Pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention relates to a pharmaceutical composition as well as a preparation method and application thereof. The pharmaceutical composition comprises eperisone or pharmaceutically acceptable salt thereof and a stabilizer citric acid. According to the eperisone hydrochloride tablet disclosed by the invention, by adding a proper stabilizer, the impurity control level of the eperisone hydrochloride tablet is improved, the stability of the product in a long-term storage process is improved, and the product quality is further improved.

Description

Technical Field

[0001] The present invention relates to the pharmaceutical field, and in particular to a pharmaceutical composition and a preparation method and application thereof. Background Art

[0002] Eperisone hydrochloride is a central muscle relaxant that can improve muscle tension caused by cervical shoulder-arm syndrome, frozen shoulder, and low back pain. It can also improve spastic paralysis caused by cerebrovascular disorders, spastic spinal cord paralysis, cervical spondylosis, surgical sequelae (including brain and spinal cord tumors), traumatic sequelae (spinal cord injury, head trauma), amyotrophic lateral sclerosis, infantile cerebral palsy, spinocerebellar degeneration, spinal vascular disorders, subacute optico-neuromyelopathy (SMON) and other cerebrospinal diseases.

[0003] The existing eperisone hydrochloride tablets were developed by Eisai (China) Pharmaceutical Co., Ltd., and eperisone hydrochloride tablets (sugar-coated tablets) were first launched in Japan in 1983, and eperisone hydrochloride tablets (film-coated tablets) were first launched in China in 2013. Currently, only the prescription of sugar-coated tablets has been published, and each tablet contains 50 mg of active substance eperisone hydrochloride, and inactive substances include carnauba wax, carboxymethyl cellulose, hydrous silicon dioxide, microcrystalline cellulose, titanium oxide, stearic acid, calcium stearate, refined sucrose, talc, precipitated calcium carbonate, corn starch, white shellac, hydroxypropyl cellulose, pullulan, povidone, and polyethylene glycol 6000.

[0004] The commercially available samples prepared by the existing technical prescriptions have an increase in impurity K of more than 0.5% and a total impurity level of more than 1.0% during long-term storage, and the stability is poor. It is required to be sealed and stored in a cool, dark and dry place, and the storage conditions are also relatively harsh. Summary of the invention

[0005] Problem that the invention aims to solve

[0006] In view of the above problems existing in the prior art, the purpose of the present invention is to improve the impurity control level of commercially available eperisone hydrochloride tablets, improve product stability by adding a suitable stabilizer, and make it suitable for commercial large-scale production.

[0007] Solutions for solving problems

[0008] The present invention provides a pharmaceutical composition, which comprises: eperisone or a pharmaceutically acceptable salt thereof, and a stabilizer, wherein the stabilizer comprises citric acid.

[0009] Preferably, the pharmaceutical composition further comprises a filler, a binder, a disintegrant and a lubricant.

[0010] Preferably, the pharmaceutically acceptable salt of eperisone is eperisone hydrochloride;

[0011] Preferably, the filler is selected from one or more of calcium hydrogen phosphate, microcrystalline cellulose, lactose, corn starch, and calcium sulfate, preferably microcrystalline cellulose and corn starch;

[0012] Preferably, the binder is selected from one or more of ethyl cellulose, hydroxypropyl cellulose, povidone K30, and hydroxypropyl methyl cellulose, preferably hydroxypropyl cellulose;

[0013] Preferably, the stabilizer further comprises one or more of malic acid, lactic acid, sorbic acid, alginic acid, fumaric acid, tartaric acid, calcium citrate, and stearic acid, preferably tartaric acid, calcium citrate, and stearic acid;

[0014] Preferably, the disintegrant is selected from one or more of sodium carboxymethyl starch, corn starch, and low-substituted hydroxypropyl cellulose, preferably corn starch;

[0015] Preferably, the lubricant is selected from one or more of magnesium stearate, calcium stearate, hydrogenated vegetable oil, polyethylene glycols and magnesium laurate sulfate, preferably calcium stearate.

[0016] Preferably, the pharmaceutical composition consists of eperisone hydrochloride, microcrystalline cellulose, corn starch, hydroxypropyl cellulose, citric acid and calcium stearate.

[0017] Preferably, the pharmaceutical composition is composed of the following ingredients in weight percentage: 50%-70% eperisone, 20%-40% filler, 1%-10% binder, 0.5%-3% stabilizer, 1%-10% disintegrant and 0.5%-5% lubricant;

[0018] More preferably, the pharmaceutical composition is composed of the following ingredients in weight percentage: 62.5% eperisone, 25.9% filler, 5% binder, 1% stabilizer, 5% disintegrant and 0.6% lubricant;

[0019] Most preferably, the pharmaceutical composition consists of the following ingredients in weight percentage: 62.5% eperisone hydrochloride, 9.9% microcrystalline cellulose, 21% corn starch, 5% hydroxypropyl cellulose, 1% citric acid and 0.6% calcium stearate.

[0020] The present invention also provides a method for preparing the pharmaceutical composition, which comprises the following steps:

[0021] (1) Weighing ingredients;

[0022] (2) granulation and dry mixing;

[0023] (3) Making soft materials, sieving wet granules;

[0024] (4) Drying;

[0025] (5) Whole grains;

[0026] (6) Total mixing;

[0027] (7) tableting;

[0028] (8) coating;

[0029] (9) Aluminum-plastic packaging.

[0030] Preferably, the weighing is according to the prescription amount;

[0031] Preferably, the dry mixing is adding eperisone, filler and binder into a granulation pot of a wet granulator and mixing;

[0032] Preferably, the soft material is prepared by dissolving citric acid in water and atomizing the obtained solution using a spray gun to prepare the soft material;

[0033] Preferably, the sieving wet granulation is to transfer the soft material to a crushing granulator for granulation;

[0034] Preferably, the drying is fluidized bed drying;

[0035] Preferably, the granulation is 18-mesh sieve granulation;

[0036] Preferably, the total mixing is to add the lubricant and disintegrant into a mixer and mix them evenly;

[0037] Preferably, the tabletting is performed by adding the granules obtained by the total mixing into a hopper of a tablet press, using a Φ6mm shallow arc die, and tabletting to obtain a plain tablet;

[0038] Preferably, the coating is a coating solution prepared with a concentration of 18%, which is used for coating plain tablets;

[0039] Preferably, the aluminum-plastic packaging is carried out after coating is completed.

[0040] The present invention also provides an application of the pharmaceutical composition in preparing a medicine for improving muscle tension or spastic paralysis.

[0041] Preferably, the muscle tension state includes the muscle tension state caused by cervical shoulder-arm syndrome, frozen shoulder, and low back pain, and the spastic paralysis includes cerebrovascular disorders, spastic spinal cord paralysis, cervical spondylosis, surgical sequelae, traumatic sequelae, amyotrophic lateral sclerosis, infantile cerebral palsy, spinal cerebellar degeneration, spinal vascular disorders, subacute optico-neuropathy (SMON) and other cerebrospinal diseases.

[0042] Preferably, the pharmaceutical composition is a granule, capsule, tablet, pill, powder or other oral preparation; more preferably, the pharmaceutical composition is a tablet.

[0043] Effects of the Invention

[0044] The eperisone hydrochloride tablets of the present invention improve the impurity control level of the eperisone hydrochloride tablets by adding a suitable stabilizer, improve the stability of the product during long-term storage, and thus improve the product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The present invention is a process flow chart of the preparation method of Eperisone Hydrochloride Tablets. DETAILED DESCRIPTION

[0046] In order to make the technical solutions and beneficial effects of the present invention more clearly understandable, the following is a detailed description by listing specific embodiments. The drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

[0047] The materials, consumables and equipment information, reference preparations and control substances involved in the examples and comparative examples are shown in the following table.

[0048] Table 1 Material information

[0049]

[0050]

[0051] Table 2 Equipment information

[0052] Instrument Name model Wet Mixing Granulator Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd. Fluidized bed granulation dryer Jiangsu Fanqun Drying Equipment Factory Granulating machine Zhejiang Canaan Pharmaceutical Equipment Co., Ltd. Automatic lifting hopper mixer Zhejiang Canaan Pharmaceutical Equipment Co., Ltd. Fully automatic high speed rotary tablet press Longlife (Beijing) Technology Co., Ltd. High efficiency coating machine Beijing Aeronautical Industry Beijing Aeronautical Manufacturing Engineering Research Institute Fully automatic high speed blister packaging machine Zhejiang Mingtian Machinery Co., Ltd.

[0053] Table 3 Sample information

[0054] name source Specification batch number Eperisone Hydrochloride Tablets Qingdao Guohai 50mg 21100704 Eperisone Hydrochloride Tablets Hunan Asia University 50mg 20210712 Eperisone Hydrochloride Tablets self made 50mg /

[0055] The specific experimental steps or conditions not specified in the examples are all carried out according to the operations or conditions of the conventional experimental steps described in the literature in the field. The materials, consumables and equipment used are all conventional products that can be purchased commercially, including but not limited to the materials, consumables and equipment used in the examples of this application.

[0056] As used herein, the term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Non-limiting examples of pharmaceutically acceptable salts include inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, nitrates, perchlorates, and organic acid salts such as methanesulfonates, ethanesulfonates, acetates, trifluoroacetates, glycolates, isethionates, oxalates, maleates, tartrates, citrates, succinates, malonates, benzenesulfonates, p-toluenesulfonates, malate, fumarate, lactate, lactobionate, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, malonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, and the like.

[0057] As used herein, the term "pharmaceutically acceptable excipient" refers to any pharmaceutically acceptable inactive component of the composition. As is well known in the art, excipients include diluents, thickeners, buffers, binders, lubricants, stabilizers, disintegrants, colorants, antioxidants / preservatives, pH-adjusting agents, etc.

[0058] As used herein, the term "filler" refers to an inert substance that produces the desired volume, flow properties, and compression characteristics in the formulation of a liquid or solid dosage form. Such compounds include, by way of example and without limitation, liquid carriers (e.g., water, alcohol, solvents, etc.), dibasic calcium phosphate, kaolin, lactose, dextrose, magnesium carbonate, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, and starch, as well as other substances known to those of ordinary skill in the art.

[0059] As used herein, the term "stabilizer" refers to an ingredient or combination of ingredients that keeps a product from changing over time.

[0060] As used herein, the term "binder" refers to an agent used to impart adhesive properties to a powdered substance. "Binders," as they are sometimes known, impart cohesiveness to a tablet, thereby ensuring that the tablet remains intact after compression and improving free-flowing properties by formulating particles of the desired hardness and size. Materials used as binders include starch; gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, microcrystalline cellulose, microcrystalline glucose, amylose, and larch arabinogalactan, among others.

[0061] As used herein, the term "soft material" refers to an intermediate before granulation in wet granulation.

[0062] As used herein, the term "granulation" refers to the process of passing a material through a certain process to compress or extrude it into a granular material with a certain shape and size.

[0063] As used herein, the term "sizing" refers to the operation of converting bulk particles of different sizes into granules of a certain shape and size.

[0064] The present invention provides a pharmaceutical composition, which comprises: eperisone or a pharmaceutically acceptable salt thereof, and a stabilizer, wherein the stabilizer comprises citric acid.

[0065] In certain embodiments, the pharmaceutical composition further comprises a filler, a binder, a disintegrant, and a lubricant.

[0066] In certain embodiments, the pharmaceutically acceptable salt of eperisone is eperisone hydrochloride.

[0067] In certain embodiments, the filler is selected from one or more of dibasic calcium phosphate, microcrystalline cellulose, lactose, corn starch, and calcium sulfate.

[0068] In certain embodiments, the fillers are microcrystalline cellulose and corn starch.

[0069] In certain embodiments, the binder is selected from one or more of ethyl cellulose, hydroxypropyl cellulose, povidone K30, and hydroxypropyl methyl cellulose.

[0070] In certain embodiments, the binder is hydroxypropylcellulose.

[0071] In certain embodiments, the stabilizer further comprises one or more of malic acid, lactic acid, sorbic acid, alginic acid, fumaric acid, tartaric acid, calcium citrate, and stearic acid.

[0072] In certain embodiments, the stabilizer further comprises tartaric acid, calcium citrate, and stearic acid.

[0073] In certain embodiments, the disintegrant is selected from one or more of sodium starch glycolate, corn starch, and low-substituted hydroxypropyl cellulose.

[0074] In certain embodiments, the disintegrant is corn starch.

[0075] In certain embodiments, the lubricant is selected from one or more of magnesium stearate, calcium stearate, hydrogenated vegetable oil, polyethylene glycols and magnesium laurate sulfate.

[0076] In certain embodiments, the lubricant is calcium stearate.

[0077] In certain embodiments, the pharmaceutical composition consists of eperisone hydrochloride, microcrystalline cellulose, corn starch, hydroxypropyl cellulose, citric acid, and calcium stearate.

[0078] In certain embodiments, the pharmaceutical composition is composed of the following ingredients in weight percentage: 50%-70% eperisone, 20%-40% filler, 1%-10% binder, 0.5%-3% stabilizer, 1%-10% disintegrant, and 0.5%-5% lubricant.

[0079] In certain embodiments, the pharmaceutical composition is composed of the following ingredients in weight percentages: 62.5% eperisone, 25.9% filler, 5% binder, 1.0% stabilizer, 5% disintegrant, and 0.6% lubricant.

[0080] In certain embodiments, the pharmaceutical composition is composed of the following ingredients in weight percentage: 62.5% eperisone hydrochloride, 9.9% microcrystalline cellulose, 21% corn starch, 5% hydroxypropyl cellulose, 1% citric acid, and 0.6% calcium stearate.

[0081] The present invention also provides a method for preparing the pharmaceutical composition, which comprises the following steps:

[0082] (1) Weighing ingredients;

[0083] (2) granulation and dry mixing;

[0084] (3) Making soft materials, sieving wet granules;

[0085] (4) Drying;

[0086] (5) Whole grains;

[0087] (6) Total mixing;

[0088] (7) tableting;

[0089] (8) coating;

[0090] (9) Aluminum-plastic packaging.

[0091] In certain embodiments, the weighing is a prescribed amount.

[0092] In certain embodiments, the prescription amounts are as shown in Table 4.

[0093] In certain embodiments, the prescription amount includes: 50 mg of eperisone hydrochloride, 7.92 mg of microcrystalline cellulose, 4 mg of hydroxypropyl cellulose, 0.8 mg of citric acid, 12.8 mg of corn starch (internal addition), 4 mg of corn starch (external addition), and 0.48 mg of calcium stearate.

[0094] In certain embodiments, the internal addition is added as a filler during the granulation process.

[0095] In certain embodiments, the external additive is added during the overall mixing as a disintegrant.

[0096] In certain embodiments, the dry blending is performed by adding the eperisone, filler, and binder into a granulation pan of a wet granulator and mixing.

[0097] In certain embodiments, the dry blending is to sequentially add eperisone hydrochloride, microcrystalline cellulose, hydroxypropyl cellulose, and corn starch (added internally) into a granulation pot of a wet granulator for mixing.

[0098] In certain embodiments, the dry blending is to sequentially add 50 mg of eperisone hydrochloride, 7.92 mg of microcrystalline cellulose, 4 mg of hydroxypropyl cellulose, and 12.8 mg of corn starch into a granulation pot of a wet granulator and mix them.

[0099] In certain embodiments, the soft material is prepared by dissolving citric acid in water and atomizing the obtained solution using a spray gun to prepare the soft material.

[0100] In certain embodiments, the soft material is prepared by dissolving 0.8 mg of citric acid in water to obtain a citric acid solution, and atomizing the obtained solution using a spray gun to prepare the soft material.

[0101] In certain embodiments, the sieving wet granulation is to transfer the soft material to a crushing granulator for granulation.

[0102] In certain embodiments, the sieving wet granulation is to transfer the soft material to a crushing and granulating machine and granulate it through a 10-mesh screen.

[0103] In certain embodiments, the drying is fluid drying.

[0104] In certain embodiments, the drying is boiling drying, and the drying is stopped when the moisture content of the particles is 2-4%.

[0105] In certain embodiments, the granulation is 18 mesh granulation.

[0106] In certain embodiments, the total mixing is to add the lubricant and disintegrant into a mixer and mix them evenly.

[0107] In certain embodiments, the total mixing is to add calcium stearate and corn starch (external) into a mixer hopper and mix them evenly.

[0108] In certain embodiments, the total mixing is performed by adding 0.48 mg of calcium stearate and 4 mg of corn starch into a mixer hopper and mixing them evenly.

[0109] In certain embodiments, the tableting is performed by tableting the granules obtained by the overall blending using a tablet press hopper.

[0110] In certain embodiments, the tableting is performed by adding the granules obtained by the total mixing into a tablet press hopper, and tableting is performed using a Φ6mm shallow arc die to obtain plain tablets.

[0111] In certain embodiments, the tablet hardness is >2.5 kg.

[0112] In certain embodiments, the coating is a coating solution formulated at a concentration of 18% for coating plain tablets.

[0113] In certain embodiments, the preparation is to weigh the film coating premix, add it into purified water, and stir until it is completely dissolved to obtain a coating solution with a concentration of 18%.

[0114] In certain embodiments, the coating has a weight gain of 2-4%.

[0115] In certain embodiments, the blister packaging is performed after coating is completed.

[0116] The present invention also provides an application of the pharmaceutical composition in preparing a medicine for improving muscle tension or spastic paralysis.

[0117] In certain embodiments, the muscle tension state includes the muscle tension state caused by cervical shoulder-arm syndrome, frozen shoulder, and low back pain, and the spastic paralysis includes cerebrovascular disorders, spastic spinal cord paralysis, cervical spondylosis, surgical sequelae, sequelae of trauma, amyotrophic lateral sclerosis, infantile cerebral palsy, spinocerebellar degeneration, spinal vascular disorders, subacute optico-neuromyelopathy (SMON) and other cerebrospinal cord diseases.

[0118] In certain embodiments, the pharmaceutical composition is a granule, capsule, tablet, pill, powder or other oral preparation.

[0119] In certain embodiments, the pharmaceutical composition is a tablet.

[0120] Example 1: Preparation of Eperisone Hydrochloride Tablets Using Citric Acid as a Stabilizer

[0121] Preparation process Figure 1 As shown, the specific steps are as follows:

[0122] 1. Weighing ingredients: Weigh eperisone hydrochloride, microcrystalline cellulose, hydroxypropyl cellulose (HPC-L), citric acid, corn starch (internal addition: added as a filler during granulation), corn starch (external addition: added as a disintegrant during total mixing) and calcium stearate according to the prescription amount (as shown in Table 4), and the tablet weight is 80 mg.

[0123] Table 4 Prescription of Eperisone Hydrochloride Tablets

[0124] Element Content (mg / tablet) Eperisone Hydrochloride 50 Microcrystalline Cellulose 7.92 Hydroxypropylcellulose (HPC-L) 4.0 Citric acid 0.8 Corn starch (added) 12.8 Corn starch (added) 4.0 Calcium stearate 0.48

[0125] 2. Granulation dry mixing: Add eperisone hydrochloride, microcrystalline cellulose, hydroxypropyl cellulose and corn starch (added internally) into the granulation pot of the wet granulator and mix them in sequence.

[0126] 3. Prepare soft material, sieve wet granulation: After the above materials are mixed evenly, dissolve the prescribed amount of citric acid in purified water to obtain a citric acid solution, and use a spray gun to atomize the solution to prepare soft material. Transfer the soft material to a crushing and granulating machine and granulate it through a 10-mesh screen.

[0127] 4. Drying: Boiling drying, stop drying when the moisture content of the particles is 2-4%.

[0128] 5. Whole grain: sieve with 18 mesh.

[0129] 6. Total mixing: Add the specified amount of calcium stearate and corn starch (external) into the mixer hopper and mix evenly.

[0130] 7. Tablet pressing: Φ6mm shallow arc die, tablet pressing, hardness>2.5kg.

[0131] 8. Coating: Weigh the film coating premix, add it into purified water, stir until completely dissolved, and obtain a coating solution with a concentration of 18%. Use it for coating plain tablets, and the coating weight gain is 2-4%.

[0132] 9. Aluminum-plastic packaging: Aluminum-plastic packaging is carried out after coating is completed.

[0133] Example 2: Preparation of Eperisone Hydrochloride Tablets Using Tartaric Acid as a Stabilizer

[0134] Tartaric acid was used to replace citric acid as a stabilizer, and the rest of the formula and process were the same as in Example 1.

[0135] Example 3: Preparation of Eperisone Hydrochloride Tablets Using Stearic Acid as a Stabilizer

[0136] Stearic acid was used to replace citric acid as a stabilizer, and the rest of the formula and process were the same as in Example 1.

[0137] Example 4: Preparation of Eperisone Hydrochloride Tablets Using Calcium Citrate as a Stabilizer

[0138] Calcium citrate was used to replace citric acid as a stabilizer, and the rest of the formula and process were the same as in Example 1.

[0139] Comparative Example 1: Preparation of Eperisone Hydrochloride Tablets without Adding Stabilizer

[0140] Without adding citric acid, the rest of the prescription and process are the same as those in Example 1.

[0141] Example 5: Quality Inspection of Eperisone Hydrochloride Tablets

[0142] 1. Determination of related substances by high performance liquid chromatography, the specific steps are as follows:

[0143] (1) Test solution: Take an appropriate amount of fine powder of the product (equivalent to 250 mg of eperisone hydrochloride) and place it in a 100 ml volumetric flask. Add an appropriate amount of 0.1 mol / L hydrochloric acid solution and dissolve it by ultrasonication. Let it cool and dilute it to the mark with 0.1 mol / L hydrochloric acid solution. Shake well and filter. Take the filtrate.

[0144] (2) Reference solution: Accurately measure an appropriate amount of the test sample solution and quantitatively dilute it with 0.1 mol / L hydrochloric acid solution to make a solution containing approximately 12.5 μg per 1 ml.

[0145] (3) Sensitivity solution: Accurately measure an appropriate amount of the control solution and quantitatively dilute it with 0.1 mol / L hydrochloric acid solution to make a solution containing approximately 1.25 μg per 1 ml.

[0146] (4) System suitability solution: Take about 10 mg of eperisone hydrochloride and place it in a 10 ml stoppered test tube. Add 2 ml of 30% hydrogen peroxide solution and heat it in a water bath until about 1 ml remains. Dilute it to the mark with 0.1 mol / L hydrochloric acid solution and shake well.

[0147] (5) Chromatographic conditions: Octadecylsilane bonded silica gel was used as the filler (Agilent C18, 250 mm × 4.6 mm, 5 μm or a chromatographic column of equivalent performance); methanol-water-diethylamine (700:300:5, pH adjusted to 7.5 with glacial acetic acid) was used as the mobile phase; the detection wavelength was 254 nm; the injection volume of the system suitability solution and the sensitivity solution was 10 μl, and the injection volume of other solutions was 20 μl.

[0148] (6) System suitability requirements: In the system suitability solution chromatogram, the theoretical plate number calculated based on the eperisone hydrochloride peak should be no less than 2000, and the separation between the eperisone hydrochloride peak and the impurity peak with a relative retention time of about 1.2 should be greater than 2. In the sensitivity solution chromatogram, the signal-to-noise ratio of the main component peak height should be greater than 10.

[0149] (7) Determination method: Accurately measure the test solution and the control solution, inject them into the liquid chromatograph respectively, and record the chromatogram until 3 times the retention time of the main component peak.

[0150] If there are impurity peaks in the chromatogram of the test solution, the area of ​​a single impurity peak shall not be greater than the main peak area of ​​the control solution (0.5%), and the sum of the areas of the impurity peaks shall not be greater than twice the main peak area of ​​the control solution (1.0%). Chromatographic peaks smaller than the main peak area of ​​the sensitivity solution shall be ignored (0.05%). The experimental results are shown in Table 5.

[0151] 2. Determine the content of eperisone hydrochloride by UV-visible spectrophotometry. The specific steps are as follows:

[0152] (1) Test solution: Take 20 tablets of this product (remove the coating if necessary), accurately weigh, grind, accurately weigh an appropriate amount (equivalent to 50 mg of eperisone hydrochloride), place in a 100 ml volumetric flask, add an appropriate amount of 0.1 mol / L hydrochloric acid solution, shake to dissolve the eperisone hydrochloride, dilute to the scale with 0.1 mol / L hydrochloric acid solution, shake well, filter, accurately measure 2 ml of the filtrate, place in a 100 ml volumetric flask, dilute to the scale with 0.1 mol / L hydrochloric acid solution, and shake well.

[0153] (2) Reference solution: Take an appropriate amount of the reference substance, accurately weigh it, dissolve it in 0.1 mol / L hydrochloric acid solution and quantitatively dilute it to make a solution containing about 10 μg per 1 ml.

[0154] Take the test solution and the reference solution, and measure the absorbance at a wavelength of 261 nm and calculate the content according to the UV-visible spectrophotometry (General Chapter 0401 of the Chinese Pharmacopoeia). The results are shown in Table 5.

[0155] Table 5 Test results of related substance content of Eperisone Hydrochloride Tablets

[0156]

[0157]

[0158]

[0159] According to the results of the related substance detection of the influencing factors placed at 60°C for 10 days, the increase in the impurity K and the total impurity of the samples prepared by adding citric acid, tartaric acid or stearic acid to the prescription was small, both <0.2. The increase in the impurity K and the total impurity of the samples prepared by adding calcium citrate and without adding stabilizer to the prescription was large, among which the increase in impurity K was >0.4 and the increase in total impurity was >0.5.

[0160] In addition, compared with the commercial samples of Qingdao Guohai and Hunan Yada, the homemade samples with citric acid, tartaric acid or stearic acid as stabilizers had a lower increase in total impurities, and the product quality was better. Among them, the product with citric acid as stabilizer had an increase in impurity K and total impurities of <0.1, and the quality was the best.

[0161] It should be understood that the above embodiments are exemplary and are not intended to include all possible implementations included in the claims. Various modifications and changes may be made on the basis of the above embodiments without departing from the scope of the present disclosure. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only express several implementations of the present invention and do not limit the scope of protection of the patent of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: eperisone or a pharmaceutically acceptable salt thereof, and a stabilizer, wherein the stabilizer comprises citric acid.

2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises a filler, a binder, a disintegrant and a lubricant.

3. The pharmaceutical composition according to claim 2, characterized in that Preferably, the pharmaceutically acceptable salt of eperisone is eperisone hydrochloride; Preferably, the filler is selected from one or more of calcium hydrogen phosphate, microcrystalline cellulose, lactose, corn starch, and calcium sulfate, preferably microcrystalline cellulose and corn starch; Preferably, the binder is selected from one or more of ethyl cellulose, hydroxypropyl cellulose, povidone K30, and hydroxypropyl methyl cellulose, preferably hydroxypropyl cellulose; Preferably, the stabilizer further comprises one or more of malic acid, lactic acid, sorbic acid, alginic acid, fumaric acid, tartaric acid, calcium citrate, and stearic acid, preferably tartaric acid, calcium citrate, and stearic acid; Preferably, the disintegrant is selected from one or more of sodium carboxymethyl starch, corn starch, and low-substituted hydroxypropyl cellulose, preferably corn starch; Preferably, the lubricant is selected from one or more of magnesium stearate, calcium stearate, hydrogenated vegetable oil, polyethylene glycols and magnesium laurate sulfate, preferably calcium stearate.

4. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition consists of eperisone hydrochloride, microcrystalline cellulose, corn starch, hydroxypropyl cellulose, citric acid and calcium stearate.

5. The pharmaceutical composition according to any one of claims 2 to 4, characterized in that The pharmaceutical composition is composed of the following ingredients in weight percentage: 50%-70% eperisone, 20%-40% filler, 1%-10% binder, 0.5%-3% stabilizer, 1%-10% disintegrant and 0.5%-5% lubricant; Preferably, the pharmaceutical composition is composed of the following ingredients in weight percentage: 62.5% eperisone, 25.9% filler, 5% binder, 1.0% stabilizer, 5% disintegrant and 0.6% lubricant; More preferably, the pharmaceutical composition is composed of the following ingredients in weight percentage: 62.5% eperisone hydrochloride, 9.9% microcrystalline cellulose, 21% corn starch, 5% hydroxypropyl cellulose, 1% citric acid, and 0.6% calcium stearate.

6. A method for preparing the pharmaceutical composition according to any one of claims 1 to 5, characterized in that: The method comprises the following steps: (1) Weighing ingredients; (2) granulation and dry mixing; (3) Making soft materials, sieving wet granules; (4) Drying; (5) Whole grains; (6) Total mixing; (7) tableting; (8) coating; (9) Aluminum-plastic packaging.

7. The method according to claim 6, characterized in that The weighing is according to the prescription amount; Preferably, the dry mixing is adding eperisone, filler and binder into a granulation pot of a wet granulator and mixing; Preferably, the soft material is prepared by dissolving citric acid in water and atomizing the obtained solution using a spray gun to prepare the soft material; Preferably, the sieving wet granulation is to transfer the soft material to a crushing granulator for granulation; Preferably, the drying is fluidized bed drying; Preferably, the granulation is 18-mesh sieve granulation; Preferably, the total mixing is to add the lubricant and disintegrant into a mixer and mix them evenly; Preferably, the tabletting is performed by adding the granules obtained by the total mixing into a hopper of a tablet press, using a Φ6mm shallow arc die, and tabletting to obtain a plain tablet; Preferably, the coating is a coating solution prepared with a concentration of 18%, which is used for coating plain tablets; Preferably, the aluminum-plastic packaging is carried out after coating is completed.

8. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a medicament for improving muscle tension or spastic paralysis.

9. The use according to claim 8, characterized in that: The muscle tension state includes the muscle tension state caused by cervical shoulder-arm syndrome, frozen shoulder, and low back pain; the spastic paralysis includes cerebrovascular disorders, spastic spinal cord paralysis, cervical spondylosis, surgical sequelae, traumatic sequelae, amyotrophic lateral sclerosis, infantile cerebral palsy, spinal cerebellar degeneration, spinal vascular disorders, subacute optico-neuropathy (SMON) and spastic paralysis caused by other brain and spinal cord diseases.

10. The use according to claim 8, characterized in that: The pharmaceutical composition is a granule, capsule, tablet, pill, powder or other oral preparation; preferably, the pharmaceutical composition is a tablet.

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