Edaravone oral dissolving film immediate-release formulation composition, formulation thereof, and use thereof

Abstract

Disclosed in the present application is an edaravone film immediate-release formulation composition, comprising edaravone or a pharmaceutically acceptable salt, a prodrug, a metabolite, a solvate, a crystal, or a deuterated compound thereof, and an auxiliary material. Based on the weight of the composition, the weight percentage of the edaravone or the pharmaceutically acceptable salt, the prodrug, the metabolite, the solvate, the crystal, or the deuterated compound thereof is 1%-60%. The edaravone oral dissolving film immediate-release formulation of the present application is used for sublingual administration, and is characterized by fast disintegration and good mouthfeel.

Description

Edaravone oral dissolving film immediate release preparation composition, preparation and use thereof TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to an edaravone oral dissolving film immediate release preparation and a preparation method, preparation and use thereof. BACKGROUND

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

[0003] Cerebral vascular disease, particularly ischemic cerebral vascular disease, is an acute disease that needs to be quickly relieved, and therefore injection administration is the preferred method for first aid. However, intramuscular injection or intravenous injection can cause pain and irritation at the injection site, and requires professional medical personnel to operate, and also requires injection supplies, and is subject to certain medical limitations in application, and is not suitable for patients with out-of-hospital onset.

[0004] Sublingual oral dissolving film preparations are directly absorbed by the sublingual mucosa, the sublingual mucosa has a large surface area and strong permeability, and a large number of capillaries under the mucosa converge into the internal jugular vein and directly enter the blood circulation through the superior vena cava, so that the drug is rapidly absorbed after administration, has a fast onset, is accurate in dosage, and is convenient to use, and can avoid the first-pass effect of oral drugs. Compared with injections, sublingual oral dissolving films can greatly improve the convenience of drug use and the compliance of clinical patients. Oral dissolving films have a significant advantage over ordinary tablets in terms of medication compliance for patients with difficulty swallowing, such as amyotrophic lateral sclerosis and stroke, who have no self-administration. SUMMARY

[0005] The purpose of one or more embodiments of the present application includes providing an edaravone immediate release sublingual oral dissolving film containing an active ingredient edaravone or a salt thereof and excipients, which has a fast disintegration rate, can shorten the onset time of edaravone, has a good taste, is convenient to use, effectively improves the medication compliance of the elderly and other patients who have difficulty swallowing, and improves the privacy of adult medication.

[0006] One or more embodiments of the present application provide an oral dissolving film immediate release formulation composition of edaravone, comprising edaravone or a pharmaceutically acceptable salt, prodrug, metabolite, solvate, crystal, or deuterated form thereof and an excipient, the weight percentage of the edaravone or the pharmaceutically acceptable salt, prodrug, metabolite, solvate, crystal, or deuterated form thereof being 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 excipient comprising a film forming material and a flavoring agent.

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

[0008] In one or more embodiments, the excipient further comprises a thickening agent and / or a plasticizer.

[0009] In one or more embodiments, the weight percentage of the thickening agent is 0-20% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%) and the weight percentage of the plasticizer is 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), IR, hydroxypropyl cellulose, gelatin, pullulan, polyvinyl alcohol, sodium alginate, gum arabic, povidone, acrylic acid copolymer, hydroxypropyl cellulose, polyoxyethylene, shellac, starch, agar, zein, polylactic acid, and silicone rubber.

[0011] In one or more embodiments, the film forming material is one or more of HPMC, 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 thickening agent is one or more of MAE 30DP, xanthan gum, sodium carboxymethylcellulose, PVP (polyvinylpyrrolidone), tragacanth, gum arabic, carbomer, carrageenan, guar gum, agar agar, methylcellulose, ethylcellulose, polyoxyethylene, and polyacrylic acid.

[0014] In one or more embodiments, the thickening agent is MAE 30DP, PVP, xanthan gum, or sodium carboxymethylcellulose.

[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 glycerol.

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

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

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

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

[0021] In one or more embodiments, the edaravone oral dissolving film formulation forms an oral dissolving film having a thickness of 20-100 microns (e.g., 30, 40, 50, 60, 70, 80, 90, 100 microns).

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

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

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

[0025] (1) Take the film-forming material and flavoring agent and optionally thickening agent and / or plasticizer of the weight percentage and kind described above;

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

[0027] (3) Take the edaravone or pharmaceutically acceptable salt, prodrug, metabolite, solvate, crystal, or deuterated form thereof of the weight percentage described above and add to the solution obtained in step (2), continue stirring to disperse uniformly, to obtain a glue solution;

[0028] (4) Defoam the glue solution at low speed for several hours (1-10 h);

[0029] (5) Pour the glue solution onto a release film for coating;

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

[0031] (7) Cut the film and package.

[0032] In one or more embodiments, in step (3), heating to 50-70°C, e.g. 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 25-50°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 at 50°C.

[0036] One or more embodiments of the present application provide a kit comprising the edaravone oral dissolving film preparation of the present application.

[0037] In one or more embodiments, the package of the kit is printed with a dosage scale for accurately taking the corresponding dose according to the patient's body weight.

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

[0039] One or more embodiments of the present application provide the Edaravone buccal film immediate release preparation composition of the present application, the Edaravone buccal film preparation of the present application, or the kit of the present application for use as a medicament.

[0040] One or more embodiments of the present application provide the Edaravone buccal film immediate release preparation composition of the present application, the Edaravone buccal film preparation of the present application, or the kit of the present application for use in the treatment and / or prevention of amyotrophic lateral sclerosis, Alzheimer's disease, stroke, neurological defects, cerebral infarction, cerebral edema.

[0041] One or more embodiments of the present application provide a method for treating and / or preventing amyotrophic lateral sclerosis, Alzheimer's disease, stroke, neurological defects, cerebral infarction, cerebral edema, comprising administering to a subject in need thereof a therapeutically effective amount of the Edaravone buccal film immediate release preparation composition of the present application or the Edaravone buccal film preparation of the present application.

[0042] One or more embodiments of the present application provide an Edaravone buccal film composition, a preparation method thereof and applications thereof.

[0043] One or more embodiments of the present application provide an Edaravone buccal film composition comprising Edaravone or a pharmaceutically acceptable salt thereof, one or more of a film-forming material, a thickening agent, a plasticizer and a flavoring agent.

[0044] The Edaravone buccal film composition provided by the present application has precise dose markings, a fast dissolution rate, no grit feeling after dissolving in the oral cavity, uniform appearance, good flexibility, good taste masking effect, no need to use water when taking medicine, and is convenient for patients with swallowing difficulties or special conditions such as the elderly and children to take, and improves the privacy of adult medication, and does not settle during the preparation of the film liquid, and the content uniformity meets the requirements.

[0045] The present application also includes a preparation method of the Edaravone immediate release buccal film, which is simple, easy to control, low in cost, environmentally friendly, and suitable for industrial mass production.

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

[0047] In a first aspect of the present application, an Edaravone immediate release buccal film is provided, comprising an active ingredient of Edaravone or a salt thereof and excipients, wherein the excipients include a film-forming material, a thickening agent, a plasticizer, and / or a flavoring agent.

[0048] Further preferably, the weight percentage of the active ingredient in the buccal film is 1-60%, preferably 10-35%.

[0049] Further preferably, the content of the film-forming material is 1-50% by weight of the oral dissolving film, the content of the thickening agent is 1-20% by weight of the oral dissolving film, the content of the plasticizer is 1-15% by weight of the oral dissolving film, and the content of the flavoring agent is 1-10% by weight of the oral dissolving film.

[0050] Further 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, zein, hydroxypropyl cellulose, polyoxyethylene, acrylic acid copolymer, polylactic acid, and silicone rubber, preferably HPMC, IR, polyvinyl alcohol, and one or more of polyoxyethylene.

[0051] Further preferably, the thickening agent is selected from xanthan gum, sodium carboxymethyl cellulose, tragacanth gum, gum arabic, sodium alginate, povidone, carbomer, carrageenan, guar gum, agar, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, polyoxyethylene, polyacrylic acid, etc., preferably xanthan gum, sodium carboxymethyl cellulose, and gum arabic.

[0052] Further preferably, the plasticizer is selected from glycerol, polyethylene glycol.

[0053] Further preferably, the flavoring agent is selected from any one or more of neotame, aspartame, sucralose, cyclamate, sucrose, mannitol, xylitol, sorbitol, rebaudioside, sugar syrup, essence, sodium saccharin, and acesulfame, preferably any one or more of sucrose, mannitol, neotame, aspartame, sucralose, acesulfame, and essence; the essence is selected from any one or more of apple essence, banana essence, sweet orange essence, tangerine essence, and strawberry essence.

[0054] The oral dissolving film of the present application can be prepared by coating.

[0055] In another aspect of the present application, a preparation method of an edaravone oral dissolving film comprising an active ingredient edaravone or a salt thereof and excipients is provided, which is prepared according to the following steps:

[0056] 1. Weigh the prescribed amount of the active ingredient, the thickening agent, the plasticizer, and the flavoring agent;

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

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

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

[0060] 5. Pour the glue solution onto a release film for coating;

[0061] 6. After coating, dry the release film at 50℃;

[0062] 7. Cut the film and pack.

[0063] In one or more embodiments, the edaravone oral dissolving film has a specification of, for example, 10 mg, 20 mg, 30 mg.

[0064] The accurate dosage is calculated according to the body weight, and the film piece with the accurate dosage is cut out on the oral dissolving film according to the scale line, and is placed under the tongue without water, and the film piece is quickly disintegrated in the oral cavity to release the drug.

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

[0066] 1. The immediate-release oral dissolving film of the present application has a film thickness of less than 100 microns through the design of its prescription, so as to ensure that the film has no grit feeling in the oral cavity.

[0067] 2. The disintegration time in the oral cavity is less than 60 seconds (for example, 40 seconds), the preparation process of the optimized prescription is simple, the production cost is low, and the present application is suitable for industrial mass production.

[0068] 3. According to experiments, the edaravone immediate-release preparation provided by the present application has a good taste, which masks the bad taste of edaravone, and the dosage is easy to control, so that it is convenient for the elderly or patients with difficulty in swallowing to use.

[0069] Therefore, the present application provides an edaravone immediate-release preparation which meets various requirements. DETAILED DESCRIPTION

[0070] The present application will be further described below in conjunction with examples, and the following description is only for the purpose of explaining the present application and does not limit the content thereof in any way.

[0071] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0072] The edaravone oral dissolving film and the preparation method thereof according to the embodiments of the present application will be specifically described below.

[0073] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0074] Examples 1-5

[0075] Kollicoat-IR as film forming material; arabic gum, xanthan gum, sodium alginate, carbomer, carboxymethyl cellulose (CM-cellulose) and the like as thickening agent; in the case of edaravone loading (loading = the mass of edaravone / total weight after film forming x 100%) of 30%, the prescription is optimized, and the film forming effect of Kollicoat-IR is good (Table 1).

[0076] Table 1 Edaravone prescription optimization

[0077] Examples 6-12

[0078] HPMC, Kollicoat-IR, polyoxyethylene, polyvinyl alcohol and the like as film forming material, and good film forming effect can be achieved with the aid of suitable thickening agent or plasticizer (Table 2).

[0079] Table 2 Edaravone prescription optimization

[0080] Examples 13-18

[0081] The obtained prescription containing Kollicoat-IR is flavored, including adding flavoring agents (such as sweeteners) (Table 3), and the flavoring effect of neotame is better, because its use amount is less, and it basically does not affect the properties of the film, and its sweet taste is pure and the taste is good. Aspartame, sucralose, cyclamate and the like sweeteners can also achieve good flavoring effect by adjusting the prescription.

[0082] Table 3 Edaravone Kollicoat-IR prescription flavoring optimization

[0083] Examples 19-30

[0084] The obtained prescription containing HPMC, polyoxyethylene, polyvinyl alcohol is flavored, including adding flavoring agents (such as sweeteners) (Table 4, Table 5), and the flavoring effect of neotame is better, because its use amount is less, and it basically does not affect the properties of the film, and the prescription achieves good flavoring effect with the aid of suitable essence.

[0085] Table 4 Edaravone HPMC and polyoxyethylene prescription flavoring optimization

[0086] Table 5 Edaravone polyvinyl alcohol prescription flavoring optimization

[0087] Preparation and testing of oral dissolving film

[0088] The specific preparation method of oral dissolving film is as follows:

[0089] The film-forming material, flavoring agent, and optional thickening agent and / or plasticizer are dissolved in the prescribed amount of water, and then edaravone is added and stirred to disperse uniformly. The resulting glue solution is left to stand overnight with low-speed stirring to remove bubbles, and then poured onto a release film for coating. After coating, the release film is transferred to a vacuum drying oven at 50°C for drying, and the film is peeled off and cut into pieces, which are then packed in a bag with printed dimensions.

[0090] The characterization method of the resulting oral dissolving film is described in detail as follows:

[0091] Film thickness measurement: The thickness of ten films (average and SD) was measured using a micrometer.

[0092] Disintegration time measurement: One piece of the drug film was clamped with a paperclip and placed in a disintegration tester, and the disintegration time was measured according to the method described in the fourth volume of the Pharmacopoeia of the People's Republic of China (2020 edition) - General Rules - 0921 Disintegration Time Test.

[0093] Disintegration test method

[0094] Apparatus: consisting of a 200 ml glass beaker and an overhead stirrer (100 rpm).

[0095] Procedure

[0096] 1. Add 100 ml of solvent (e.g. water, saliva, gastric juice) to a 200 ml glass beaker.

[0097] 2. Heat the temperature of the solvent to 37°C.

[0098] 3. Set the overhead stirrer to 100 rpm, but do not turn it on.

[0099] 4. Place the beaker under the overhead stirrer, with the stirrer head immersed in the solvent.

[0100] 5. Measure the thickness of the oral dissolving film sample (n > 10; average and SD).

[0101] 6. Place the sample on the inner wall of the beaker. Make sure the sample is completely immersed in the solvent.

[0102] 7. Turn on the overhead stirrer.

[0103] 8. Record the time required for the thin film sample to completely disintegrate. Start timing when the overhead stirrer is turned on.

[0104] 9. Repeat the process 2 more times and calculate the average time.

[0105] The test results are shown in Table 6.

[0106] Table 6 Test results of 10 edaravone flavored oral dissolving films

Claims

1. An edaravone oral film-dissolving immediate-release formulation composition comprising edaravone or a pharmaceutically acceptable salt thereof, a prodrug, a metabolite, a solvate, a crystal, or a deuterated form thereof, and excipients, wherein the weight percentage of edaravone or a pharmaceutically acceptable salt thereof, a prodrug, a metabolite, a solvate, a crystal, or a 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; preferably, the weight percentage of the film-forming material is 1%-50% based on the weight of the composition, and the weight percentage of the flavoring agent is 1%-10%.

2. The edaravone oral film-dissolving immediate-release formulation composition according to claim 1, wherein the excipients further comprise a thickener and / or a plasticizer; preferably, based on the weight of the composition, the thickener is 0%-20% by weight and the plasticizer is 0%-15% by weight.

3. The edaravone oral film-dissolving immediate-release formulation composition according to claim 1 or 2, wherein the film-forming material is HPMC, IR, SR, 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 are selected as one or more of these; preferably, the film-forming material is HPMC. IR, hydroxypropyl cellulose, pullulan, polyoxyethylene, or polyvinyl alcohol; more preferably, the HPMC is HPMC E30, HPMC E15, or HPMC E5.

4. The edaravone oral film-dissolving immediate-release formulation composition according to claim 2, wherein the thickener is... The thickener is one or more of MAE 30DP, xanthan gum, sodium carboxymethyl cellulose, PVP, tragacanth gum, povidone, carbomer, carrageenan, guar gum, agar, methylcellulose, ethylcellulose, polyoxyethylene, and polyacrylic acid; preferably, the thickener is PVP, xanthan gum, or sodium carboxymethyl cellulose.

5. The edaravone oral film-dissolving immediate-release formulation composition according to claim 2, wherein the plasticizer is one or more of glycerol, polyethylene glycol, or triethyl citrate; preferably, the plasticizer is glycerol.

6. 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; preferably, the flavoring agent is sucralose, mannitol, neotame, aspartame, cyclamate, acesulfame potassium, or flavoring; more preferably, the flavoring is one or more of banana flavoring, lemon flavoring, sweet orange flavoring, tangerine flavoring, and strawberry flavoring.

7. An edaravone oral dissolving film formulation, prepared from any one of the edaravone oral dissolving film immediate-release formulation compositions according to claims 1-6; preferably, the oral dissolving film formed by the edaravone oral dissolving film formulation has a thickness of 10-100 micrometers; preferably, the edaravone oral dissolving film disintegrates in 10-60 seconds, more preferably in 2-30 seconds.

8. The method for preparing the edaravone oral dissolving film formulation according to claim 7, comprising the following steps: (1) Weigh the film-forming material and flavoring agent of any weight percentage and type as described in any one of claims 1-6, as well as optional thickeners and / or plasticizers; (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; (3) Weigh out the weight percentage of edaravone or its pharmaceutically acceptable salt, prodrug, metabolite, solvate, crystal or deuterated form as described in any one of claims 1-6 and add it to the solution obtained in step (2), and continue stirring to disperse it evenly to obtain a gel; preferably, heat to 50-70°C; more preferably heat to 60°C; (4) Stir the adhesive solution for 1 to 10 hours to remove bubbles; preferably, the stirring rate is 100 rpm; (5) Pour the adhesive onto the release film for coating; preferably, the coating temperature is 25°C-50°C and the coating speed is 10-20mm / s. (6) Dry the coated release film at 40-60°C, preferably at 50°C; (7) Cut the film and package it to obtain the product.

9. A kit comprising the edaravone oral dissolving film formulation of claim 7; preferably, the kit packaging is printed with a dosage scale for accurately dispensing the appropriate dose according to the patient's weight.

10. Use of the edaravone oral film-dissolving immediate-release formulation composition according to any one of claims 1-6, the edaravone oral film-dissolving formulation according to claim 7, or the kit according to claim 9 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.

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