所述的药物组合物，其特征在于：The pharmaceutical composition of claim 5, wherein:
    所述的含药层片芯包括以下组分：5.0％～60.0％的依达拉奉药物活性成分，5.0％～60.0％的聚合物载体，10.0％～50.0％的溶胀剂，10.0％～40.0％的增稠剂，0％～50.0％的渗透压调节剂，0.1％～3.0％的润滑剂；所述的百分比是指各组分占含药层片芯总重量的百分比；The drug-containing layer tablet core comprises the following components: 5.0%-60.0% of edaravone pharmaceutical active ingredient, 5.0%-60.0% of polymer carrier, 10.0%-50.0% of swelling agent, 10.0%-40.0% % of thickener, 0% to 50.0% of osmotic pressure regulator, and 0.1% to 3.0% of lubricant; the percentages refer to the percentage of each component in the total weight of the drug-containing layer tablet core;
    优选地，所述的含药层片芯选自具有以下重量百分比的任一组分：Preferably, the drug-containing layer tablet core is selected from any of the following components by weight:
    组分一：20.00％依达拉奉药物活性成分，20.00％醋酸羟丙甲纤维素琥珀酸酯，20.00％山梨醇，10.00％氯化钠，10.00％羟丙甲纤维素，10.00％共聚维酮，9.00％交联聚维酮，1.00％硬脂酸镁；Component 1: 20.00% edaravone active ingredient, 20.00% hypromellose acetate succinate, 20.00% sorbitol, 10.00% sodium chloride, 10.00% hypromellose, 10.00% copovidone , 9.00% crospovidone, 1.00% magnesium stearate;
    组分二：20.00％依达拉奉药物活性成分，20.00％醋酸羟丙甲纤维素琥珀酸酯，40.00％山梨醇，10.00％氯化钠，4.00％羟丙甲纤维素，5.00％共聚维酮，1.00％硬脂酸镁；Component 2: 20.00% edaravone active ingredient, 20.00% hypromellose acetate succinate, 40.00% sorbitol, 10.00% sodium chloride, 4.00% hypromellose, 5.00% copovidone , 1.00% magnesium stearate;
    组分三：30.03％依达拉奉药物活性成分，30.03％醋酸羟丙甲纤维素琥珀酸酯，27.02％聚乙烯吡咯烷酮，6.01％甘露醇，6.01％氯化钠，0.90％硬脂酸镁；Component 3: 30.03% edaravone active ingredient, 30.03% hypromellose acetate succinate, 27.02% polyvinylpyrrolidone, 6.01% mannitol, 6.01% sodium chloride, 0.90% magnesium stearate;
    组分四：30.03％依达拉奉药物活性成分，30.03％醋酸羟丙甲纤维素琥珀酸酯，30.03％海藻酸钠，9.02％氯化钠，0.90％硬脂酸镁；Component four: 30.03% edaravone active ingredient, 30.03% hypromellose acetate succinate, 30.03% sodium alginate, 9.02% sodium chloride, 0.90% magnesium stearate;
    组分五：30.03％依达拉奉药物活性成分，30.03％醋酸羟丙甲纤维素琥珀酸酯，18.02％聚氧乙烯，6.01％羟丙甲纤维素，15.01％山梨醇，0.90％硬脂酸镁；所述的百分比是指各组分占含药层片芯总重量的百分比。Component five: 30.03% edaravone active pharmaceutical ingredients, 30.03% hypromellose acetate succinate, 18.02% polyoxyethylene, 6.01% hypromellose, 15.01% sorbitol, 0.90% stearic acid Magnesium; the stated percentage refers to the percentage of each component in the total weight of the drug-containing layer tablet core.
  7. 如权利要求2所述的药物组合物，其特征在于：The pharmaceutical composition of claim 2, wherein:
    所述的助推层片芯中，所述的渗透压调节剂选自氯化钠、氯化钾、甘露醇、山梨醇、硫酸钠、硫酸镁、葡萄糖、果糖、蔗糖和乳糖中的一种或多种；In the described booster layer tablet core, the osmotic pressure regulator is selected from a kind of sodium chloride, potassium chloride, mannitol, sorbitol, sodium sulfate, magnesium sulfate, glucose, fructose, sucrose and lactose or more;
    和/或，and / or,
    所述的助推层片芯中，所述的溶胀剂选自聚乙烯吡咯烷酮、羟丙甲基纤维素、阿拉伯胶、羟乙基纤维素、卡波姆、羧甲淀粉钠、共聚维酮、海藻酸钠和聚氧乙烯中的一种或多种；In the core of the booster layer, the swelling agent is selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, acacia, hydroxyethylcellulose, carbomer, sodium starch glycolate, copovidone, One or more of sodium alginate and polyoxyethylene;
    和/或，and / or,
    所述的助推层片芯中，所述的着色剂选自氧化铁红、氧化铁黄和氧化铁黑中的一种或多种；In the core of the booster layer, the colorant is selected from one or more of red iron oxide, yellow iron oxide and black iron oxide;
    和/或，and / or,
    所述的助推层片芯中，所述的润滑剂选自硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯和微粉硅胶中的一种或多种；In the described booster layer tablet core, the lubricant is selected from one or more of stearic acid metal salt, stearic acid, talc, stearate and micropowder silica gel;
    优选地，所述的渗透压调节剂的含量为0％～50.0％，所述的含量是指 渗透压调节剂的重量占助推层片芯总重量的百分比；Preferably, the content of the osmotic pressure regulator is 0% to 50.0%, and the content refers to the percentage of the weight of the osmotic pressure regulator to the total weight of the booster layer core;
    和/或，and / or,
    所述的溶胀剂的含量为40.0％～90.0％，所述的含量是指溶胀剂的重量占助推层片芯总重量的百分比；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 layer tablet core;
    和/或，and / or,
    所述的着色剂的含量为0.5％～3.0％，所述的含量是指着色剂的重量占助推层片芯总重量的百分比；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 layer core;
    和/或，and / or,
    所述的润滑剂的含量为0.5％～3.0％，所述的含量是指润滑剂的重量占助推层片芯总重量的百分比。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 layer core.
  8. 如权利要求2所述的药物组合物，其特征在于：The pharmaceutical composition of claim 2, wherein:
    所述的助推层片芯包括以下组分：0％～50.0％的渗透压调节剂，40.0％～90.0％的溶胀剂，0.5％～3.0％的着色剂和0.5％～3.0％的润滑剂，其中所述的百分比是指各组分的重量占助推层片芯总重量的百分比；The booster layer core comprises the following components: 0%-50.0% of osmotic pressure regulator, 40.0%-90.0% of swelling agent, 0.5%-3.0% of colorant and 0.5%-3.0% of lubricant , wherein the percentage refers to the percentage of the weight of each component in the total weight of the booster layer core;
    优选地，所述的助推层片芯选自具有以下重量百分比的任一组分：Preferably, the booster layer core is selected from any of the following components by weight:
    组分一：73.65％聚氧乙烯，23.95％氯化钠，1.20％氧化铁红，1.20％硬脂酸镁；Component 1: 73.65% polyoxyethylene, 23.95% sodium chloride, 1.20% red iron oxide, 1.20% magnesium stearate;
    组分二：73.65％聚氧乙烯，11.98％氯化钠，11.97％山梨醇，1.20％氧化铁红，1.20％硬脂酸镁；Component 2: 73.65% polyoxyethylene, 11.98% sodium chloride, 11.97% sorbitol, 1.20% red iron oxide, 1.20% magnesium stearate;
    组分三：64.67％聚氧乙烯，32.93％氯化钠，1.20％氧化铁红，1.20％硬脂酸镁。Component three: 64.67% polyoxyethylene, 32.93% sodium chloride, 1.20% red iron oxide, 1.20% magnesium stearate.
  9. 如权利要求2所述的药物组合物，其特征在于：所述的包衣材料为半透膜材料；The pharmaceutical composition of claim 2, wherein the coating material is a semipermeable membrane material;
    优选地，所述的半透膜材料包括成膜材料、增塑剂和致孔剂中的一种或多种；Preferably, the semipermeable membrane material includes one or more of a film-forming material, a plasticizer and a porogen;
    优选地，所述的成膜材料为醋酸纤维素、乙基纤维素、邻苯二甲酸醋酸纤维素和(甲基)丙烯酸树脂中的一种或多种；Preferably, the film-forming material is one or more of cellulose acetate, ethyl cellulose, cellulose acetate phthalate and (meth)acrylic resin;
    和/或，and / or,
    所述的增塑剂选自聚乙二醇、三醋酸甘油酯、柠檬酸甘油酯、甘油酯和邻苯二甲酸酯中的一种或多种；Described plasticizer is selected from one or more in polyethylene glycol, triacetin, citric acid glyceride, glyceride and phthalate;
    和/或，and / or,
    所述的致孔剂选自聚乙二醇和/或羟丙基纤维素。The porogen is selected from polyethylene glycol and/or hydroxypropyl cellulose.
    更优选地，所述的成膜材料的含量为5.0％～15.0％，所述的百分比是指成膜材料的重量占药片片芯总重量的百分比；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;
    和/或，and / or,
    所述的增塑剂的含量为0％～5.0％，所述的百分比是指增塑剂的重量占药片片芯总重量的百分比；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;
    和/或，and / or,
    所述的致孔剂的含量为0.1％～15.0％，所述的百分比是指致孔剂的重量占药片片芯总重量的百分比；The content of the porogen is 0.1% to 15.0%, and the percentage refers to the percentage of the weight of the porogen to the total weight of the tablet core;
    更优选地，所述的半透膜材料包括以下组分：5.0％～15.0％的成膜材料、0％～5.0％的增塑剂和0.1％～15.0％的致孔剂；More preferably, the semipermeable membrane material comprises the following components: 5.0%-15.0% of film-forming material, 0%-5.0% of plasticizer and 0.1%-15.0% of porogen;
    更优选地，所述的半透膜材料选自具有如下百分比的任一组分：More preferably, the semipermeable membrane material is selected from any component with the following percentages:
    包衣一：9.00％醋酸纤维素和1.00％聚乙二醇，所述的百分比是指各组分的质量占药片片芯总质量的百分比；Coating 1: 9.00% cellulose acetate and 1.00% polyethylene glycol, the percentage refers to the percentage of the mass of each component in the total mass of the tablet core;
    包衣二：7.20％醋酸纤维素和0.80％聚乙二醇4000，所述的百分比是指各组分的质量占药片片芯总质量的百分比。Coating II: 7.20% cellulose acetate and 0.80% polyethylene glycol 4000, the percentages refer to the percentage of the mass of each component in the total mass of the tablet core.
  10. 一种依达拉奉药物活性成分分散体，包括分散于聚合物载体中的依达拉奉药物活性成分；An edaravone pharmaceutical active ingredient dispersion, comprising the edaravone pharmaceutical active ingredient dispersed in a polymer carrier;
    优选地，所述的聚合物载体选自聚乙二醇、共聚维酮、羟丙甲纤维素、醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素邻苯二甲酸酯、聚醋酸乙 烯酯聚维酮混合物、泊洛沙姆和羧甲基乙基纤维素中的一种或多种；Preferably, the polymer carrier is selected from polyethylene glycol, copovidone, hypromellose, hypromellose acetate succinate, hypromellose phthalate, polyacetate One or more of vinyl ester povidone mixture, poloxamer and carboxymethyl ethyl cellulose;
    优选地，在所述依达拉奉药物活性成分分散体中，依达拉奉药物活性成分与聚合物载体的质量比可以为1:1或更低，例如1:2、1:3、1:4、1:5、1:6或更低。Preferably, in the edaravone active pharmaceutical ingredient dispersion, the mass ratio of the active pharmaceutical ingredient of edaravone to the polymer carrier may be 1:1 or lower, such as 1:2, 1:3, 1 :4, 1:5, 1:6 or lower.
  11. 如权利要求1-9任一项所述的药物组合物的制备方法，其特征在于：所述的药物组合物的制备方法为直接压片法、湿法制粒法或干法制粒法。The preparation method of the pharmaceutical composition according to any one of claims 1-9, wherein the preparation method of the pharmaceutical composition is a direct compression method, a wet granulation method or a dry granulation method.
  12. 如权利要求1-9任一项所述的药物组合物或权利要求10所述的分散体在制备治疗和/或预防氧化性应激相关疾病的药物中的应用；Use of the pharmaceutical composition according to any one of claims 1-9 or the dispersion according to claim 10 in the preparation of a medicament for the treatment and/or prevention of oxidative stress-related diseases;
    优选地，所述的氧化性应激相关疾病选自老年痴呆症、肌萎缩侧索硬化症、帕金森氏病、缺血性心脏病、脑梗/中风、血栓性静脉炎、慢性阻塞性肺疾病、人类免疫系统病/获得性免疫系统综合症和糖尿病。Preferably, the oxidative stress-related disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, ischemic heart disease, cerebral infarction/stroke, thrombophlebitis, chronic obstructive pulmonary disease Diseases, Human Immune System Disorders/Acquired Immune System Syndrome and Diabetes.
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WANG , RUYI; LIU, YI: "Application of Hydroxypropyl Methylcellulose Acetate Succinate to Preparation of Solid Dispersions", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 47, no. 1, 31 December 2016 (2016-12-31), CN , pages 111 - 116, XP009522381, ISSN: 1001-8255, DOI: 10.16522/j.cnki.cjph.2016.01.024 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114767872A (en) * 2022-03-21 2022-07-22 则正(上海)生物科技有限公司 Application of polacrilin potassium in preparation of osmotic pump boosting layer, nifedipine osmotic pump tablet and preparation method
CN114767872B (en) * 2022-03-21 2023-08-22 则正(上海)生物科技有限公司 Application of polacrilin potassium in preparation of osmotic pump boosting layer, nifedipine osmotic pump tablet and preparation method

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