Edaravone oral dissolving film agent and preparation method thereof

Abstract

The invention relates to an edaravone oral soluble film agent and a preparation method thereof, belongs to the technical field of pharmaceutical preparations, and provides an oral soluble film agent which comprises edaravone, a film forming material, a plasticizer, a surfactant and a solvent. The invention also provides a preparation method of the oral dissolving film agent. The finally prepared oral dissolving film agent is good in strength and toughness, convenient to take, simple in preparation process and rapid in effect.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to an orodispersible film containing edaravone and a preparation method thereof. Background Art

[0002] Edaravone, trade name Radicut, is an antioxidant stress drug developed by Mitsubishi Tanabe Pharma Co., Ltd. in Japan. The preparation of Edaravone is a 30mg / 100ml injection, which was launched in Japan in June 2001 for the treatment of acute ischemic stroke and amyotrophic lateral sclerosis (ALS). It was launched in the United States in May 2017 for the treatment of amyotrophic lateral sclerosis (ALS). It is the second drug approved by the FDA for the treatment of amyotrophic lateral sclerosis (ALS). In China, the first Edaravone injection produced by Simcere Pharmaceuticals was launched in 2003.

[0003] Edaravone, also known as MCI-186, chemical name: 3-methyl-1-phenyl-2-pyrazol-5-one, molecular formula C 10 H 10 N2O, molecular weight 174.20, structural formula:

[0004]

[0005] It is a strong synthetic oxygen free radical scavenger with antioxidant effects to reduce oxidative stress and inhibit lipid peroxidation via non-enzymatic lipid peroxidation and lipoxygenase pathways. In addition, edaravone also shows beneficial effects on inflammation, matrix metalloproteinases, nitric oxide production and apoptosis.

[0006] Currently, there are only parenteral preparations of edaravone on the market, such as injections, but such preparations are not suitable for long-term treatment in terms of patient compliance. Therefore, in order to achieve the best therapeutic effect, other dosage forms of edaravone, especially oral dosage forms, are urgently needed. However, preliminary data from the inventors and other researchers show that edaravone has poor water solubility, bioavailability and stability, a short half-life, and side effects such as liver toxicity and kidney toxicity, which are the main obstacles to achieving the expected therapeutic effect in preclinical and clinical studies for any oxidative stress-related diseases.

[0007] For research on oral administration of edaravone, see Chinese patent application CN101953832A, which discloses an oral pharmaceutical composition of edaravone encapsulated in β-cyclodextrin and a preparation method thereof, wherein the mass ratio of the composition is 1 part of edaravone and 6-100 parts of cyclodextrin. However, there is still a demand in the art for a dosage form with better effects.

[0008] In order to solve the above technical problems, the present application adopts an orodispersible film formulation strategy, thereby achieving the best therapeutic effect of the new dosage form. Summary of the invention

[0009] Technical problem to be solved: The present invention provides an orodispersible film containing edaravone and a preparation method thereof, which solves the technical problems of poor water solubility and bioavailability of edaravone and poor clinical compliance.

[0010] Technical solution: The present invention provides an edaravone orodispersible film-forming agent, comprising one or more film-forming agents, one or more plasticizers, and one or more surfactants. The components include the following weight percentages:

[0011] Edaravone 10%-40%

[0012] Film former 10-90%

[0013] Plasticizer 0%-20%

[0014] Surfactant 0%-2%

[0015] Other auxiliary materials 0%-8%

[0016] The sum of the percentages of the individual components is 100%.

[0017] Furthermore, the film-forming agent is one or two of polyvinyl alcohol (PVA) 04-88, polyvinyl alcohol (PVA) 18-88, polyoxyethylene (PEO), hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E50, povidone K30, copovidone S630, and a combination of two or more, preferably a combination of polyvinyl alcohol (PVA) 04-88, hydroxypropyl methylcellulose E5, and copovidone S630.

[0018] The preferred mass ratio of the polyvinyl alcohol (PVA) 04-88, hydroxypropyl methylcellulose E5, and copovidone S630 is 6:2:1.

[0019] The plasticizer is one or two or a combination of two or more of glycerol, mannitol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, diethyl phthalate, ethyl citrate, and glycerol triacetate, preferably glycerol.

[0020] The surfactant is one or two or a combination of two or more of poloxamer, sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauric acid, stearic acid, lecithin, sucrose fatty acid ester, fatty acid glyceride, and fatty acid sorbitan, preferably polysorbate 80.

[0021] The other auxiliary materials may be conventional auxiliary materials in the art, such as one or more of sweeteners, flavors and colorants.

[0022] The sweetener is conventional in the art, preferably one or more of sucralose, xylitol, maltitol, steviol glycoside, saccharin sodium, aspartame, acesulfame potassium and sodium cyclamate.

[0023] The flavor may be conventional in the art, such as one or more of sweet apricot flavor, sweet orange flavor, strawberry flavor, lemon flavor, mint flavor or pineapple flavor.

[0024] The colorant can be one or more of titanium dioxide or food coloring.

[0025] The preparation method is:

[0026] a: Add edaravone into ethanol and dissolve;

[0027] b: Disperse PVA in water, heat to 60-90℃ to dissolve, cool to room temperature, add the above components, and stir evenly;

[0028] c: Add b to a, stir, disperse, mix to obtain slurry, apply and mold; dry and cut to obtain the product.

[0029] The weight amount of anhydrous ethanol is 1-5 times the weight of edaravone.

[0030] The weight amount of water is 1-25 times the weight of edaravone.

[0031] The slurry is a solution with certain viscosity and good fluidity.

[0032] Beneficial effects:

[0033] The film-forming agent composition and dosage are screened to ensure the solubility of edaravone and the formability of the orodissolving film without affecting the disintegration of the orodissolving film, thereby realizing rapid disintegration in the mouth. Bubbles are inevitably generated during the preparation of the orodissolving film. In order to ensure that the orodissolving film is flat and does not generate bubbles, static defoaming is adopted to ensure that the appearance of the orodissolving film is qualified.

[0034] Edaravone is an antioxidant stress-resistant drug used to treat acute ischemic stroke and amyotrophic lateral sclerosis (ALS), and currently only an injection is available on the market, which has poor patient compliance. The orodispersible film of edaravone disclosed by the present invention can be attached to the oral mucosa, on the tongue or under the tongue, without the need to drink water, thereby improving patient compliance.

[0035] The edaravone orodispersible film-forming agent of the present invention has a simple coating method as its preparation process, and the preparation process is relatively simple and easy to operate. DETAILED DESCRIPTION

[0036] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0037] Example 1: Edaravone oral film-dissolving formulation composition and preparation process

[0038] Table 1. Composition of the prescription of Edaravone oral film-dissolving agent

[0039]

[0040]

[0041] Preparation method:

[0042] a: Add 3g of edaravone to 9g of anhydrous ethanol and dissolve;

[0043] b: Disperse 4.47g PVA in 75g water, heat at 60-90℃ to dissolve, cool to room temperature, add 1.49g hydroxypropyl methylcellulose E5, 0.74g copolyvidone S-630, 0.1g Tween 80, 0.2g glycerol, and stir evenly;

[0044] c: Add b to a, stir, disperse, mix, let stand to defoam, apply, dry, drying temperature 70-80℃, drying time 5-30min, then remove and cut into pieces according to 30mg / piece.

[0045] Comparative Example 1: Prescription composition and preparation process of edaravone orodispersible film-dissolving agent (PVA: hydroxypropyl methylcellulose E5: copolyvidone S630 mass ratio is 2:2:1)

[0046] Table 2 Prescription composition of Edaravone oral film-dissolving agent

[0047]

[0048] Preparation method:

[0049] a: Add 3g of edaravone to 9g of anhydrous ethanol and dissolve;

[0050] b: Disperse 2.68g PVA in 75g water, heat at 60-90℃ to dissolve, cool to room temperature, add 2.68g hydroxypropyl methylcellulose E5, 1.34g copolyvidone S-630, 0.1g Tween 80, 0.2g glycerol, and stir evenly;

[0051] c: Add b to a, stir, disperse, mix, let stand to defoam, apply, dry, drying temperature 70-80℃, drying time 5-30min, then remove and cut into pieces according to 30mg / piece.

[0052] Comparative Example 2: Prescription composition and preparation process of edaravone orodispersible film-dissolving agent (PVA: hydroxypropyl methylcellulose E5: copolyvidone S630 mass ratio is 4:2:1)

[0053] Table 3. Composition of the prescription of Edaravone oral film-dissolving agent

[0054]

[0055] Preparation method:

[0056] a: Add 3g of edaravone to 9g of anhydrous ethanol and dissolve;

[0057] b: Disperse 3.83g PVA in 75g water, heat at 60-90℃ to dissolve, cool to room temperature, add 1.91g hydroxypropyl methylcellulose E5, 0.96g copolyvidone S-630, 0.1g Tween 80, 0.2g glycerol, and stir evenly;

[0058] c: Add b to a, stir, disperse, mix, let stand to defoam, apply, dry, drying temperature 70-80℃, drying time 5-30min, then remove and cut into pieces according to 30mg / piece.

[0059] Comparative Example 3: Prescription composition and preparation process of edaravone orodispersible film (PVA: hydroxypropyl methylcellulose E5: copolyvidone S630 mass ratio is 8:2:1)

[0060] Table 4. Composition of the formula of edaravone oral film-dissolving agent

[0061]

[0062]

[0063] Preparation method:

[0064] a: Add 3g of edaravone to 9g of anhydrous ethanol and dissolve;

[0065] b: Disperse 4.87g PVA in 75g water, heat at 60-90℃ to dissolve, cool to room temperature, add 1.22g hydroxypropyl methylcellulose E5, 0.61g copolyvidone S-630, 0.1g Tween 80, 0.2g glycerol, and stir evenly;

[0066] c: Add b to a, stir, disperse, mix, let stand to defoam, apply, dry, drying temperature 70-80℃, drying time 5-30min, then remove and cut into pieces according to 30mg / piece.

[0067] Comparative Example 4: Prescription composition and preparation process of edaravone orodispersible film (PVA: hydroxypropyl methylcellulose E5: copolyvidone S630 mass ratio is 10:2:1)

[0068] Table 5. Composition of the prescription of Edaravone oral film-dissolving agent

[0069]

[0070] Preparation method:

[0071] a: Add 3g of edaravone to 9g of anhydrous ethanol and dissolve;

[0072] b: Disperse 5.15g PVA in 75g water, heat at 60-90℃ to dissolve, cool to room temperature, add 1.03g hydroxypropyl methylcellulose E5, 0.92g copolyvidone S-630, 0.1g Tween 80, 0.2g glycerol, and stir evenly;

[0073] c: Add b to a, stir, disperse, mix, let stand to defoam, apply, dry, drying temperature 70-80℃, drying time 5-30min, then remove and cut into pieces according to 30mg / piece.

[0074] Embodiment 1 performance test:

[0075] 1. Basic performance Table 6 Appearance results of different mass ratios of PVA: Hydroxypropyl methylcellulose E5: Copolyvidone S630

[0076]

[0077] 2. Dissolution time

[0078] Six pieces of the orodispersible film in each of the above examples were selected and placed in a 37°C, 20 ml, pH 6.8 phosphate buffer solution without installing a basket and rotating the film with the shaft. The total dissolution time of the orodispersible film was recorded. The results are shown in Table 7. Dissolution time results of different mass ratios of PVA: hydroxypropyl methylcellulose E5: copolyvidone S630

[0079]

[0080] Through the above experiments, under the same drug loading of edaravone, when the mass ratio of PVA:hydroxypropyl methylcellulose E5:copovidone S630 in the film-forming agent component is 6:2:1, the performance of the film is better and the dissolution is faster. When the proportion of hydroxypropyl methylcellulose is too small, the dissolution time of the film is significantly prolonged.

[0081] Example 2: Edaravone oral film-dissolving formulation composition and preparation process

[0082] Table 8 Edaravone oral film-dissolving formulation composition (Edaravone 10 mg / tablet)

[0083]

[0084] Preparation method:

[0085] a: Add 2g of edaravone to 6g of anhydrous ethanol and dissolve;

[0086] b: Disperse 5.8g PVA in 50g water, heat at 60-90℃ to dissolve, cool to room temperature, add 1.93g hydroxypropyl methylcellulose E5, 0.97g copolyvidone S-630, 0.1g Tween 80, 0.2g glycerol, and stir evenly;

[0087] c: Add b to a, stir, disperse, mix, let stand to defoam, apply, dry, drying temperature 70-80℃, drying time 5-30min, then remove and cut into pieces according to 10mg / piece.

[0088] Example 3: Edaravone oral film-dissolving formulation composition and preparation process

[0089] Table 9 Prescription composition of edaravone orodispersible film (edaravone 20 mg / tablet)

[0090]

[0091] Preparation method:

[0092] a: Add 2g of edaravone to 6g of anhydrous ethanol and dissolve;

[0093] b: Disperse 5.13g PVA in 50g water, heat at 60-90℃ to dissolve, cool to room temperature, add 1.71g hydroxypropyl methylcellulose E5, 0.86g copolyvidone S-630, 0.1g Tween 80, 0.2g glycerol, and stir evenly;

[0094] c: Add b to a, stir, disperse, mix, let stand to defoam, apply, dry, drying temperature 70-80℃, drying time 5-20min, then remove and cut into pieces according to 20mg / piece.

[0095] Example 4: Edaravone oral film-dissolving formulation composition and preparation process

[0096] Table 10 Prescription composition of edaravone orodispersible film (edaravone 40 mg / tablet)

[0097]

[0098]

[0099] Preparation method:

[0100] a: Add 4g of edaravone to 12g of anhydrous ethanol and dissolve;

[0101] b: Disperse 4g PVA in 100g water, heat at 60-90℃ to dissolve, cool to room temperature, add 1.27g hydroxypropyl methylcellulose E5, 0.63g copovidone S-630, 0.1g Tween 80, 0.2g glycerol, and stir evenly;

[0102] c: Add b to a, stir, disperse, mix, let stand to defoam, apply, dry, drying temperature 70-80℃, drying time 5-20min, then remove and cut into 40mg / piece.

[0103] Embodiment 1 performance test:

[0104] 1. Basic performance Table 11 Appearance results of different drug loadings of Edaravone

[0105]

[0106] 2. Dissolution time

[0107] Six pieces of the orodispersible film in each of the above examples were selected and placed in a 37°C, 20 ml, pH 6.8 phosphate buffer solution without installing a basket and rotating the film with the shaft. The total dissolution time of the orodispersible film was recorded. The results are shown in Table 12 Dissolution time results of different drug loadings of edaravone

[0108]

[0109] The above experiments showed that when the drug loading of edaravone was 30 mg / tablet, the performance of the membrane was better and it dissolved faster.

[0110] It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations within the meaning and scope of the equivalent elements of the claims be included in the invention. Any marking in a claim should not be considered as limiting the claim to which it relates.

Claims

1. An orodispersible film-dissolving preparation of edaravone, characterized in that: The composition comprises the following weight percentages: Edaravone 10%-40% Film former 10-90% Plasticizer 0%-20% Surfactant 0%-2% Other auxiliary materials 0%-8% The sum of the percentages of the individual components is 100%.

2. The orodispersible film-dissolving preparation of Edaravone according to claim 1, characterized in that The film-forming agent is one or two or a combination of two or more of polyvinyl alcohol (PVA) 04-88, polyvinyl alcohol (PVA) 18-88, polyoxyethylene (PEO), hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E50, povidone K30 and copovidone S630.

3. The orodispersible film-dissolving preparation of Edaravone according to claim 1, characterized in that: The plasticizer is one or two or a combination of two or more of glycerol, mannitol, propylene glycol, polyethylene glycol 200, polyethylene glycol 400, diethyl phthalate, ethyl citrate and triacetin.

4. The orodispersible film-dissolving preparation of Edaravone according to claim 1, characterized in that: The surfactant is one or two or a combination of two or more of poloxamer, sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauric acid, stearic acid, lecithin, sucrose fatty acid ester, fatty acid glyceride and fatty acid sorbitan.

5. The orodispersible film-dissolving preparation of Edaravone according to claim 1, characterized in that: The other auxiliary materials are one or a combination of two or more of sweeteners, flavors and colorants.

6. The method for preparing the orodispersible film-forming agent of any one of claims 1 to 5, characterized in that: The steps include: a: Add edaravone into ethanol and dissolve; b: Disperse the film-forming agent in water, heat to 60-90℃ to dissolve, cool to room temperature, add plasticizer, surfactant and other auxiliary materials, and stir evenly; c: Add the product prepared in b to the product prepared in a, stir, disperse, mix to obtain slurry, apply and mold, dry, and cut to obtain the product.

7. The method for preparing the orodispersible film-dissolving agent of Edaravone according to claim 5, characterized in that: The weight amount of the anhydrous ethanol is 1-5 times the weight of Edaravone; the weight amount of water is 1-25 times the weight of Edaravone.

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