Edaravone Oral Film-Release Formulations, Their Formulations and Uses

Abstract

This invention discloses an edaravone membrane-release formulation composition comprising edaravone or a pharmaceutically acceptable salt thereof, a prodrug, a metabolite, a solvate, crystals, or a deuterated derivative, and excipients. Based on the weight of the composition, the weight percentage of the edaravone or its pharmaceutically acceptable salt, prodrug, metabolite, solvate, crystals, or deuterated derivative is 1%-60%. The edaravone oral membrane-release formulation of this invention is for sublingual administration and features rapid disintegration and a pleasant taste.

Description

[Technical Field]

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to edaravone oral film-dissolving immediate-release preparations, their preparation methods, formulations, and uses. [Previous Technology]

[0002] Edaravone (chemical name: 3-methyl-1-phenyl-2-pyrazolin-5-one) is a marketed neuroprotective agent (Yakugaku Zasshi. 2004, 124 (3): 99-111). Studies have shown that edaravone has antioxidant activity, can significantly improve neurological deficit symptoms in animals with cerebral ischemia-reperfusion injury, reduce infarct area, reduce the degree of brain injury, alleviate cerebral edema, and inhibit lipid peroxidation in damaged brain tissue.

[0003] Cerebrovascular diseases, especially ischemic cerebrovascular diseases, are acute illnesses that require rapid relief of symptoms. Therefore, injection is the preferred method of emergency treatment. However, intramuscular or intravenous injections can cause pain and irritation at the injection site, require professional medical personnel to perform, and necessitate injection supplies. Their application is subject to certain medical limitations and is not suitable for patients who develop the disease outside of a hospital.

[0004] Sublingual orally dissolving films are absorbed directly through the sublingual mucosa. The sublingual mucosa has a large surface area and strong permeability, and numerous capillaries converge there, leading to the internal jugular vein and then directly into the bloodstream via the superior vena cava. This results in rapid drug absorption, fast onset of action, accurate dosing, and convenient use, avoiding the first-pass effect of oral medications. Compared to injections, sublingual orally dissolving films significantly improve the convenience of medication administration and patient compliance. For patients with amyotrophic lateral sclerosis (ALS), stroke, or other conditions involving dysphagia and lack of self-medication, orally dissolving films offer a significant advantage in medication compliance compared to ordinary tablets. [Summary of the Invention]

[0005] The object of one or more embodiments of the present invention includes providing an edaravone immediate-release sublingual oral film comprising the active ingredient edaravone or its salts and excipients, which disintegrates rapidly, shortens the onset time of edaravone, has a good taste, is convenient to use, effectively improves medication compliance in the elderly and other patients with difficulty swallowing, and enhances medication privacy for adults.

[0006] One or more embodiments of the present invention provide an edaravone oral film-dissolving immediate-release formulation composition comprising edaravone or a pharmaceutically acceptable salt thereof, a prodrug, a metabolite, a solvate, crystals, or a deuterated form thereof, and excipients, wherein the weight percentage of the edaravone or a pharmaceutically acceptable salt thereof, a prodrug, a metabolite, a solvate, crystals, or a deuterated form thereof is 1%–60% (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%) based on the weight of the composition; the excipients comprise film-forming materials and flavoring agents.

[0007] In one or more embodiments, based on the weight of the composition, the film-forming material is 1%-50% by weight (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%), and the flavoring agent is 1%-10% by weight (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%).

[0008] In one or more embodiments, the excipients further comprise thickeners and / or plasticizers.

[0009] In one or more embodiments, the thickener is present in a weight percentage of 0%-20% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%) and the plasticizer is present in a weight percentage of 0%-15% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%), based on the weight of the composition.

[0010] In one or more embodiments, the film-forming material is one or more of HPMC (hydroxypropyl methylcellulose), Kollicoat® IR, hydroxypropyl cellulose, gelatin, pullulan, polyvinyl alcohol, sodium alginate, gum arabic, povidone, acrylic acid copolymer, hydroxypropyl cellulose, polyoxyethylene, shellac, starch, agar, corn gluten, polylactic acid, and silicone rubber.

[0011] In one or more embodiments, the film-forming material is HPMC, Kollicoat® IR, hydroxypropyl cellulose, pullulan, polyoxyethylene, or polyvinyl alcohol.

[0012] In one or more embodiments, the HPMC is HPMC E30, HPMC E15, or HPMC E5.

[0013] In one or more embodiments, the thickener is one or more of Kollicoat® MAE 30DP, xanthan gum, sodium carboxymethyl cellulose, PVP (polyvinylpyrrolidone), tragacanth gum, gum arabic, carbomer, carrageenan, guar gum, agar, methylcellulose, ethylcellulose, polyoxyethylene, and polyacrylic acid.

[0014] In one or more embodiments, the thickener is Kollicoat® MAE 30DP, PVP, xanthan gum, or sodium carboxymethyl cellulose.

[0015] In one or more embodiments, the plasticizer is one or more of glycerol, polyethylene glycol or triethyl citrate.

[0016] In one or more embodiments, the plasticizer is glycerin.

[0017] In one or more embodiments, the flavoring agent is one or more of neotame, aspartame, sucralose, cyclamate, sucrose, mannitol, xylitol, sorbitol, steviol glycoside, syrup, flavoring, sodium saccharin, acesulfame potassium, citric acid, malic acid, lactic acid, and tartaric acid.

[0018] In one or more embodiments, the flavoring agent is sucrose, mannitol, neotame, aspartame, sodium saccharin, sucralose, acesulfame potassium, or flavoring.

[0019] In one or more embodiments, the flavoring is one or more of banana flavoring, lemon flavoring, sweet orange flavoring, tangerine flavoring, and strawberry flavoring.

[0020] One or more embodiments of the present invention provide an edaravone oral film-dissolving formulation prepared from the edaravone oral film-dissolving immediate-release formulation composition of the present invention.

[0021] In one or more embodiments, the oral film thickness formed by the edaravone oral film formulation is 20-100 micrometers (e.g., 30, 40, 50, 60, 70, 80, 90, 100 micrometers).

[0022] In one or more embodiments, the edaravone oral lysine film disintegrates in 10-60 s (e.g., 20, 30, 40, 50 s).

[0023] In one or more embodiments, the edaravone oral lysine film disintegrates in 2-30 s (e.g., 10 s, 20 s).

[0024] One or more embodiments of the present invention provide a method for preparing an edaravone oral dissolving film formulation, comprising the following steps:

[0025] (1) Weigh the film-forming materials and flavoring agents of the weight percentage and type described above, as well as optional thickeners and / or plasticizers;

[0026] (2) Add the film-forming material and flavoring agent weighed in step (1) and optional thickener and / or plasticizer to water and stir to dissolve;

[0027] (3)Weigh out the weight percentage of edaravone or its pharmaceutically acceptable salt, prodrug, metabolite, solvate, crystal or deuterated product as described above and add it to the solution obtained in step (2), and continue stirring to disperse it evenly to obtain a gel.

[0028] (4) Stir the adhesive solution at low speed for several hours (1~10 h) to remove bubbles;

[0029] (5) Pour the adhesive liquid onto the release film and coat it;

[0030] (6) Dry the coated release film at 40-60°C (e.g., 50°C);

[0031] (7) Cut the film and repackage it.

[0032] In one or more embodiments, in step (3), the temperature is raised to 50-70°C, for example 60°C.

[0033] In one or more embodiments, in step (4), the stirring rate is 100 rpm.

[0034] In one or more embodiments, in step (5), the coating temperature is 25°C-50°C (e.g., 30, 40, 45°C) and the coating speed is 10-20 mm / s (e.g., 15 mm / s).

[0035] In one or more embodiments, in step (6), drying is performed at 50°C.

[0036] One or more embodiments of the present invention provide a kit comprising the edaravone oral dissolving formulation of the present invention.

[0037] In one or more embodiments, the kit packaging is printed with a dosage scale for accurately dispensing the appropriate dose according to the patient's weight.

[0038] One or more embodiments of the present invention provide the use of the edaravone oral film-dissolving immediate-release formulation composition of the present invention, the edaravone oral film-dissolving formulation of the present invention, or the kit of the present invention in the preparation of a medicament for the treatment and / or prevention of amyotrophic lateral sclerosis, Alzheimer's disease, stroke, neurological deficits, cerebral infarction, and cerebral edema.

[0039] One or more embodiments of the present invention provide the edaravone oral film-dissolving immediate-release formulation composition of the present invention, the edaravone oral film-dissolving formulation of the present invention, or the kit of the present invention, which are used as pharmaceuticals.

[0040] One or more embodiments of the present invention provide the edaravone oral film-dissolving immediate-release formulation composition of the present invention, the edaravone oral film-dissolving formulation of the present invention, or the kit of the present invention for the treatment and / or prevention of amyotrophic lateral sclerosis, Alzheimer's disease, stroke, neurological defects, cerebral infarction, and cerebral edema.

[0041] One or more embodiments of the present invention provide a method for treating and / or preventing amyotrophic lateral sclerosis, Alzheimer's disease, stroke, neurological deficits, cerebral infarction, and cerebral edema, comprising administering a therapeutically effective amount of the edaravone oral film-dissolving immediate-release formulation composition of the present invention or the edaravone oral film-dissolving formulation of the present invention to an object in need.

[0042] One or more embodiments of the present invention provide an edaravone oral lysate composition, a method for its preparation, and its application.

[0043] One or more embodiments of the present invention provide an edaravone oral film composition comprising one or more of edaravone or a pharmaceutically acceptable salt thereof, a film-forming material, a thickener, a plasticizer, and a flavoring agent.

[0044] The edaravone oral dissolving film composition provided by the present invention has precise dosage marking, fast dissolution rate, no gritty feeling after dissolving in the oral cavity, uniform appearance, good flexibility, good taste masking effect, and no need for water to take the medicine, which is convenient for elderly people, children and other patients with difficulty swallowing or special circumstances, and improves the privacy of adult medication. At the same time, no sedimentation occurs during the preparation of the film solution, and the content uniformity meets the requirements.

[0045] The present invention also includes a method for preparing an edaravone immediate-release oral lysine film, which is simple, easy to control, low in cost, environmentally friendly, and suitable for large-scale industrial production.

[0046] To achieve at least one of the above objectives, the present invention adopts the following technical solution:

[0047] In a first aspect, the present invention provides an edaravone immediate-release oral dissolving film, comprising the active ingredient edaravone or its salt and excipients, wherein the excipients include film-forming materials, thickeners, plasticizers, and / or flavoring agents.

[0048] More preferably, the active ingredient in the oral lysate is 1-60% by weight, and more preferably, the oral lysate is 10-35% by weight.

[0049] More preferably, the content of film-forming material is 1-50% based on the weight of oral soluble film, the content of thickener is 1-20% based on the weight of oral soluble film, the content of plasticizer is 1-15% based on the weight of oral soluble film, and the content of flavoring agent is 1-10% based on the weight of oral soluble film.

[0050] More preferably, the film-forming material is selected from one or more of HPMC, gelatin, pullulan, polyvinyl alcohol, sodium alginate, gum arabic, povidone, shellac, starch, agar, corn gluten, hydroxypropyl cellulose, polyoxyethylene, acrylic acid copolymer, polylactic acid, and silicone rubber, preferably one or more of HPMC, Kollicoat® IR, polyvinyl alcohol, and polyoxyethylene.

[0051] More preferably, the thickener is selected from xanthan gum, sodium carboxymethyl cellulose, tragacanth gum, gum arabic, sodium alginate, povidone, carbomer, carrageenan, guar gum, agar, methylcellulose, ethylcellulose, hydroxypropyl cellulose, polyoxyethylene, polyacrylic acid, etc., and is preferably xanthan gum, sodium carboxymethyl cellulose, and gum arabic.

[0052] More preferably, the plasticizer is selected from glycerin and polyethylene glycol.

[0053] More preferably, the flavoring agent is selected from any one or more of neotame, aspartame, sucralose, cyclamate, sucrose, mannitol, xylitol, sorbitol, steviol glycoside, syrup, flavoring, sodium saccharin, and acesulfame potassium, and is preferably selected from any one or more of sucrose, mannitol, neotame, aspartame, sucralose, acesulfame potassium, and flavoring; the flavoring is selected from any one or more of apple flavoring, banana flavoring, sweet orange flavoring, citrus flavoring, and strawberry flavoring.

[0054] The oral dissolving agent of the present invention can be prepared by coating method.

[0055] In another aspect of the present invention, a method for preparing an edaravone oral dissolving film comprising the active ingredient edaravone or its salt and excipients is provided, specifically prepared according to the following steps:

[0056] 1. Weigh the prescribed amounts of active ingredients, thickeners, plasticizers, and flavoring agents;

[0057] 2. Add the above excipients to the prescribed amount of water and stir to dissolve;

[0058] 3. Weigh the prescribed amount of film-forming material and add it to the above solution, continue stirring to disperse it evenly;

[0059] 4. Stir the obtained adhesive solution at low speed to remove bubbles;

[0060] 5. Pour the adhesive solution onto the release film and apply it;

[0061] 6. After coating, the release film is dried at 50°C;

[0062] 7. Cutting and packaging.

[0063] In one or more embodiments, the edaravone oral lysate is available in, for example, 10 mg, 20 mg, or 30 mg.

[0064] Calculate the precise dosage based on body weight, cut out a film of the precise dosage from the oral dissolution film according to the scale lines, place it under the tongue, and release the drug rapidly in the oral cavity without the need for water.

[0065] By using the above technical solutions, the film thickness and disintegration time of the edaravone immediate-release oral dissolving film are limited, and the present invention has at least one of the following beneficial effects:

[0066] 1. The instant-release oral lysine film of the present invention, through its formulation design, has a film thickness of less than 100 micrometers, ensuring that the film has no gritty feeling in the oral cavity.

[0067] 2. The disintegration time in the oral cavity is within 60s (e.g., 40s). The preparation process of the optimized formula is simple, the production cost is low, and it is suitable for large-scale industrial production.

[0068] 3. According to experimental results, the edaravone immediate-release formulation provided by the present invention has a good taste, masks the unpleasant taste of edaravone, and the dosage is easy to control, making it convenient for elderly patients or patients with difficulty swallowing in special circumstances to use.

[0069] Therefore, the present invention provides an edaravone immediate-release formulation that meets various needs.

Implementation Method

[0071] The present invention will be further described below with reference to the embodiments. The following description is only for explaining the present invention and does not limit its content in any way.

[0072] Unless otherwise specified in the examples, the conditions shall be performed according to conventional conditions or the manufacturer's recommendations. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0073] The following is a detailed description of the edaravone oral lysate and its preparation method according to embodiments of the present invention.

[0074] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0075] Examples 1-5

[0076] With Kollicoat-IR as the film-forming material and gum arabic, xanthan gum, sodium alginate, carbomer, and carboxymethyl cellulose (CM-cellulose) as thickeners, the formulation was optimized with an edaravone loading (loading = quality of edaravone / total weight after film formation × 100%) of 30%. Kollicoat-IR showed excellent film-forming effect (Table 1).

[0077] Table 1 Optimization of Edaravone Prescription Element Example 1 Example 2 Example 3 Example 4 Example 5 Edaravone (mg) 450 450 450 450 450 Kollicoat-IR (mg) 1000 1000 1000 1000 1000 Gum arabic (mg) 25 — — — — Xanthan gum (mg) — 25 — — — Sodium alginate (mg) — — 25 — — Carbomer (mg) — — — — 25 CM-cellulose (mg) — — — 25 — Water (mL) 5.0 5.0 5.0 5.0 5.0 Drug loading (%) 30.5% 30.5% 30.5% 30.5% 30.5% Film thickness (um) 70±5 67±7 60±5 65±6 68±7 Mechanical strength good good good good good friability good good good good good Difficulty of membrane peeling easy easy easy easy easy Disintegration time (s) 50±8 48±7 52±6 51±7 57±6

[0078] Examples 6-12

[0079] Using HPMC, Kollicoat-IR, polyethylene oxide, polyvinyl alcohol, etc. as film-forming materials, good film-forming effects can be achieved with the assistance of appropriate thickeners or plasticizers (Table 2).

[0080] Table 2 Optimization of Edaravone Prescription Element Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 HPMC E15 (mg) — 600 750 — — — — Edaravone (mg) 450 450 450 450 450 450 450 Kollicoat-IR (mg) 1000 — — — — — — Polyvinyl alcohol (mg) — — — 1000 — — — PVP-30 (mg) — 400 — — — — — Glycerin (mg) — 100 100 — — 120 — Polyoxyethylene (mg) — — — — 600 600 600 Gelatin (mg) 25 — — — 60 — — Pullulan (mg) — — 75 — — — — Xanthan gum (mg) — — — — — — 25 Water (mL) 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Drug loading (%) 30.5% 29% 32.7% 31% 40.5% 38.5% 41.9% Film thickness (um) 70±6 72±5 65±7 68±6 62±5 64±6 66±7 Mechanical strength good good good good good better good friability good good good good good good good Difficulty of membrane peeling easy easy easy easy Not easy Not easy Not easy Disintegration time (s) 55±7 58±6 50±5 52±8 50±6 51±8 54±6

[0081] Examples 13-18

[0082] The obtained formula containing Kollicoat-IR was flavored, including the addition of flavoring agents (e.g., sweeteners) (Table 3). Neotame had a better flavoring effect because it was used in small amounts and had little impact on the properties of the membrane. At the same time, it had a pure sweetness and good taste. Aspartame, sucralose, cyclamate, and other sweeteners could also achieve good flavoring effects by adjusting the formula.

[0083] Table 3 Flavor Optimization of Edaravone Kollicoat-IR Prescription Element Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Kollicoat-IR (mg) 1000 1000 1000 1000 1000 1000 Sweetener (mg) 100g of sucralose Aspartan 100 cyclamate 100 Neotame 3.0 Neotame 3.0 Neotame 3.0 Xanthan gum (mg) 25 25 25 25 25 25 Flavoring (mg) — — — — Strawberry flavoring 25 Orange flavoring 25 Edaravone (mg) 450 450 450 450 450 450 Water (mL) 5.0 5.0 5.0 5.0 5.0 5.0 Drug loading (%) 28.6% 28.6% 28.6% 30% 30% 30% Film thickness (um) 80±5 81±6 85±4 75±5 76±7 77±5 friability good good good good good good Difficulty of membrane peeling easy easy easy easy easy easy Disintegration time (s) 55±5 54±6 56±3 52±6 53±5 51±5 taste The taste is acceptable. The taste is acceptable. The taste is acceptable. Good taste Good taste Good taste

[0084] Examples 19-30

[0085] The obtained formulation containing HPMC, polyoxyethylene and polyvinyl alcohol is flavored by adding flavoring agents (e.g. sweeteners) (Tables 4 and 5). Neotame has a better flavoring effect among sweeteners because it is used in small amounts and has little effect on the properties of the membrane. At the same time, the addition of a suitable flavoring makes the formulation achieve a better flavoring effect.

[0086] Table 4 Flavoring Optimization of Edaravone HPMC and Polyoxyethylene Formulation Element Example 19 Example 20 Example 21 Example 22 Example 23 Example 24 HPMC-E15 (mg) 750 750 750 — — — Polyoxyethylene — — — 600 600 600 Sweetener (mg) 100g of sucralose Aspartan 100 Neotame 3.0 100g of sucralose Neotame 3.0 Neotame 3.0 Pullulan (mg) 75 75 75 — — — Glycerin (mg) 100 100 100 — 60 60 Xanthan Gum — — — 25 25 25 Flavoring (mg) — Strawberry flavoring 25 Strawberry flavoring 25 — — Orange flavoring 25 Edaravone (mg) 450 450 450 400 400 400 Water (mL) 5.0 5.0 5.0 5.0 5.0 5.0 Drug loading (%) 30% 30% 32% 35.6% 36% 36% Film thickness (um) 76±5 77±6 76±4 72±5 71±7 74±5 friability good good good good good good Difficulty of membrane peeling easy easy easy easy easy easy Disintegration time (s) 51±4 52±6 54±3 53±6 51±5 53±6 taste The taste is acceptable. Good taste Good taste The taste is acceptable. Good taste Good taste

[0087] Table 5 Flavoring Optimization of Edaravone Polyvinyl Alcohol Formulation Element Example 25 Example 26 Example 27 Example 28 Example 29 Example 30 Polyvinyl alcohol 1000 1000 1000 1000 1000 1000 Sweetener (mg) 100g of sucralose Aspartan 100 Neotame 3.0 Neotame 3.0 Aspartan 100 Aspartan 100 Xanthan Gum — 25 — — 25 25 Flavoring (mg) Strawberry flavoring 25 — — Strawberry flavoring 25 Strawberry flavoring 25 Orange flavoring 25 Edaravone (mg) 450 450 450 450 450 450 Water (mL) 5.0 5.0 5.0 5.0 5.0 5.0 Drug loading (%) 28.6% 28.6% 31% 31% 28% 28% Film thickness (um) 70±5 72±6 70±4 70±8 70±8 72±6 friability good good good good good good Difficulty of membrane peeling easy easy easy easy easy easy Disintegration time (s) 49±6 51±6 50±3 51±7 53±5 51±6 taste Good taste The taste is acceptable. Good taste Good taste Good taste Good taste

[0088] Preparation and Testing Examples of Oral Dissolution Films

[0089] The specific preparation method of the oral lysis film is as follows:

[0090] Take the film-forming material, flavoring agent, and optional thickener and / or plasticizer, dissolve them in the prescribed amount of water, add edaravone and continue stirring to disperse them evenly. Stir the resulting adhesive solution at low speed to remove bubbles overnight, then pour it onto a release film for coating. After coating, transfer the release film to a vacuum drying oven at 50°C to dry. Peel off the film, cut it, and pack it into a packaging bag with the printed dimensions.

[0091] The characterization method of the obtained oral lysate is described in detail below:

[0092] Membrane thickness measurement: The thickness of ten membranes was measured using a micrometer (average value and SD).

[0093] Disintegration time test: Take one piece of the drug film, clamp it with a paperclip, put it into the disintegration tester, and perform the test according to the disintegration time test method of Part IV - General Chapter - 0921 of the Pharmacopoeia of the People's Republic of China (2020 Edition).

[0094] Disintegration Test Method

[0095] Apparatus: Consists of a 200 ml glass beaker and a top stirrer (100 rpm).

[0096] Step

[0097] 1. Add 100 ml of solvent (e.g., water, saliva, gastric juice) to a 200 ml glass beaker.

[0098] 2. Heat the solvent to 37°C.

[0099] 3. Set the top mixer to 100 rpm, but do not turn on the mixer.

[0100] 4. Place the beaker under the top stirrer, with the stirrer head immersed in the solvent.

[0101] 5. Measure the thickness of the oral lysate sample (n>10; mean and SD).

[0102] 6. Place the sample on the inner wall of the beaker. Ensure the sample is completely immersed in the solvent.

[0103] 7. Turn on the top mixer.

[0104] 8. Record the time required for the film sample to completely disintegrate. Start timing when the top stirrer is turned on.

[0105] 9. Repeat the process twice more and calculate the average time.

[0106] The test results are shown in Table 6.

[0107] Table 6 Results of oral dissolution film detection for 10 edaravone flavored prescriptions Example Test results Appearance Disintegration timeout / s Content / % Content uniformity 13 A light yellow, smooth, sheet-like film with no observed raw material aggregation and good toughness. 55±5 99 Compliant 14 A light yellow, smooth, sheet-like film with no observed raw material aggregation and good toughness. 54±6 101 Compliant 16 A light yellow, smooth, sheet-like film with no observed raw material aggregation and good toughness. 52±6 100 Compliant 17 A light yellow, smooth, sheet-like film with no observed raw material aggregation and good toughness. 53±5 98.9 Compliant 19 A light yellow, smooth, sheet-like film with no observed raw material aggregation and good toughness. 51±4 99.1 Compliant 20 A light yellow, smooth, sheet-like film with no observed raw material aggregation and good toughness. 52±6 99.4 Compliant twenty three A light yellow, smooth, sheet-like film with no observed raw material aggregation and good toughness. 51±5 102.6 Compliant 27 A light yellow, smooth, sheet-like film with no observed raw material aggregation and good toughness. 50±3 101.4 Compliant 28 A light yellow, smooth, sheet-like film with no observed raw material aggregation and good toughness. 51±7 101.6 Compliant 29 A light yellow, smooth, sheet-like film with no observed raw material aggregation and good toughness. 53±5 101.9 Compliant [Simplified Explanation of the Diagram]

[0070] None

Claims

1. An edaravone oral film-dissolving immediate-release formulation composition comprising edaravone or a pharmaceutically acceptable salt or deuterated form thereof, and excipients, wherein the weight percentage of edaravone or a pharmaceutically acceptable salt or deuterated form thereof is 1%-60% based on the weight of the composition, and the excipients comprise a film-forming material and a flavoring agent; the film-forming material is HPMC, Kollicoat® IR, hydroxypropyl cellulose, pullulan, polyoxyethylene, or polyvinyl alcohol; and the oral film thickness formed by the edaravone oral film-dissolving formulation is 10-100 micrometers.

2. The edaravone oral film-dissolving immediate-release formulation composition according to claim 1, wherein, based on the weight of the composition, the film-forming material is 1%-50% by weight and the flavoring agent is 1%-10% by weight.

3. The edaravone oral film-dissolving immediate-release formulation composition according to claim 1, wherein the excipients further comprise a thickener and / or a plasticizer.

4. The edaravone oral film-dissolving immediate-release formulation composition according to claim 3, wherein the thickener is 0%-20% by weight and the plasticizer is 0%-15% by weight, based on the weight of the composition.

5. The edaravone oral film-dissolving immediate-release formulation composition according to claim 1, wherein the HPMC is HPMC E30, HPMC E15, or HPMC E5.

6. The edaravone oral film-dissolving immediate-release formulation composition according to claim 3, wherein the thickener is one or more selected from Kollicoat® MAE 30DP, xanthan gum, sodium carboxymethyl cellulose, PVP, tragacanth gum, povidone, carbomer, carrageenan, guar gum, agar, methylcellulose, ethylcellulose, polyoxyethylene, and polyacrylic acid.

7. The edaravone oral film-dissolving immediate-release formulation composition according to claim 6, wherein the thickener is PVP, xanthan gum, or sodium carboxymethyl cellulose.

8. The edaravone oral film-dissolving immediate-release formulation composition according to claim 3, wherein the plasticizer is one or more of glycerol, polyethylene glycol, or triethyl citrate.

9. The edaravone oral film-dissolving immediate-release formulation composition according to claim 8, wherein the plasticizer is glycerin.

10. The edaravone oral film-dissolving immediate-release formulation composition according to claim 1 or 2, wherein the flavoring agent is one or more of neotame, aspartame, sucralose, cyclamate, sucrose, mannitol, xylitol, sorbitol, steviol glycoside, syrup, cocoa butter, flavoring, sodium saccharin, acesulfame potassium, citric acid, malic acid, lactic acid, and tartaric acid.

11. The edaravone oral film-dissolving immediate-release formulation composition according to claim 10, wherein the flavoring agent is sucralose, mannitol, neotame, aspartame, cyclamate, acesulfame potassium, or flavoring.

12. The edaravone oral film-dissolving immediate-release formulation composition according to claim 10, wherein the flavoring is one or more of banana flavoring, lemon flavoring, sweet orange flavoring, tangerine flavoring, and strawberry flavoring.

13. An edaravone oral dissolution formulation prepared from any one of claims 1-12.

14. The edaravone oral dissolving film formulation according to claim 13, wherein the edaravone oral dissolving film disintegrates in 10-60 s.

15. The edaravone oral dissolving film formulation according to claim 14, wherein the edaravone oral dissolving film disintegrates in 2-30 s.

16. A method for preparing an edaravone oral dissolving film formulation according to any one of claims 13-15, comprising the following steps: (1) Weigh the film-forming material and flavoring agent, and optionally thickener and / or plasticizer, according to any of the weight percentages and types of claims 1-12; (2) Add the film-forming material and flavoring agent, and optionally thickener and / or plasticizer weighed in step (1) to water and stir to dissolve; (3) Weigh the edaravone or its pharmaceutically acceptable salt or deuterated derivative, according to any of the weight percentages of claims 1-12, and add it to the solution obtained in step (2), and continue stirring to disperse it evenly to obtain a gel; (4) Stir the gel for 1-10 h to remove bubbles; (5) Pour the gel onto a release film for coating; (6) Dry the coated release film at 40-60°C; (7) Cut the film and package it to obtain the final product.

17. The method for preparing edaravone oral dissolving film formulation according to claim 16, wherein in step (3) the temperature is heated to 50-70°C; in step (4) the stirring rate is 100 rpm; in step (5) the coating temperature is 25°C-50°C and the coating speed is 10-20 mm / s; and in step (6) the coated release film is dried at 50°C.

18. A kit comprising any one of claims 13-15 of an edaravone oral dissolving film formulation.

19. The kit according to claim 18, wherein the packaging of the kit is printed with a dosage scale for accurately dispensing the appropriate dose according to the patient's weight.

20. Use of any one of claims 1-12, any one of claims 13-15, or any one of claims 18-19, in the preparation of a medicament for the treatment and / or prevention of amyotrophic lateral sclerosis, Alzheimer's disease, cerebral hemorrhage, neurological deficits, cerebral infarction, and cerebral edema.