Edaravone patch and preparation method thereof

Abstract

The invention relates to an edaravone-containing patch and a preparation method thereof, edaravone is used for preparing a skin local patch, and belongs to the technical field of pharmaceutical preparations, the invention provides a patch, and the patch comprises the following three parts: (1) a backing layer; (2) a drug-containing adhesive skeleton layer; and (3) a protective layer. The invention also provides a preparation method of the patch, and the preparation process comprises the following steps: dissolving the pressure-sensitive adhesive material in a proper solvent, dissolving or dispersing the medicine in the pressure-sensitive adhesive solution, then coating the mixed solution on the backing layer or the protective layer by a proper process, drying to volatilize the solvent, covering the protective layer or the backing layer, and cutting and dividing doses. The finally prepared patch 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 a patch 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 N 2 O, 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 is only a parenteral formulation of edaravone on the market, such as an injection, but this formulation is not suitable for long-term treatment in terms of patient compliance, so in order to achieve the best therapeutic effect, other formulations of edaravone are urgently needed. However, preliminary data from the present 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] In order to solve the above technical problems, the present application adopts a patch preparation strategy, thereby obtaining the best therapeutic effect of the new dosage form. Summary of the invention

[0008] Technical problem solved: The present invention provides a patch containing edaravone and a preparation method thereof, which solves the technical problems of poor water solubility and bioavailability of edaravone and poor clinical compliance.

[0009] Technical solution: The present invention provides an edaravone patch, and edaravone is used to prepare a local skin patch.

[0010] As an optimization, the patch is composed of the following three parts: (1) a backing layer; (2) a drug-containing adhesive skeleton layer; and (3) a protective layer.

[0011] As an optimization, the backing layer is one or two or a combination of two or more of polyester film, polyethylene composite film, polyvinylidene chloride copolymer (PVDC), polyurea, cotton cloth, polyester cloth, polyester-cotton cloth, acetate cloth, stretch cloth, spunlace non-woven fabric, hot-rolled non-woven fabric, hot-melt non-woven fabric, microporous film and multi-layer composite aluminum foil.

[0012] As an optimization, the drug-containing adhesive skeleton layer is one or a combination of two or more of polyacrylate, acrylic resin, polyisobutylene pressure-sensitive adhesive, silicone rubber, polyethylene copolymer and polyvinyl chloride.

[0013] As an optimization, the drug-containing adhesive skeleton layer also includes a plasticizer, and the plasticizer is one or a combination of two or more of diethyl sebacate, triethyl citrate, diethyl phthalate and mineral oil.

[0014] As an optimization, the drug-containing adhesive skeleton layer also includes a tackifier, which is one or a combination of two or more of rosin, hydrogenated rosin, polymerized rosin, rosin glycerol ester, hydrogenated rosin glycerol ester, terpene resin, petroleum resin and polybasic organic acid.

[0015] As an optimization, the drug-containing adhesive skeleton layer also includes a transdermal absorption enhancer, which is one or a combination of two or more of ethanol, propylene glycol, oleic acid, laurocapram, peppermint oil and eucalyptus oil.

[0016] As an optimization, the protective layer is one or a combination of two or more of release paper, polyethylene film, polypropylene film, polystyrene film, polytetrafluoroethylene film, siliconized polyester, aluminum foil and paper composite film.

[0017] The preparation method of the edaravone patch as described in any one of the above items comprises the following steps: dissolving the pressure-sensitive adhesive material in a solvent, dissolving or dispersing the drug in the pressure-sensitive adhesive solution, then coating the mixed solution on a backing layer or a protective layer, drying the volatilized solvent, covering the protective layer or the backing layer, and cutting the patch into doses.

[0018] Beneficial effects:

[0019] The present invention screens the composition and dosage of the patch to ensure the solubility of edaravone and the formability of the patch.

[0020] Edaravone is an anti-oxidative stress 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 edaravone patch of the present invention can be attached to the skin to improve patient compliance.

[0021] The edaravone patch of the present invention has a simple coating process for preparation, and the preparation process is relatively simple and easy to operate. DETAILED DESCRIPTION

[0022] 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 creative work are within the scope of protection of the present invention.

[0023] Example 1: Edaravone patch prescription composition and preparation process

[0024] Table 1. Composition of Edaravone Patch

[0025]

[0026] Preparation method:

[0027] Take 300 parts of polyisobutylene pressure-sensitive adhesive, dissolve in 1200 parts of chloroform, add 30 parts of edaravone, dissolve and disperse evenly, add 60 parts of diethyl phthalate, 5 parts of hydrogenated rosin, and 5 parts of laurocapram, dissolve and disperse evenly, then apply the mixed solution on the backing layer, dry the volatilized solvent, cover and protect, and cut into doses of 30 mg / patch.

[0028] Comparative Example 1: Edaravone Patch Prescription Composition and Preparation Process

[0029] Table 2 Edaravone patch prescription composition (without plasticizer)

[0030]

[0031] Preparation method:

[0032] Take 300 parts of polyisobutylene pressure-sensitive adhesive, dissolve in 1200 parts of chloroform, add 30 parts of edaravone, dissolve and disperse evenly, add 5 parts of hydrogenated rosin, 5 parts of laurocapram, dissolve and disperse evenly, then apply the mixed solution on the backing layer, dry and volatilize the solvent, cover and protect, and cut into doses of 30 mg / patch.

[0033] Comparative Example 2: Edaravone Patch Prescription Composition and Preparation Process

[0034] Table 3 Edaravone patch prescription composition (without viscosity enhancer)

[0035]

[0036]

[0037] Preparation method:

[0038] Take 300 parts of polyisobutylene pressure-sensitive adhesive, dissolve in 1200 parts of chloroform, add 30 parts of edaravone, dissolve and disperse evenly, add 60 parts of diethyl phthalate and 5 parts of laurocapram, dissolve and disperse evenly, then apply the mixed solution on the backing layer, dry and volatilize the solvent, cover and protect, and cut into doses of 30 mg / patch.

[0039] Comparative Example 3: Edaravone Patch Prescription Composition and Preparation Process

[0040] Table 4 Edaravone patch prescription composition (without transdermal absorption enhancer)

[0041]

[0042] Preparation method:

[0043] Take 300 parts of polyisobutylene pressure-sensitive adhesive, dissolve in 1200 parts of chloroform, add 30 parts of edaravone, dissolve and disperse evenly, add 60 parts of diethyl phthalate and 5 parts of hydrogenated rosin, dissolve and disperse evenly, then apply the mixed solution on the backing layer, dry the volatile solvent, cover and protect, and cut into doses of 30 mg / patch.

[0044] Embodiment 1 performance test:

[0045] 1. Basic performance Table 5 Appearance results

[0046]

[0047] 2. Absorption effect

[0048] The patch in each of the above embodiments was subjected to a transdermal absorption experiment to observe the absorption effect. The results are shown in Table 6.

[0049]

[0050] Through the above experiments, under the same drug loading of edaravone, the patch has better formability, toughness and viscosity by adding plasticizer and thickener, and the patch has better absorption effect by adding transdermal absorption enhancer.

[0051] Example 2: Edaravone patch prescription composition and preparation process

[0052] Table 7 Edaravone patch prescription composition

[0053]

[0054] Preparation method:

[0055] Take 300 parts of polyisobutylene pressure-sensitive adhesive, dissolve in 1200 parts of chloroform, add 10 parts of edaravone, dissolve and disperse evenly, add 60 parts of diethyl phthalate, 5 parts of hydrogenated rosin, and 5 parts of laurocapram, dissolve and disperse evenly, then apply the mixed solution on the backing layer, dry the volatilized solvent, cover and protect, and cut into doses of 10 mg / patch.

[0056] Example 3: Edaravone patch prescription composition and preparation process

[0057] Table 8 Edaravone patch prescription composition

[0058]

[0059]

[0060] Preparation method:

[0061] Take 300 parts of polyisobutylene pressure-sensitive adhesive, dissolve in 1200 parts of chloroform, add 20 parts of edaravone, dissolve and disperse evenly, add 60 parts of diethyl phthalate, 5 parts of hydrogenated rosin, and 5 parts of laurocapram, dissolve and disperse evenly, then apply the mixed solution on the backing layer, dry the volatilized solvent, cover and protect, and cut into doses of 20 mg / patch.

[0062] Example 4: Edaravone patch prescription composition and preparation process

[0063] Table 9 Prescription composition of Edaravone patch

[0064]

[0065] Preparation method:

[0066] Take 300 parts of polyisobutylene pressure-sensitive adhesive, dissolve in 1200 parts of chloroform, add 40 parts of edaravone, dissolve and disperse evenly, add 60 parts of diethyl phthalate, 5 parts of hydrogenated rosin, and 5 parts of laurocapram, dissolve and disperse evenly, then apply the mixed solution on the backing layer, dry the volatilized solvent, cover and protect, and cut into doses of 40 mg / patch.

[0067] Embodiment 1 performance test:

[0068] 1. Basic performance Table 10 Appearance results of different drug loadings of Edaravone

[0069]

[0070]

[0071] 2. Absorption effect

[0072] The percutaneous absorption test was carried out on the patch in each of the above examples to observe the absorption effect. The results are shown in Table 11. Dissolution time results of different drug loading amounts of edaravone

[0073]

[0074] Through the above experiments, when the drug loading of Idarubicin is 30 mg / patch, the appearance of the patch is better and the absorption effect is better.

[0075] 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 edaravone patch, characterized in that: Edaravone is used to prepare a topical patch for skin application.

2. The patch according to claim 1, characterized in that The patch is composed of the following three parts: (1) a backing layer; (2) a drug-containing adhesive skeleton layer; and (3) a protective layer.

3. The patch according to claim 2, characterized in that: The backing layer is one or two or a combination of two or more of polyester film, polyethylene composite film, polyvinylidene chloride copolymer (PVDC), polyurea, cotton cloth, polyester cloth, polyester-cotton cloth, acetate cloth, stretch cloth, spunlace nonwoven fabric, hot-rolled nonwoven fabric, hot-melt nonwoven fabric, microporous film and multi-layer composite aluminum foil.

4. The patch according to claim 2, characterized in that: The drug-containing adhesive skeleton layer is one or a combination of two or more of polyacrylate, acrylic resin, polyisobutylene pressure-sensitive adhesive, silicone rubber, polyethylene copolymer and polyvinyl chloride.

5. The patch according to claim 4, characterized in that: The drug-containing adhesive skeleton layer also includes a plasticizer, which is one or a combination of two or more of diethyl sebacate, triethyl citrate, diethyl phthalate and mineral oil.

6. The patch according to claim 4, characterized in that: The drug-containing adhesive skeleton layer also includes a tackifier, which is one or a combination of two or more of rosin, hydrogenated rosin, polymerized rosin, rosin glycerol ester, hydrogenated rosin glycerol ester, terpene resin, petroleum resin and polybasic organic acid.

7. The patch according to claim 4, characterized in that: The drug-containing adhesive skeleton layer also includes a transdermal absorption enhancer, which is one or a combination of two or more of ethanol, propylene glycol, oleic acid, laurocapram, peppermint oil and eucalyptus oil.

8. The patch according to claim 2, characterized in that: The protective layer is one or a combination of two or more of release paper, polyethylene film, polypropylene film, polystyrene film, polytetrafluoroethylene film, siliconized polyester, aluminum foil and paper composite film.

9. The method for preparing the Edaravone patch according to any one of claims 1 to 8, characterized in that: The following steps are involved: The pressure-sensitive adhesive material is dissolved in a solvent, the drug is dissolved or dispersed in the pressure-sensitive adhesive solution, and then the mixed solution is coated on a backing layer or a protective layer, the solvent is dried to evaporate, the protective layer or the backing layer is covered, and the drug is cut in divided doses.

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