A kind of tizanidine liquid preparation and use thereof

Abstract

The invention discloses a tizanidine liquid preparation, the liquid preparation includes active ingredients, disodium EDTA and other pharmaceutical excipients; the active ingredient is tizanidine or one or more of its pharmaceutically acceptable salt, solvate, and hydrate; the invention also discloses the use of tizanidine liquid preparation in the preparation of a medicine for treating muscle spasm. The liquid preparation of the present invention has good chemical and physical stability, and its bioavailability before and after meals is equivalent to that of the existing listed tizanidine solid preparation, and food has little effect on its drug action speed, and its drug action speed under postprandial conditions is faster than that of solid preparations, and at the same time, it reduces the incidence of adverse reactions, has the advantage of more convenient dosage titration adjustment, and is also easy to improve the compliance of medication for patients such as infants, the elderly, patients with dysphagia, some mental illness patients and patients with difficulty in changing bed position, so as to meet clinical needs.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and more specifically, to a tizanidine liquid preparation and application thereof. Background Art

[0002] Tizanidine is a centrally acting alpha-2 adrenergic agonist used to treat muscle spasms.

[0003] The chemical structure of tizanidine is shown below:

[0004]

[0005] The brand name of tizanidine currently on the market is Used to treat muscle spasms due to spinal cord injury or multiple sclerosis.

[0006] Among the population of people who are prescribed tizanidine, the elderly account for the largest proportion. According to the Medical Expenditure Survey (MEPS) of the Agency for Healthcare Research and Quality (AHRQ) in the United States, the number of people prescribed tizanidine is about 2.06 million. According to the data on some prescription drugs from MEDICARED in the United States, in 2018, about 1.46 million elderly / disabled / severely ill patients were prescribed tizanidine. It can be inferred that the elderly account for more than 60%.

[0007] Elderly people with neurological diseases are more likely to suffer from dysphagia: dysphagia is a common clinical symptom, and central nervous system diseases are common diseases that cause dysphagia. Abroad, the incidence of dysphagia in acute stroke patients is 37%-78%; in China, the incidence of dysphagia is 51%-73%. Although most patients recover their swallowing function one month after the stroke, some patients still have dysphagia six months after the stroke. The overall prevalence of dysphagia in MS patients is about 33-43%, the incidence of dysphagia in acute cervical spinal cord injury is about 30.9%, and the incidence of dysphagia in brain injury is 27-30%.

[0008] Solid oral dosage forms play the largest and most important role in the whole pharmaceutical preparation. At present, the tizanidine listed dosage forms are mostly common tablets, and capsule preparations are also available; because the medicine of common tablets / capsules generally needs to help swallowing with drinking water when taking, therefore, the common tablets / capsules of tizanidine hydrochloride for some special populations such as infants, the elderly, patients with dysphagia, some mental patients and patients with difficult changes in bed position have poor compliance, can not meet the needs of clinical medication. In clinical practice, tablets are often crushed or capsules are opened to give patients with dysphagia, crushing / opening / mixing other drugs for administration has the risk of causing adverse reactions and medical malpractice. Because a large amount of patients have difficulty swallowing solid oral dosage forms, therefore medically developed oral medicines in multiple solid forms such as lozenges, sublingual tablets, effervescent tablets, chewable tablets, orodisintegrating tablets, soluble tablets.

[0009] There are certain limitations in the dosage titration process of oral solid preparations: 1) inaccurate dose segmentation; 2) multiple specifications need to be developed, which increases the cost of enterprise preparation development; 3) during the dosage titration process according to the changes in the patient's condition, changes in specification requirements can easily lead to waste. However, liquid preparations do not have the above problems in the dosage titration process.

[0010] This shows that, compared with oral solid preparations, the development of tizanidine liquid preparations has the advantage that dosage titration is more convenient, and is also easy to improve the compliance of medication of patients such as infants, the elderly, dysphagia, some mental illness patients and patients with difficult changes in bedridden body position, meeting clinical needs.

[0011] It is well known that active pharmaceutical preparations in liquid form are more susceptible to chemical instability than active pharmaceutical preparations in solid form. Although active pharmaceutical preparations in liquid form have obvious clinical advantages, they are often deterred from developing formulations due to stability issues.

[0012] The detection of impurities in drug-related substances is an important indicator to measure the chemical stability of drugs. The higher the content of impurities in related substances, the worse the chemical stability. The chemical stability of liquid preparations greatly affects their clinical promotion and use. At the same time, the content of impurities in related substances affects the safety of medication. The more impurities there are, the greater the possible risk of medication.

[0013] Because there is no listed product of tizanidine liquid preparation in the market at present, pharmacopoeia does not do relevant regulation to the related substance of tizanidine liquid preparation, therefore the related substance of tizanidine liquid preparation should be referred to in the relevant regulation about tizanidine tablet related substance in the Chinese Pharmacopoeia--the total amount of impurities of tizanidine tablet related substance must not be greater than 0.5%.

[0014] At present, the common tablets and capsule preparations of tizanidine on the market have a greater probability of adverse reactions after human body takes them. (Tizanidine hydrochloride) tablet and capsule are taken as an example, and its specification sheet states clearly, under the single-dose administration situation, among the adverse reactions that the patient occurs, only the incidence rate of this adverse reaction of 'somnolence (somnolence)' is as high as 78% (single dose 8mg) / 92% (single dose 16mg). Adverse drug reaction refers to the reaction that the drug produces in the middle of normal usage and dosage use that is irrelevant to the medication purpose or is harmful to the collective, not only refers to the side effect of the drug. The quality, dosage form, impurity, adjuvant, content etc. of the drug are all one of the factors that cause adverse drug reaction to occur. The common tablet and capsule preparation adverse reactions of tizanidine have greatly affected the safety of tizanidine drug use, meanwhile, the high incidence rate of somnolence in its adverse reactions has also affected the normal life of the patient taking the drug to a certain extent, greatly reducing the compliance of the patient taking the drug. Therefore, how to reduce the adverse reaction incidence rate of tizanidine drug under normal use is of great significance for enhancing the safety of drug use and the compliance of the patient taking the drug.

[0015] Meanwhile, for muscle spasm, the faster the speed of drug action, the more quickly the pain of the patient can be relieved.And for oral medication, food is often larger on the impact of drug action speed, and the drug peak time of the common tablets and capsule preparations of existing tizanidine under postprandial conditions is significantly extended, which is not conducive to quickly alleviating the pain of the patient.Therefore, how to reduce the impact of food on drug peak time, accelerate the drug action speed of tizanidine medicine under postprandial conditions, is also one of the problems to be solved.

[0016] In addition to the consideration of factors such as stability, adverse reactions and drug action speed, the development of new dosage forms of tizanidine liquid drugs also requires the impact of dosage form changes on drug efficacy. The drug dosage form determines the route and method of administration, directly affects the degree of drug absorption, and thus affects the drug efficacy; the physical and chemical properties of the drug will directly affect the release of the drug, thereby affecting the therapeutic effect of the drug; the choice of excipients in drug preparations not only affects the production process and the appearance and physical properties of the preparation, but also changes the bioavailability of the preparation, thereby affecting the efficacy of the preparation.

[0017] Therefore, develop a kind of impurity content is few, stability is strong, adverse reaction rate is little, food has little influence on drug action speed, drug action speed is fast under postprandial condition, and meeting clinical needs with the tizanidine liquid preparation equivalent to solid preparation bioavailability is a problem demanding urgent solution. Summary of the invention

[0018] In view of this, the object of the present invention is to provide a kind of tizanidine liquid preparation, the content of its impurity is few, strong stability; Compared to tizanidine solid preparation, its adverse reaction rate is little, food has little influence on drug action speed, drug action speed is fast under postprandial condition, and is equivalent to tizanidine solid preparation bioavailability.

[0019] In the present invention, the tizanidine liquid preparation comprises an active ingredient, disodium EDTA and other pharmaceutical excipients; the active ingredient is one or more of tizanidine or its pharmaceutically acceptable salt, solvate and hydrate.

[0020] Preferably, the pH value of the tizanidine liquid preparation is greater than 3.5 and less than 6.5.

[0021] Preferably, the pH value of the tizanidine liquid preparation is 4.0-6.1.

[0022] Preferably, the tizanidine liquid preparation comprises a solvent, and the solvent is water.

[0023] Preferably, the other pharmaceutical excipients are one or more of a pH regulator, a preservative, a solubilizer, a thickener, a flavoring agent, a sweetener and a coloring agent.

[0024] Preferably, the pH regulator is one or more of citric acid, ascorbic acid, acetic acid, tartaric acid, trisodium citrate, sodium citrate, potassium citrate, sodium phosphate, tricalcium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, calcium carbonate, magnesium hydroxide, hydrochloric acid, and sodium hydroxide;

[0025] The cosolvent is one or more of sorbitol, maltitol, mannitol, isomalt, xylitol, glucose and fructose;

[0026] The preservative is one or more of sodium benzoate, ethylparaben, propylparaben, sodium methylparaben, sodium ethylparaben, sodium propylparaben, benzoic acid, potassium phenylpropionate, sorbic acid, sodium sorbate, calcium sorbate, potassium sorbate, dehydroacetic acid, sodium diacetate, and calcium propionate;

[0027] The thickener is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, colloidal silicon dioxide, methylcellulose, sodium carboxymethyl cellulose, sodium alginate, and cyclodextrin;

[0028] The aroma is one or more of strawberry aroma, orange aroma, banana aroma, cherry aroma, lemon aroma, cardamom aroma, fennel aroma, mint aroma, menthol aroma, and vanillin aroma;

[0029] The sweetener is one or more of sucralose, glycerol, sodium saccharin, glucose, stevioside, stevioside, aspartame, cyclamate, acesulfame potassium, alitame, and neotame;

[0030] The colorant is one or more of amaranth, carmine, erythrosine, new red, lemon yellow, sunset yellow, indigo, beetroot red, lac red, bilberry red, chili red, and red rice red.

[0031] Preferably, the pH adjuster is a mixture of citric acid and sodium citrate;

[0032] The preservative is a mixture of sodium methylparaben and sodium propylparaben, or sodium benzoate;

[0033] The cosolvent is sorbitol;

[0034] The thickener is a mixture of hydroxypropyl cellulose and colloidal silicon dioxide, or hydroxypropyl cellulose;

[0035] The aroma is strawberry aroma;

[0036] The sweetener is sucralose.

[0037] Preferably, each 100 mL of the liquid preparation includes the following components: 0.02-1 g of active ingredient and 0-0.2 g of disodium EDTA; wherein the content of disodium EDTA is not 0.

[0038] Preferably, each 100 mL of the liquid preparation includes the following components:

[0039] Tizanidine 0.02-1g

[0040] Disodium EDTA 0.005-0.2g.

[0041] Preferably, each 100 mL of the liquid preparation includes the following components:

[0042]

[0043] Preferably, each 100 mL of the liquid preparation includes the following components:

[0044]

[0045] Preferably, the tizanidine liquid preparation comprises the following components:

[0046] Tizanidine, sodium methylparaben, sodium propylparaben, disodium EDTA, sucralose, citric acid, sodium citrate, strawberry flavor, and water;

[0047] Or, tizanidine, sodium methylparaben, sodium propylparaben, sorbitol, disodium EDTA, sucralose, citric acid, sodium citrate, strawberry flavor, and water;

[0048] Or, tizanidine, hydroxypropylcellulose, sodium methylparaben, sodium propylparaben, sorbitol, disodium EDTA, sucralose, citric acid, sodium citrate, strawberry flavor, and water;

[0049] Or, tizanidine, hydroxypropylcellulose, colloidal silicon dioxide, sodium methylparaben, sodium propylparaben, sorbitol, disodium EDTA, sucralose, citric acid, sodium citrate, strawberry flavor, and water;

[0050] Or, tizanidine, hydroxypropylcellulose, sodium benzoate, glycerin, sorbitol, disodium EDTA, sucralose, strawberry flavor and water.

[0051] Preferably, each 100 mL of liquid preparation includes the following components:

[0052] Tizanidine hydrochloride 0.046g, methylparaben sodium 0.1g, propylparaben sodium 0.01g, disodium EDTA 0.1g, sucralose 0.05g, citric acid 0.083g, sodium citrate 0.042g, strawberry flavor 0.05g, and the rest is water;

[0053] Or, 0.046g of tizanidine hydrochloride, 0.1g of sodium methylparaben, 0.01g of sodium propylparaben, 25g of 70% sorbitol solution, 0.1g of disodium EDTA, 0.05g of sucralose, 0.09g of citric acid, 0.035g of sodium citrate, 0.05g of strawberry flavor, and the rest is water;

[0054] Or, 0.046g of tizanidine hydrochloride, 2.5g of hydroxypropylcellulose, 0.1g of sodium methylparaben, 0.01g of sodium propylparaben, 15g of 70% sorbitol solution, 0.1g of disodium EDTA, 0.05g of sucralose, 0.09g of citric acid, 0.046g of sodium citrate, 0.05g of strawberry flavor, and the rest is water;

[0055] Or, 0.046 g of tizanidine hydrochloride, 2.5 g of hydroxypropyl cellulose, 0.5 g of colloidal silicon dioxide, 0.1 g of sodium methylparaben, 0.01 g of sodium propylparaben, 15 g of 70% sorbitol solution, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.09 g of citric acid, 0.04 g of sodium citrate, 0.05 g of strawberry flavor, and the rest is water;

[0056] Or, 0.046g tizanidine hydrochloride, 5g hydroxypropyl cellulose, 0.1g sodium benzoate, 15g glycerol, 25g 70% sorbitol solution, 0.1g disodium EDTA, 0.05g sucralose, 0.05g strawberry flavor, and the rest is water.

[0057] The pharmaceutically active ingredient in the tizanidine liquid preparation of the present invention is preferably tizanidine hydrochloride, and the content of the pharmaceutically active ingredient tizanidine hydrochloride is 0.046g / 100mL, and the liquid preparation of the present invention also contains disodium EDTA; when the liquid preparation is stored at room temperature, the total amount of related substance impurities is ≤0.2%, and / or, after the liquid preparation is administered, the tizanidine C max Mean, AUC 0-t Mean and / or AUC 0-∞ The mean value of tizanidine C was calculated after the following liquid preparations were administered at the same dose as tizanidine. max Mean, AUC 0-t Mean and / or AUC 0-∞ Within 80%-120% of the mean:

[0058] (1) Each 100 mL of the liquid preparation contains 0.046 g of tizanidine hydrochloride, 0.1 g of methylparaben sodium, 0.01 g of propylparaben sodium, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.083 g of citric acid, 0.042 g of sodium citrate, 0.05 g of strawberry flavor, and the remainder is water; or

[0059] (2) Each 100 mL of the liquid preparation contains 0.046 g of tizanidine hydrochloride, 0.1 g of methylparaben sodium, 0.01 g of propylparaben sodium, 25 g of 70% sorbitol solution, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.09 g of citric acid, 0.035 g of sodium citrate, 0.05 g of strawberry flavor, and the remainder is water; or,

[0060] (3) Each 100 mL of the liquid preparation contains 0.046 g of tizanidine hydrochloride, 2.5 g of hydroxypropylcellulose, 0.1 g of sodium methylparaben, 0.01 g of sodium propylparaben, 15 g of 70% sorbitol solution, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.09 g of citric acid, 0.046 g of sodium citrate, 0.05 g of strawberry flavor, and the remainder is water; or

[0061] (4) Each 100 mL of the liquid preparation contains 0.046 g of tizanidine hydrochloride, 2.5 g of hydroxypropylcellulose, 0.5 g of colloidal silicon dioxide, 0.1 g of sodium methylparaben, 0.01 g of sodium propylparaben, 15 g of 70% sorbitol solution, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.09 g of citric acid, 0.04 g of sodium citrate, 0.05 g of strawberry flavor, and the remainder is water; or

[0062] (5) Each 100 mL of the liquid preparation contains 0.046 g of tizanidine hydrochloride, 5 g of hydroxypropyl cellulose, 0.1 g of sodium benzoate, 15 g of glycerol, 25 g of 70% sorbitol solution, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.05 g of strawberry flavor, and the remainder is water.

[0063] The tizanidine liquid preparation of the present invention is sealed and stored for 0-3 months under the condition of 40°C / 75%RH, and its total amount of related impurities is ≤0.2%, and / or, the tizanidine liquid preparation of the present invention is sealed and stored for 0-6 months under the condition of 25°C / 60%RH, and its total amount of related impurities is ≤0.2%. The bioavailability of tizanidine tablets before and after meals is equivalent, and / or, liquid preparation of the present invention and The bioavailability of tizanidine capsules before and after meals is equivalent.

[0064] The evaluation criteria of bioavailability equivalence under the postprandial condition of liquid preparation of the present invention and tizanidine tablet / capsule are:

[0065] C max The upper limit of the one-sided 95% confidence interval is ≤0;

[0066] AUC 0-t The 90% confidence interval is between 80% and 125%;

[0067] AUC 0-∞ The 90% confidence interval is between 80% and 125%.

[0068] T of the tizanidine liquid preparation of the present invention under postprandial conditions max The mean value is less than the T of tizanidine tablets / capsules under postprandial conditions. max Mean.

[0069] Under the same dosage administration condition of tizanidine, the adverse reaction incidence of the tizanidine liquid preparation of the present invention is lower than the adverse reaction incidence of tizanidine tablets / capsules.

[0070] More specifically, under the same dosage administration condition of tizanidine, the incidence rate of the pre-meal adverse reaction item-drowsiness of the tizanidine liquid preparation of the present invention is less than that of tizanidine tablets / capsules;

[0071] And / or, the incidence of the postprandial adverse reaction item - drowsiness of the liquid preparation of the present invention is lower than that of tizanidine tablets / capsules;

[0072] And / or, the incidence of the postprandial adverse reaction item - headache of the liquid preparation of the present invention is less than that of tizanidine tablets / capsules;

[0073] And / or, the incidence of vomiting, an adverse reaction item after meal, of the liquid preparation of the present invention is lower than that of tizanidine capsules.

[0074] The invention discloses application of a tizanidine liquid preparation in preparing a medicine for treating muscle spasm.

[0075] There are many factors that affect the chemical stability of drugs, among which temperature is one of the important factors affecting the stability of drug preparations. Generally speaking, as the temperature rises, the degradation reaction speeds up. Light is also a factor that may affect the stability of drug preparations. Light can trigger a chain reaction and accelerate the degradation rate. The presence of oxygen may also accelerate the oxidation reaction and affect the stability of drugs. Other factors such as environmental humidity, packaging materials, pH value, excipients, etc. may also affect the chemical stability of drugs. Different drugs have different factors affecting their stability.

[0076] Preparation researcher of the present invention found in the research process that the metal ion in the solution has an impact on the chemical stability of tizanidine solution, and the existence of metal ion has the effect of accelerating the degradation of tizanidine related substances. The present invention adopts disodium EDTA as chelating agent, and it can combine the metal ion in tizanidine solution, prepares the tizanidine liquid preparation whose chemical stability is strong and related substance impurity content meets the pharmacopoeia regulations. Disodium EDTA can be combined with minerals such as chromium, iron, lead, mercury, copper, aluminium, nickel, zinc, calcium, cobalt, manganese and magnesium and metal ions and keep after being soluble in water, and when these minerals and metal ions are combined, they no longer have an impact on the chemical stability of tizanidine solution, and greatly ensure the chemical stability of tizanidine liquid preparation of the present invention.

[0077] Tizanidine liquid preparation of the present invention all has good chemical stability in conventional storage glass bottle and polyester bottle of liquid medicine, and it can be seen that the present invention is not harsh to storage container requirement, and can select storage container according to actual needs in the storage and transportation process.Medicinal liquid of the present invention can be preserved at normal temperatures, is conducive to reducing storage and transportation cost.

[0078] The tizanidine liquid preparation of the present invention has a clear appearance, does not have precipitation, turbidity and the like after being placed for a long time, and has strong physical stability; the impurity content of the related substances is much lower than the limit specified in the pharmacopoeia for the impurity content of the related substances of the tizanidine product, meets the requirement of drug declaration, and can be promoted and applied clinically.

[0079] Compared with the existing tizanidine solid preparations on the market, the tizanidine liquid preparation prepared by the invention has reduced adverse reactions in human body, and improves the safety of tizanidine medicine use and the compliance of patients in taking medicine.

[0080] The liquid preparation of the present invention is administered by oral administration, preferably oral administration, and has the advantages of accurate dosage titration, and is convenient for infants, the elderly, patients with dysphagia, patients with certain mental illnesses, and patients who are bedridden and have difficulty changing their body position.

[0081] Meanwhile, the tizanidine liquid preparation prepared by the present invention is compared with existing tablets and capsules, and aspect human bioavailability, the present invention has all achieved equivalence before and after meals, has the drug effect that is not less than existing solid preparations.And, the impact of food on the liquid preparation drug action speed of the present invention is less than its impact on existing solid preparations, and the present invention is faster than existing solid preparations in that drug action takes effect under postprandial conditions, can more quickly alleviate the suffering of patients.

[0082] In summary, the present invention obtains the tizanidine liquid preparation that impurity is few, chemical and physical stability is strong, its untoward reaction is few and its bioavailability is equivalent to existing tizanidine solid preparation before meal / after meal, meanwhile, liquid preparation of the present invention takes effect faster than its drug action of existing tizanidine solid preparation under postprandial condition, meets the demand to tizanidine oral pharmaceutical dosage form on the market, meets clinical demand. DETAILED DESCRIPTION

[0083] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the preferred embodiments of the present invention, rather than all 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.

[0084] The present invention provides a kind of stable tizanidine liquid preparation, the pharmaceutically active ingredient of described liquid preparation is one or more in tizanidine or its pharmaceutically acceptable salt, solvate, hydrate.Stable in described term of the present invention refers to chemical stability and / or physical stability.

[0085] No matter which existence form of pharmaceutical active ingredient of the present invention is described, after it is dissolved, what produces pharmacodynamic effect is the tizanidine dissolved in the medicinal liquid.For the convenience of data comparison, embodiments of the present invention preferably use tizanidine hydrochloride as bulk drug, carry out various aspects of investigation.

[0086] The pH range of tizanidine hydrochloride bulk drug solution was investigated:

[0087] Experimental methods:

[0088] (1) take tizanidine hydrochloride 0.323g, and dissolve in 400mL purified water;

[0089] (2) Divide the solution from the previous step into four equal parts and adjust the pH to 3.5, 4.5, 5.5, and 6.5 with 0.1N HCl and 0.1N NaOH;

[0090] (3) Freeze-thaw test: Four sample solutions were placed at 2-8°C, room temperature, and 40°C / 75% RH for 24 hours, and repeated three times.

[0091] The variation difference of the related substance detection of measuring tizanidine hydrochloride bulk drug solution pH and outward appearance and freeze-thaw test is as follows:

[0092] Table 1 Tizanidine hydrochloride bulk drug solution pH impact investigation table

[0093] sample pH Appearance Total impurities of related substances % increase (±) 1 3.5 Clear colorless solution 0.79％ 2 4.5 Clear colorless solution 0.21％ 3 5.5 Clear colorless solution 0.34％ 4 6.5 Clear light yellow solution 0.22％

[0094] Physical observations showed that when the pH was 6.5, the color of the solution changed from colorless to light yellow.

[0095] The sample solution No. 1 in the above table has the largest difference in the total impurity change of related substances before and after the freeze-thaw experiment, and the change in the total impurity of related substances before and after the freeze-thaw experiment is 0.79%.

[0096] By the total miscellaneous variation difference of related substances before and after tizanidine hydrochloride bulk drug solution appearance change and freeze-thaw experiment, it can be known that the pH value of tizanidine hydrochloride bulk drug solution has more excellent stability in the interval range greater than 3.5 and less than 6.5.

[0097] Therefore, the pH value of the present invention is preferably greater than 3.5 and less than 6.5.

[0098] Next, the stability of tizanidine liquid preparation of the present invention is investigated by specific embodiment.

[0099] Glass bottles / polyester bottles are one of the commonly used inner packaging for solid tablets or liquid preparations. Glass bottles have excellent properties such as good heat resistance and low adsorption, but they are relatively brittle, easy to break, and cannot be squeezed, which brings inconvenience to production and transportation, and the trace metal ions contained in the glass may affect the stability of the medicine; polyester bottles are not easy to break, the breakage rate is zero, the price is low, and the production and transportation costs are low, but their heat resistance is poor, and more additives are added during the production process, which can easily lead to changes in the quality of the medicine. At the same time, polyester bottles also have the disadvantages of being breathable and easy to adsorb, which can also accelerate the oxidation and deterioration of the medicine and cause the medicine to deteriorate.

[0100] Therefore, the present invention, in the stability investigation process, is stored in these two kinds of commonly used medicine storage containers of glass bottle and polyester bottle with tizanidine liquid preparation, carries out the related substance detection.

[0101] The test method for stability investigation of the present invention is:

[0102] a Accelerated test steps:

[0103] (1) Set the stability test chamber temperature to 40°C and relative humidity to 75%;

[0104] (2) Place the sealed liquid preparations in glass bottles and polyester bottles in a well-set stability test chamber;

[0105] (3) Take the samples after storage and test for related substances.

[0106] b. Normal temperature test steps:

[0107] (1) Set the stability test chamber temperature to 25°C and relative humidity to 60%;

[0108] (2) Place the sealed liquid preparations in glass bottles and polyester bottles in a well-set stability test chamber;

[0109] (3) Take the samples after storage and test for related substances.

[0110] The test methods of the accelerated test and the normal temperature test in all the embodiments of the present invention adopt this method.

[0111] Example 1

[0112] Liquid preparation of the present invention also comprises EDTA disodium and other one or more pharmaceutically acceptable excipients except tizanidine crude drug.Therefore, add relevant auxiliary materials, after making tizanidine hydrochloride liquid preparation, stability and pH value scope of this liquid preparation are studied:

[0113] (I) Experimental prescription:

[0114] Table 2 Prescription table

[0115]

[0116] With respect to the prescription table of the present application, it should be understood that the invention disclosed in the present application is not limited to a specific preparation volume, and when the concentration of each component of the liquid preparation is determined, the preparation volume may vary due to production and testing requirements.

[0117] The descriptions regarding the volumes of liquid formulations provided throughout this application are given only for the purpose of describing a particular embodiment or the concentration of each component and are not intended to limit the scope of the present invention.

[0118] (II) Process:

[0119] Weigh the materials according to the prescription amount for later use;

[0120] (1) Dissolve disodium EDTA in an appropriate amount of water and stir evenly;

[0121] (2) dissolving sucralose in an appropriate amount of water, adding the solution to the solution obtained in step (1), and stirring evenly;

[0122] (3) dissolving sodium methylparaben in an appropriate amount of water, adding the solution obtained in step (2), and stirring evenly;

[0123] (4) dissolving sodium propylparaben in an appropriate amount of water, adding the solution obtained in step (3), and stirring evenly;

[0124] (5) dissolving citric acid in an appropriate amount of water, adding the mixture to the solution obtained in step (4), and stirring evenly;

[0125] (6) dissolving sodium citrate in an appropriate amount of water, adding the mixture to the solution obtained in step (5), and stirring evenly;

[0126] (7) tizanidine hydrochloride is dissolved in appropriate amount of water, added in the solution gained by step (6), and stir;

[0127] (8) The pH of the solution in step (7) is adjusted to about 4.0 or 6.0 with 0.1N HCl or 0.1N NaOH, or no pH adjustment is performed.

[0128] (9) Adding strawberry essence to the solution obtained in step (8) under stirring and stirring evenly;

[0129] (10) add water, adjust volume to 1000mL, filter, and obtain tizanidine hydrochloride liquid preparation.

[0130] (III) Detection methods for relevant substances:

[0131] The related substances were determined by high performance liquid chromatography.

[0132] Test solution: take about 10g of tizanidine hydrochloride liquid preparation, accurately weigh (approximately equivalent to tizanidine 4mg), place in a 100mL measuring flask, add diluent [mobile phase A and mobile phase B are mixed in a certain proportion] and dilute to the scale, shake up, filter, and take the filtrate.

[0133] Control solution: Accurately measure 1.0 mL of the test solution, place it in a 100 mL volumetric flask, add diluent to dilute to the scale, and shake well.

[0134] The chromatographic column selected was an octadecylsilane bonded silica column C18 (4.6×250mm, 5μm), with sodium pentane sulfonate solution (3.5g of sodium pentane sulfonate was dissolved in 1000mL of water and the pH was adjusted to 3.0 with phosphoric acid solution or sodium hydroxide solution) as mobile phase A, acetonitrile as mobile phase B, and gradient elution was performed according to Table 3; the flow rate was 1.0mL / min; the detection wavelength was 230nm; the injection volume was 50μL; and the column temperature was 30°C.

[0135] Table 3 Gradient elution program

[0136] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 94 6 5 94 6 20 80 20 25 78 28 45 72 45 50 55 50 55 50 50 60 94 6 0 94 6

[0137] Limit: If impurity peaks are evident in the chromatogram of the test solution, the sum of the impurity peak areas shall not be greater than 0.5 times the area of ​​the main peak of the control solution (i.e. the total amount of related impurities shall not exceed 0.5%).

[0138] This detection method can be used to detect related substances in all embodiments in this specification, but the detection method of related substances in the present invention is not limited to this detection method; those skilled in the art can also detect related substances in the present invention by partially adjusting the detection method / detection parameters through conventional means.

[0139] Table 4 Different pH of tizanidine hydrochloride liquid preparation accelerated test related substance detection results

[0140]

[0141] Table 4 results show, under accelerated condition, when pH is 4.0 / 5.0 / 6.1, the total impurity content of the related substances of tizanidine liquid preparation 0 day, 1 month, 3 months is all less than 0.2%, far less than 0.5% of pharmacopeia regulation; Meanwhile, the liquid preparations of different pH values ​​all do not have phenomena such as turbidity, precipitation.As can be seen, when the pH of tizanidine liquid preparation of the present invention changes within the scope of 4.0-6.1, pH value has no substantial impact on the physical and chemical stability of preparation, can not affect listing and the use of medicine.

[0142] In order to further verify the liquid preparation long-term stability of the present embodiment, the tizanidine liquid preparation prepared by the present embodiment is carried out to normal temperature test.In order to save resources, this investigation is only investigated to No. 2 prescriptions not adding HCl or NaOH in table 2.

[0143] Table 5 is the related substance test results of the tizanidine hydrochloride liquid preparation room temperature test of No. 2 prescription

[0144]

[0145] The total impurities of the liquid preparation of this embodiment after being placed at room temperature for 6 months are 0.03% (glass bottle) and 0.03% (polyester bottle). The total impurity content of the related substances is less than 0.2%, which is far less than the limit of 0.5% specified in the pharmacopoeia, and has good chemical stability.

[0146] The test results of the relevant substances of the liquid preparation of this embodiment stored in glass bottles and polyester bottles are not much different. It can be seen that the liquid preparation of this embodiment does not have strict requirements on the storage container, and the storage container can be selected according to actual needs during storage and transportation.

[0147] Meanwhile, no matter in accelerated test or in normal temperature test, the present embodiment tizanidine liquid preparation does not all appear phenomena such as precipitation, turbidity, illustrates that the liquid preparation of the present embodiment all has good physical stability under accelerated condition and in long-term storage process at normal temperature.

[0148] It can be seen that the liquid preparation of this embodiment not only has a low impurity content, but also has good chemical / physical stability, complies with the provisions of the pharmacopoeia, meets the requirements for drug marketing, and has strong durability for storage containers, and can provide a variety of storage options clinically.

[0149] Example 2

[0150] In this example, an auxiliary material, a cosolvent, is added to the prescription to investigate the stability.

[0151] (I) Experimental prescription

[0152] Table 6 Prescription table

[0153]

[0154] (II) Process:

[0155] Weigh the materials according to the prescription amount for later use;

[0156] (1) Dissolve disodium EDTA in an appropriate amount of water and stir evenly;

[0157] (2) dissolving sucralose in an appropriate amount of water and adding the solution obtained in step (1);

[0158] (3) adding 70% sorbitol to the solution obtained in step (2) under stirring;

[0159] (4) dissolving sodium methylparaben and sodium propylparaben in water, and adding the mixture to the solution obtained in step (3) under stirring;

[0160] (5) adding citric acid and sodium citrate to the solution obtained in step (4) under stirring;

[0161] (6) after tizanidine hydrochloride is dissolved in water separately, under continuous stirring, be added in the solution of step (5) gained;

[0162] (7) adding strawberry essence to the solution obtained in step (6) under stirring;

[0163] (8) add water, adjust volume to 1000mL, filter, and obtain tizanidine hydrochloride liquid preparation.

[0164] (III) Stability investigation

[0165] The liquid preparation prepared in this example was subjected to an accelerated test.

[0166] Table 7 Accelerated test results of related substances

[0167]

[0168] During 0 day, the pH value of recording the present embodiment liquid preparation was 5.0. Because tizanidine liquid preparation pH value of the present invention changes in the scope of 4.0-6.1 and has no substantial impact on stability of the present invention, the present embodiment does not investigate the pH value.

[0169] Under accelerated conditions, the total impurity contents of related substances in the liquid preparation of this embodiment are all less than 0.2% at 0, 1, and 3 months, which are far less than the limit of 0.5% specified in the Pharmacopoeia. The liquid preparation has good chemical stability and complies with the provisions of the Pharmacopoeia.

[0170] In order to further verify the present embodiment liquid preparation long-term stability, the tizanidine liquid preparation prepared by the present embodiment is carried out to normal temperature test.

[0171] Table 8 Test results of related substances in normal temperature test

[0172]

[0173] The total impurities of related substances in the liquid preparation of this example after being placed at room temperature for 6 months are 0.15% (glass bottle) and 0.19% (polyester bottle), both of which are less than 0.2%, far less than the limit of 0.5% specified in the pharmacopoeia, having good chemical stability and meeting the requirements of the pharmacopoeia.

[0174] The test results of the total impurities of the liquid preparation of this embodiment stored in glass bottles and polyester bottles are not much different. It can be seen that the liquid preparation of this embodiment does not have strict requirements on the storage container, and the storage container can be selected according to actual needs during storage and transportation.

[0175] Meanwhile, no matter in accelerated test or in normal temperature test, the present embodiment tizanidine liquid preparation all does not appear phenomena such as precipitation, turbidity in outward appearance, illustrates that the liquid preparation of the present embodiment also has good physical stability under accelerated condition and in long-term storage process at normal temperature.

[0176] The liquid preparation of this embodiment not only has a low impurity content, but also has good long-term stability, complies with the provisions of the pharmacopoeia, and meets the requirements for drug marketing.

[0177] Compared with Example 1, a co-solvent is added to the formula of the liquid preparation in this example. It can be seen that the addition of the co-solvent has no substantial effect on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the marketing and use of the drug.

[0178] Example 3

[0179] In the prescription of this embodiment, an auxiliary material, a thickener, is added, and the amount of the co-solvent added is adjusted to examine the stability.

[0180] (I) Experimental prescription

[0181] Table 9 Prescription table

[0182]

[0183] (II) Process

[0184] Weigh the materials according to the prescription amount for later use;

[0185] (1) Add hydroxypropyl cellulose to an appropriate amount of water and disperse it, stirring until it becomes clear.

[0186] (2) Disodium EDTA is dissolved in water and added to the solution obtained in step (1) with stirring.

[0187] (3) Add 70% sorbitol to the solution obtained in step (2) under stirring, and stir until the solution becomes clear.

[0188] (4) dissolving sodium methylparaben and sodium propylparaben in water, and adding the mixture to the solution obtained in step (3) under stirring.

[0189] (5) Add citric acid and sodium citrate to the solution obtained in step (4) with stirring.

[0190] (6) Dissolve sucralose in water and add it to the solution obtained in step (5) with stirring.

[0191] (7) after tizanidine hydrochloride is dissolved in water separately, under continuous stirring, be added in the solution of step (6) gained.

[0192] (8) Add strawberry essence to the solution obtained in step (7) under continuous stirring.

[0193] (9) add water and adjust volume to 1000mL, filter, and obtain tizanidine hydrochloride liquid preparation.

[0194] (III) Stability investigation

[0195] The liquid preparation prepared in this example was subjected to an accelerated test.

[0196] Table 10 Accelerated test results of related substances

[0197]

[0198] 0 day time, recording the medicinal liquid pH value prepared by the present embodiment is 5.2, because tizanidine liquid preparation pH value of the present invention changes in the scope of 4.0-6.1 no substantial impact on stability of the present invention, so the present embodiment does not investigate the pH value.

[0199] Under accelerated conditions, the total impurity content of related substances in the liquid preparation of this embodiment is less than 0.2% at 0, 1, and 3 months, which is much lower than the limit of 0.5% specified in the pharmacopoeia. The liquid preparation has good chemical stability and complies with the pharmacopoeia.

[0200] In order to further verify the present embodiment liquid preparation long-term stability, the tizanidine liquid preparation prepared by the present embodiment is carried out to normal temperature test.

[0201] Table 11 Test results of related substances in normal temperature test

[0202]

[0203] The total impurities of related substances in the liquid preparation of this example after being placed at room temperature for 6 months are 0.06% (glass bottle) and 0.06% (polyester bottle), both of which are less than 0.2%, far less than the limit of 0.5% specified in the pharmacopoeia, having good chemical stability and meeting the requirements of the pharmacopoeia.

[0204] The test results of the total impurities of the liquid preparation of this embodiment stored in glass bottles and polyester bottles are not much different. It can be seen that the liquid preparation of this embodiment does not have strict requirements on the storage container, and the storage container can be selected according to actual needs during storage and transportation.

[0205] Meanwhile, no matter in accelerated test or in normal temperature test, the present embodiment tizanidine liquid preparation all does not appear phenomena such as precipitation, turbidity in outward appearance, illustrates that the liquid preparation of the present embodiment also has good physical stability under accelerated condition and in long-term storage process at normal temperature.

[0206] The liquid preparation of this embodiment not only has a low impurity content, but also has good long-term stability, complies with the provisions of the pharmacopoeia, and meets the requirements for drug marketing.

[0207] Compared with Example 2, this example adds a thickener and reduces the amount of co-solvent added. It can be seen that changing the viscosity of the liquid preparation and adjusting the amount of co-solvent added in the present invention have no substantial effect on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the marketing and use of the drug.

[0208] Example 4

[0209] In this example, the type and amount of thickener in the prescription were adjusted to examine the stability.

[0210] (I) Experimental prescription

[0211] Table 12 Prescription table

[0212]

[0213] (II) Process

[0214] Weigh the materials according to the prescription amount for later use;

[0215] (1) Add hydroxypropyl cellulose to an appropriate amount of water and disperse it, stirring until it becomes clear.

[0216] (2) Dissolve disodium EDTA in water, add it to the solution obtained in step (1) with stirring, and stir until it becomes clear.

[0217] (3) Add 70% sorbitol to the solution obtained in step (2) under stirring, and stir until the solution becomes clear.

[0218] (4) dissolving sodium methylparaben and sodium propylparaben in water, and adding the solution obtained in step (3).

[0219] (5) Dissolve citric acid and sodium citrate in water, and add the mixture to the solution obtained in step (4) with stirring.

[0220] (6) Dissolve sucralose in water and add the solution obtained in step (5).

[0221] (7) Dispersing colloidal silica in water, and adding the solution obtained in step (6) under stirring.

[0222] (8) after tizanidine hydrochloride is dissolved in water separately, under continuous stirring, be added in the solution of step (7) gained.

[0223] (9) Add strawberry essence to the solution obtained in step (8) under continuous stirring.

[0224] (10) add water and adjust volume to 1000mL, filter, and obtain tizanidine hydrochloride liquid preparation.

[0225] (III) Stability investigation

[0226] The liquid preparation prepared in this example was subjected to an accelerated test.

[0227] Table 13 Accelerated test results of related substances

[0228]

[0229] During 0 day, the pH value recording the present embodiment liquid preparation was 5.1, because tizanidine liquid preparation pH value of the present invention changes in the scope of 4.0-6.1 no substantial impact on stability of the present invention, so the present embodiment does not investigate the pH value.

[0230] Under accelerated conditions, the total impurity content of related substances in the liquid preparation of this embodiment is less than 0.2% at 0, 1, and 3 months, which is much lower than the limit of 0.5% specified in the pharmacopoeia. The liquid preparation has good chemical stability and complies with the pharmacopoeia.

[0231] The prescription of the present embodiment has added colloidal silicon dioxide on the basis of embodiment 3, and the formula of thickener is adjusted, and as can be seen from the total assorted detection comparison result of the related substances of table 10 and table 13, the change of thickener prescription has no substantial impact on chemical stability of the present invention; And, as can be seen from the comparison result of table 7 / table 10 and table 13, the tizanidine liquid preparation of the present embodiment obviously has the chemical stability of the tizanidine liquid preparation that is not less than embodiment 2 / embodiment 3, and under its accelerated condition, 0-3 month related substance impurity content meets the regulation of pharmacopoeia.

[0232] The test results of the relevant substances of the liquid preparation of this embodiment stored in glass bottles and polyester bottles are not much different. It can be seen that the liquid preparation of this embodiment does not have strict requirements on the storage container, and the storage container can be selected according to actual needs during storage and transportation.

[0233] At the same time, the liquid preparation of this embodiment did not show precipitation, turbidity and the like, and had good physical stability.

[0234] It can be seen from this that the adjustment of the formula of the thickener has no substantial effect on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the marketing and use of the drug.

[0235] Example 5

[0236] In this embodiment, the auxiliary materials are adjusted more vigorously to examine the stability.

[0237] (I) Experimental prescription

[0238] Table 14 Prescription table

[0239]

[0240] (II) Process

[0241] Weigh the materials according to the prescription amount for later use;

[0242] (1) Add hydroxypropyl cellulose to an appropriate amount of water and disperse it, stirring until it becomes clear.

[0243] (2) Dissolve sodium benzoate in water and add it to the solution obtained in step (1).

[0244] (3) Then, disodium EDTA is dissolved in water and added to the solution obtained in step (2) with stirring.

[0245] (4) Add sucralose to the solution obtained in step (3) and stir evenly.

[0246] (5) Add glycerol to the solution obtained in step (4).

[0247] (6) Add 70% sorbitol to the solution obtained in step (5) under stirring.

[0248] (7) after tizanidine hydrochloride is dissolved in water separately, under continuous stirring, be added in the solution of step (6) gained.

[0249] (8) Add strawberry essence to the solution obtained in step (7) under continuous stirring.

[0250] (9) add water and adjust volume to 1000mL, filter, and obtain tizanidine hydrochloride liquid preparation.

[0251] (III) Stability investigation

[0252] The liquid medicine prepared in this example was subjected to an accelerated test.

[0253] Table 15 Accelerated test results of related substances

[0254]

[0255] In this example, under accelerated conditions, no total impurities of related substances were detected in 0, 1, and 3 months, and the total impurity content was less than 0.2%, which is much lower than the limit of 0.5% specified in the pharmacopoeia. The sample has good chemical stability and meets the requirements of the pharmacopoeia.

[0256] In this embodiment, there is no difference in the test results of the relevant substances stored in the glass bottle and the polyester bottle. It can be seen that this embodiment does not have strict requirements on the storage container, and the storage container can be selected according to actual needs during storage and transportation.

[0257] Meanwhile, the present embodiment tizanidine liquid preparation does not appear phenomena such as precipitation, turbidity, has good physical stability.

[0258] Compared with the prescription of Example 2, the pH regulator is deleted in this example. The pH value of the liquid of this example is measured to be 4.9 at 0 days, which is within the range of pH 4.0-6.1. From the comparison results of the total impurities of related substances in this example and Example 2 under the accelerated test (Table 15 and Table 7), it can be seen that the deletion of the pH regulator has no substantial effect on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the marketing and use of the drug.

[0259] In this example, the preservative in the prescription of Example 2 is replaced with sodium benzoate. From the comparison results of the total impurities of related substances in this example and Example 2 under the accelerated test (Table 15 compared with Table 7), it can be seen that the replacement of the preservative has no substantial effect on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the marketing and use of the drug.

[0260] Compared with the prescription of Example 2, glycerol is added as a sweetener in this example. From the comparison results of the total impurities of related substances in this example and Example 2 under the accelerated test (Table 15 compared with Table 7), it can be seen that changing the sweetener prescription has no substantial effect on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the marketing and use of the drug.

[0261] Compared with the prescription of Example 2, hydroxypropyl cellulose is added as a thickener in this example. From the comparison results of the total impurities of related substances in this example and Example 2 under the accelerated test (Table 15 compared with Table 7), it can be seen that the addition of the thickener has no substantial effect on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the marketing and use of the drug.

[0262] The present embodiment and embodiment 2 prescription contrast, in the present embodiment prescription, except tizanidine hydrochloride active substance, only retain auxiliary material sorbitol, disodium EDTA and only play sucralose, strawberry flavor of flavoring, all the other auxiliary materials are all different.As can be seen, except sorbitol, disodium EDTA, other auxiliary materials make corresponding changes and deletions within the cognitive scope of those skilled in the art, and the physical and chemical stability of liquid preparation of the present invention is not substantially affected, and the listing and the use of medicine will not be affected.

[0263] At the same time, from the comparison between Example 1 and Example 2, it can be seen that the addition of the co-solvent - sorbitol or not has no substantial effect on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the marketing and use of the drug.

[0264] It can be seen that the change and deletion of other excipients except EDTA disodium of the present invention will not have a substantial impact on the physical and chemical stability of the present invention, and the other excipients include but are not limited to:

[0265] pH adjusters (citric acid, ascorbic acid, acetic acid, tartaric acid, trisodium citrate, sodium citrate, potassium citrate, sodium phosphate, tricalcium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, calcium carbonate, magnesium hydroxide, hydrochloric acid, sodium hydroxide, etc.);

[0266] and / or, cosolvents (sorbitol, maltitol, mannitol, isomalt, xylitol, glucose, fructose, etc.);

[0267] and / or, preservatives (sodium benzoate, ethylparaben, propylparaben, sodium methylparaben, sodium ethylparaben, sodium propylparaben, benzoic acid, potassium phenylpropionate, sorbic acid, sodium sorbate, calcium sorbate, potassium sorbate, dehydroacetic acid, sodium diacetate, calcium propionate, etc.);

[0268] and / or, thickeners (hydroxypropyl methylcellulose, hydroxypropyl cellulose, colloidal silicon dioxide, methylcellulose, sodium carboxymethyl cellulose, sodium alginate, cyclodextrin, etc.);

[0269] and / or, aromas (strawberry aroma, orange aroma, banana aroma, cherry aroma, lemon aroma, cardamom aroma, fennel aroma, mint aroma, menthol aroma, vanillin aroma, etc.);

[0270] And / or, sweeteners (sucralose, glycerol, saccharin sodium, glucose, stevioside, stevioside, aspartame, cyclamate, acesulfame potassium, alitame, neotame, etc.);

[0271] And / or, colorants that only have a color-enhancing effect (amaranth, carmine, erythrosine, new red, lemon yellow, sunset yellow, indigo, beetroot red, shellac red, bilberry red, paprika red, red rice red, etc.).

[0272] The investigation time of tizanidine liquid preparation stability study design of the present invention is 24 months or longer time, and the data presentation of 0-3 month accelerated test of tizanidine liquid preparation of the present invention and 0-6 month normal temperature test under 40 ℃ / 75%RH, 25 ℃ / 60%RH its related substance impurity content is all less than 0.2%, far less than 0.5% limit of pharmacopeia regulation.This shows, can expect that the stability of liquid preparation of the present invention under the medicine storage condition is suitable with the stability that stability test as mentioned above obtains.

[0273] Tizanidine liquid preparation of the present invention has added preservative, carried out preservative effect investigation, and has 24 months or longer stability investigation, and can expect that the microbial index of liquid preparation of the present invention meets the quality standard of medicine.

[0274] The following clinical trials were conducted on the human pharmacokinetic test of the present invention before meals (i.e., fasting) and after meals, and the incidence of adverse reactions was investigated:

[0275] Experimental samples:

[0276] ⅰThe tizanidine hydrochloride liquid preparation prepared by embodiment 1;

[0277] ⅱThe tizanidine hydrochloride liquid preparation prepared by embodiment 2;

[0278] ⅲ (Tizanidine hydrochloride) 4 mg tablet (standard 1);

[0279] ⅳ (Tizanidine hydrochloride) 4 mg capsule (Standard 2).

[0280] Pre-meal (fasting) bioequivalence test method and test results:

[0281] This trial was conducted in 25 healthy adult subjects under preprandial conditions, with a randomized, open, crossover, single-dose (4 mg of tizanidine), 5-cycle, 5-sequence crossover experimental design, with a cycle washout period of 2 days. The subjects fasted for at least 10 hours before administration, and were prohibited from drinking water one hour before and one hour after administration (except 240 mL of water during administration). Standard meals were provided 4h and 8h after administration; the subjects were prohibited from consuming food or beverages containing caffeine and / or xanthine (e.g., coffee, tea, caffeinated soda, cola, etc.) 48h before each cycle and throughout the trial, and were also prohibited from consuming grapefruit and / or grapefruit juice, as well as food containing poppy.

[0282] Dosage:

[0283] The liquid preparation is administered as follows: the subject remains in a sitting position, and 10 mL of I / II is injected into the subject's mouth with an oral syringe; the subject swallows it together with 50 mL of water, and the syringe is cleaned with 10 mL of water and injected into the subject's mouth, and this is repeated three times. The subject is then given water to ensure that the total amount of water given to the subject during the medication process is 240 mL; the subject remains in a sitting position within two hours after taking the medication.

[0284] The tablets / capsules are administered as follows: the subject remains seated, a single dose of ⅲ / ⅳ is placed in the subject's mouth, and the subject swallows it whole with 240 mL of water (the subject is not allowed to chew or crush the tablets / capsules); the subject remains seated for two hours after taking the medicine.

[0285] In each cycle, 2.5 mL of blood samples will be collected from the subjects before administration (0.00h) and at 0.08h, 0.16h, 0.25h, 0.33h, 0.50h, 0.67h, 0.83h, 1.00h, 1.25h, 1.50h, 1.75h, 2.00h, 2.50h, 3.00h, 4.00h, 6.00h, 8.00h, 10.00h and 12.00h after administration. Relevant pharmacokinetic parameters will be calculated.

[0286] T max The peak time of the drug.

[0287] C max Peak concentration is the maximum blood drug concentration measured.

[0288] AUC 0-t The calculation is performed using the linear trapezoidal method.

[0289] AUC 0-∞ =AUC 0-t +Ct / λz. t is the sampling time of the last measurable blood drug concentration; Ct is the last measurable sample drug concentration, and λz is the terminal elimination rate constant.

[0290] Table 16 Results of human pharmacokinetic tests under pre-meal conditions

[0291] Parameters (mean) ⅰ ⅱ ⅲ ⅳ <![CDATA[C max (pg / mL)]]> 6891.0570 6700.6869 6214.9907 6884.0184 <![CDATA[AUC 0-t (pg hr / mL)]]> 16452.1907 16750.9623 15326.0384 15937.0213 <![CDATA[AUC 0-∞ (pg hr / mL)]]> 16770.7496 17017.0368 15570.9400 16190.1320 <![CDATA[T max (hr)]]> 0.80 0.71 0.87 0.87

[0292] Table 17 Results of bioequivalence evaluation of ⅰ and ⅲ before meal conditions

[0293] parameter Lower90%CI Upper 90% CI 90% CI equivalent range result <![CDATA[C max ]]> 84.51％ 125.59％ 69.56–143.76％ Equivalence <![CDATA[AUC 0-t ]]> 84.98％ 118.93％ 73.50–136.06％ Equivalence <![CDATA[AUC 0-∞ ]]> 85.75％ 117.62％ 74.87–133.57％ Equivalence

[0294] Table 18 Bioequivalence evaluation results of ⅰ and ⅳ before meal conditions

[0295] parameter Lower90%CI Upper 90% CI 90% CI equivalent range result <![CDATA[C max ]]> 86.83％ 128.34％ 69.56–143.76％ Equivalence <![CDATA[AUC 0-t ]]> 92.29％ 128.55％ 73.50–136.06％ Equivalence <![CDATA[AUC 0-∞ ]]> 91.72％ 125.24％ 74.87–133.57％ Equivalence

[0296] Table 19 Results of bioequivalence evaluation under ⅱ and ⅲ pre-meal conditions

[0297] parameter Lower90%CI Upper 90% CI 90% CI equivalent range result <![CDATA[C max ]]> 86.42％ 128.38％ 69.56–143.76％ Equivalence <![CDATA[AUC 0-t ]]> 87.94％ 123.02％ 73.50–136.06％ Equivalence <![CDATA[AUC 0-∞ ]]> 89.03％ 122.07％ 74.87–133.57％ Equivalence

[0298] Table 20 Results of bioequivalence evaluation under pre-meal conditions of ⅱ and ⅳ

[0299] parameter Lower90%CI Upper 90% CI 90% CI equivalent range result <![CDATA[C max ]]> 88.78％ 131.22％ 69.56–143.76％ Equivalence <![CDATA[AUC 0-t ]]> 95.47％ 132.99％ 73.50–136.06％ Equivalence <![CDATA[AUC 0-∞ ]]> 95.20％ 130.00％ 74.87–133.57％ Equivalence

[0300] Conclusion: The tizanidine liquid preparation prepared by the present invention can be compared with the existing commercially available standard products under pre-meal conditions. (Tizanidine hydrochloride) 4 mg tablets / capsules are bioequivalent.

[0301] Pre-meal (fasting) adverse reaction investigation test and test results:

[0302] During the pre-meal bioequivalence study, the adverse reactions of the subjects throughout the experiment were recorded through observation, interviews and active reporting.

[0303] Table 21 Results of adverse reactions and their incidence under pre-meal conditions

[0304] sample ⅰ ⅱ ⅲ ⅳ Drowsiness none 8.00％ 40.00％ 16.00％ Headache none none none none Asthenia none none none none Vertigo none 4.00％ none none Incidence of adverse reactions 0 12.00％ 40.00％ 16.00％

[0305] As can be known from the above table experimental result, the anteprandial adverse reaction (sleepiness, headache, weakness, dizziness) incidence rate of the embodiment of the present invention 1 / embodiment 2 is 0 / 12.00%, and the adverse reaction (sleepiness, headache, weakness, dizziness) incidence rate of tablet / capsule is 40.00% / 16.00%; As can be seen, under the anteprandial condition, the adverse reaction (sleepiness, headache, weakness, dizziness) incidence rate of tizanidine liquid preparation of the present invention is less than existing solid preparation.

[0306] Postprandial bioequivalence test method and test results:

[0307] This study was conducted in 27 healthy adult subjects under postprandial conditions, using a randomized, open, crossover, single-dose (4 mg tizanidine), 6-cycle, 3-sequence partial repeated test design. The washout period was 2 days. After fasting for at least 10 hours before administration, the subjects were prohibited from drinking water one hour before and one hour after administration (except for 240 mL of water during administration). A high-calorie, high-fat, non-vegetable standard meal was provided 0.5 hours before administration, and the drug was administered within 0.5 hours after the meal, and a high-calorie, high-fat, non-vegetable standard meal was provided 4 hours, 8 hours, and 12 hours after administration; the subjects were prohibited from eating caffeinated and / or xanthine-containing foods or beverages (e.g., coffee, tea, caffeinated soda, cola, etc.) 48 hours before each cycle and throughout the trial, and grapefruit and / or grapefruit juice, as well as foods containing poppy, were prohibited.

[0308] Dosage:

[0309] The liquid preparation is administered as follows: the subject remains in a sitting position, and 10 mL of I / II is injected into the subject's mouth with an oral syringe; the subject swallows it together with 50 mL of water, and the syringe is cleaned with 10 mL of water and injected into the subject's mouth, and this is repeated three times. The subject is then given water to ensure that the total amount of water given to the subject during the medication process is 240 mL; the subject remains in a sitting position within two hours after taking the medication.

[0310] The tablets / capsules are administered as follows: the subject remains seated, a single dose of ⅲ / ⅳ is placed in the subject's mouth, and the subject swallows it whole with 240 mL of water (the subject is not allowed to chew or crush the tablets / capsules); the subject remains seated for two hours after taking the medicine.

[0311] In each cycle, 2.5 mL of blood samples will be collected from the subjects before administration (0.00h) and at 0.08h, 0.16h, 0.25h, 0.33h, 0.50h, 0.67h, 0.83h, 1.00h, 1.25h, 1.50h, 1.75h, 2.00h, 2.50h, 3.00h, 4.00h, 6.00h, 8.00h, 10.00h and 12.00h after administration. Relevant pharmacokinetic parameters will be calculated.

[0312] C max Peak concentration is the maximum blood drug concentration measured.

[0313] AUC 0-t The calculation is performed using the linear trapezoidal method.

[0314] AUC 0-∞ =AUC 0-t +Ct / λz. t is the sampling time of the last measurable blood drug concentration; Ct is the last measurable sample drug concentration, and λz is the terminal elimination rate constant.

[0315] Table 22 Results of human pharmacokinetic tests under postprandial conditions

[0316] Parameters (mean) ⅰ ⅱ ⅲ ⅳ <![CDATA[C max (pg / mL)]]> 4879.123 4852.799 5395.440 4832.833 <![CDATA[AUC 0-t (pg hr / mL)]]> 14551.615 14810.490 14943.559 15267.928 <![CDATA[AUC 0-∞ (pg hr / mL)]]> 14783.945 15051.702 15180.678 15557.618 <![CDATA[T max (hr)]]> 0.94 1.00 1.74 2.02

[0317] In the above table, T of the tizanidine hydrochloride liquid preparation of Example 1 / Example 2 of the present invention max is 0.94 / 1.00 hours; while the existing (tizanidine hydrochloride) tablets / capsules T max is 1.74 / 2.02 hours; It can be seen that under postprandial conditions, the liquid preparation of the present invention has a T of 1.74 / 2.02 hours compared with the existing solid preparation. max There was a significant reduction and the effect of the drug was significantly accelerated.

[0318] As shown in Table 16 and Table 22, the postprandial condition of the tizanidine hydrochloride liquid preparation of the embodiment of the present invention 1 / embodiment 2 is lower than that of the tizanidine hydrochloride liquid preparation of the embodiment of the present invention 1 / embodiment 2 under the preprandial condition. max The T of the existing tablets / capsules after meals was only extended by 0.14 / 0.29 hours compared with that before meals. max The T of the present invention was extended by 0.87 / 1.15 hours. max The impact is smaller than its impact on existing solid preparations.

[0319] It can be seen from this that the impact of food on the tizanidine hydrochloride liquid preparation drug action speed of the present invention is less than its impact on existing solid preparations; Under postprandial conditions, the drug action of the present invention is faster than that of existing solid preparations.

[0320] Since the postprandial bioequivalence test method adopts a partial repeated test design, it is well known to those skilled in the art that if S WR (within-subject standard deviation) ≥ 0.294 (ie, ISCV% ≥ 30%), the RSABE method can be used for equivalence evaluation (applied to AUC 0-t , AUC 0-∞ , C max Either or both of them are used); the pharmacokinetic parameters (AUC 0-t or AUC 0-∞ or C max ) The standard for bioequivalence is that the point estimate of the geometric mean ratio of the calculated parameters (hereinafter referred to as the point estimate) is within the range of 80%-125%, and at the same time, the upper limit of the one-sided 95% confidence interval of the calculated parameter (hereinafter referred to as the 95% confidence upper limit) is ≤0. WR If ISCV% is less than 0.294 (i.e., ISCV% is less than 30%), the ABE method should be used to evaluate bioequivalence.

[0321] Table 23-1 C under postprandial conditions ⅰ and ⅲ max Bioequivalence evaluation results

[0322] parameter ISCV % Point valuation (%) 95% upper confidence limit result <![CDATA[C max ]]> 51.62％ 98.60％ -0.1251 Equivalence

[0323] Table 23-2 AUC under postprandial conditions of ⅰ and ⅲ 0-t , AUC 0-∞ Bioequivalence evaluation results

[0324] parameter ISCV% Lower90%CI Upper 90% CI 90% CI equivalent range result <![CDATA[AUC 0-t ]]> 25.75％ 94.27％ 115.44％ 80.00-125.00％ Equivalence <![CDATA[AUC 0-∞ ]]> 25.62％ 94.48％ 115.54％ 80.00-125.00％ Equivalence

[0325] Table 24-1 C under postprandial conditions ⅰ and ⅳ max Bioequivalence evaluation results

[0326] parameter ISCV % Point valuation (%) 95% upper confidence limit result <![CDATA[C max ]]> 33.64％ 108.39％ -0.0241 Equivalence

[0327] Table 24-2 AUC under postprandial conditions of ⅰ and ⅳ 0-t , AUC 0-∞ Bioequivalence evaluation results

[0328] parameter ISCV % Lower90%CI Upper 90% CI 90% CI equivalent range result <![CDATA[AUC 0-t ]]> 26.04％ 92.62％ 116.22％ 80.00-125.00％ Equivalence <![CDATA[AUC 0-∞ ]]> 25.46％ 92.50％ 115.82％ 80.00-125.00％ Equivalence

[0329] Table 25-1 C under ⅱ and ⅲ postprandial conditions max Bioequivalence evaluation results

[0330] parameter ISCV % Point valuation (%) 95% upper confidence limit result <![CDATA[C max ]]> 51.62％ 103.73％ -0.122 Equivalence

[0331] Table 25-2 AUC under ⅱ and ⅲ postprandial conditions 0-t , AUC 0-∞ Bioequivalence evaluation results

[0332] parameter ISCV % Lower90%CI Upper 90% CI 90% CI equivalent range result <![CDATA[AUC 0-t ]]> 25.97％ 104.12％ 123.69％ 80.00-125.00％ Equivalence <![CDATA[AUC 0-∞ ]]> 25.74％ 104.30％ 123.74％ 80.00-125.00％ Equivalence

[0333] Table 26-1 C under ⅱ and ⅳ postprandial conditions max Bioequivalence evaluation results

[0334] parameter ISCV% Point valuation (%) 95% upper confidence limit result <![CDATA[C max ]]> 33.64％ 114.46％ -0.0041 Equivalence

[0335] Table 26-2 AUC under ⅱ and ⅳ postprandial conditions 0-t , AUC 0-∞ Bioequivalence evaluation results

[0336] parameter ISCV % Lower90%CI Upper 90% CI 90% CI equivalent range result <![CDATA[AUC 0-t ]]> 25.85％ 103.32％ 122.33％ 80.00-125.00％ Equivalence <![CDATA[AUC 0-∞ ]]> 25.30％ 103.10％ 121.88％ 80.00-125.00％ Equivalence

[0337] Conclusion: The tizanidine liquid preparation prepared by the present invention can compare with the existing commercially available standard product under postprandial conditions. (Tizanidine hydrochloride) 4 mg tablets / capsules are bioequivalent.

[0338] Postprandial adverse reaction investigation test and test results:

[0339] During the postprandial bioequivalence study, the adverse reactions of the subjects throughout the experiment were recorded through observation, interviews and active reporting.

[0340] Table 27 Investigation results of adverse reactions and their incidence under postprandial conditions

[0341] sample ⅰ ⅱ ⅲ ⅳ Drowsiness 3.70％ 3.70％ 25.92％ 22.22％ Vomiting none none none 1.85％ Headache none none 3.70％ 1.85％ Incidence of adverse reactions 3.70％ 3.70％ 29.62％ 25.92％

[0342] As can be known from the above table experimental result, the adverse reaction (drowsiness, vomiting, headache) incidence rate of the postprandial of the embodiment of the present invention 1 / embodiment 2 is 3.70% / 3.70%, and the adverse reaction (drowsiness, vomiting, headache) incidence rate of tablet / capsule is 29.62% / 25.92%; As can be seen, under the postprandial condition, the adverse reaction (drowsiness, vomiting, headache) incidence rate of tizanidine liquid preparation of the present invention is less than existing solid preparation.

[0343] As can be known from the investigation result of the untoward reaction and incidence rate thereof of Table 21 and Table 27, the incidence rate of its untoward reaction item-drowsiness (Drowsiness) of tizanidine liquid preparation of the present invention under anteprandial / postprandial condition is all less than solid preparation (i.e. tablet and capsule preparation); The incidence rate of its untoward reaction item-headache (Headache) under postprandial condition is less than solid preparation (i.e. tablet and capsule preparation); And the incidence rate of its untoward reaction item-vomiting (Vomiting) is less than capsule preparation under postprandial condition.

[0344] As can be seen here, no matter tizanidine liquid preparation of the present invention is under the condition of anteprandial or postprandial, its adverse reaction incidence rate is less than existing solid preparation.Liquid preparation of the present invention has changed tizanidine pharmaceutical dosage form and related adjuvant, so that adverse drug reaction is obviously reduced, and this is unexpected by those skilled in the art.The reduction of adverse drug reaction rate of the present invention has improved the safety of the use of medicine of the present invention and the compliance of patient's medication.

[0345] In summary, the content of tizanidine liquid preparation impurity of the present invention is few, strong stability; Compared to existing tizanidine solid preparation, its adverse reaction rate is little, food has little influence on drug action speed, drug action speed is fast under postprandial condition, and is equivalent to existing solid preparation bioavailability, meets clinical needs.

[0346] The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A tizanidine liquid preparation, characterized in that, The invention is composed of an active ingredient, disodium EDTA, a solvent and other pharmaceutical excipients; the active ingredient is tizanidine or a pharmaceutically acceptable salt thereof; the other pharmaceutical excipients are one or more of a pH regulator, a preservative, a cosolvent, a thickener, a fragrance, a sweetener and a colorant; The pH value of the tizanidine liquid preparation is 4.0-6.1; Each 100mL of tizanidine liquid preparation includes the following components: Tizanidine 0.02-1g Disodium EDTA 0.005-0.2g; The solvent is water.

2. Tizanidine liquid preparation according to claim 1, is characterized in that, The pH regulator is one or more of citric acid, ascorbic acid, acetic acid, tartaric acid, trisodium citrate, sodium citrate, potassium citrate, sodium phosphate, tricalcium phosphate, calcium carbonate, sodium bicarbonate, calcium phosphate, calcium carbonate, magnesium hydroxide, hydrochloric acid, and sodium hydroxide; The cosolvent is one or more of sorbitol, maltitol, mannitol, isomalt, xylitol, glucose and fructose; The preservative is one or more of sodium benzoate, ethylparaben, propylparaben, sodium methylparaben, sodium ethylparaben, sodium propylparaben, benzoic acid, potassium phenylpropionate, sorbic acid, sodium sorbate, calcium sorbate, potassium sorbate, dehydroacetic acid, sodium diacetate, and calcium propionate; The thickener is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, colloidal silicon dioxide, methylcellulose, sodium carboxymethyl cellulose, sodium alginate, and cyclodextrin; The fragrance is one or more of strawberry fragrance, orange fragrance, banana fragrance, cherry fragrance, lemon fragrance, cardamom fragrance, fennel fragrance, mint fragrance, menthol fragrance, and vanillin fragrance; The sweetener is one or more of sucralose, glycerol, saccharin sodium, glucose, stevioside, stevioside, aspartame, cyclamate, acesulfame potassium, alitame, and neotame; The colorant is one or more of amaranth, carmine, erythrosine, new red, lemon yellow, sunset yellow, indigo, beetroot red, lac red, bilberry red, capsicum red, and red rice red.

3. tizanidine liquid preparation according to claim 2, is characterized in that, The pH regulator is a mixture of citric acid and sodium citrate; The preservative is a mixture of sodium methylparaben and sodium propylparaben, or sodium benzoate; The cosolvent is sorbitol; The thickener is a mixture of hydroxypropyl cellulose and colloidal silicon dioxide, or hydroxypropyl cellulose; The aroma is strawberry aroma; The sweetener is sucralose.

4. tizanidine liquid preparation according to claim 2, is characterized in that, Each 100 mL of liquid preparation contains the following components: Tizanidine 0.02-1g Disodium EDTA 0.005-0.2g Citric acid 0.01-0.2g Sodium citrate 0.01-0.1g.

5. tizanidine liquid preparation according to claim 2, is characterized in that, Each 100 mL of liquid preparation contains the following components: Tizanidine 0.04-0.09g Disodium EDTA 0.008-0.12g Citric acid 0.06-0.14g Sodium citrate 0.02-0.06g.

6. tizanidine liquid preparation according to claim 2, is characterized in that, The liquid preparation comprises the following components: Tizanidine, sodium methylparaben, sodium propylparaben, disodium EDTA, sucralose, citric acid, sodium citrate, strawberry flavor, and water; Or, tizanidine, sodium methylparaben, sodium propylparaben, sorbitol, disodium EDTA, sucralose, citric acid, sodium citrate, strawberry flavor, and water; Or, tizanidine, hydroxypropylcellulose, sodium methylparaben, sodium propylparaben, sorbitol, disodium EDTA, sucralose, citric acid, sodium citrate, strawberry flavor, and water; Or, tizanidine, hydroxypropylcellulose, colloidal silicon dioxide, sodium methylparaben, sodium propylparaben, sorbitol, disodium EDTA, sucralose, citric acid, sodium citrate, strawberry flavor, and water; Or, tizanidine, hydroxypropylcellulose, sodium benzoate, glycerin, sorbitol, disodium EDTA, sucralose, strawberry flavor and water.

7. Tizanidine liquid preparation according to claim 6, is characterized in that, Each 100 mL of the liquid preparation includes the following components: Tizanidine hydrochloride 0.046g, methylparaben sodium 0.1g, propylparaben sodium 0.01g, disodium EDTA 0.1g, sucralose 0.05g, citric acid 0.083g, sodium citrate 0.042g, strawberry flavor 0.05g, and the rest is water; Or, 0.046g of tizanidine hydrochloride, 0.1g of sodium methylparaben, 0.01g of sodium propylparaben, 25g of 70% sorbitol solution, 0.1g of disodium EDTA, 0.05g of sucralose, 0.09g of citric acid, 0.035g of sodium citrate, 0.05g of strawberry flavor, and the rest is water; Or, 0.046g of tizanidine hydrochloride, 2.5g of hydroxypropylcellulose, 0.1g of sodium methylparaben, 0.01g of sodium propylparaben, 15g of 70% sorbitol solution, 0.1g of disodium EDTA, 0.05g of sucralose, 0.09g of citric acid, 0.046g of sodium citrate, 0.05g of strawberry flavor, and the rest is water; Or, 0.046 g of tizanidine hydrochloride, 2.5 g of hydroxypropyl cellulose, 0.5 g of colloidal silicon dioxide, 0.1 g of sodium methylparaben, 0.01 g of sodium propylparaben, 15 g of 70% sorbitol solution, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.09 g of citric acid, 0.04 g of sodium citrate, 0.05 g of strawberry flavor, and the rest is water; Or, 0.046g tizanidine hydrochloride, 5g hydroxypropyl cellulose, 0.1g sodium benzoate, 15g glycerol, 25g 70% sorbitol solution, 0.1g disodium EDTA, 0.05g sucralose, 0.05g strawberry flavor, and the rest is water.

8. according to any one of claims 1-7 described tizanidine liquid preparation, it is characterized in that, The liquid preparation has a tizanidine hydrochloride content of 0.046 g / 100 mL and contains disodium EDTA; and the liquid preparation has a total amount of related impurities of ≤0.2% when stored at room temperature, and / or, after administration of the liquid preparation, the tizanidine C max Mean, AUC 0-t Mean and / or AUC 0-∞ The mean values ​​of tizanidine C were calculated after the following liquid preparations were administered at the same dose as tizanidine. max Mean, AUC 0-t Mean and / or AUC 0-∞ Within 80%-120% of the mean: (1) Each 100 mL of the liquid preparation contains 0.046 g of tizanidine hydrochloride, 0.1 g of methylparaben sodium, 0.01 g of propylparaben sodium, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.083 g of citric acid, 0.042 g of sodium citrate, 0.05 g of strawberry flavor, and the remainder is water; or (2) Each 100 mL of the liquid preparation contains 0.046 g of tizanidine hydrochloride, 0.1 g of methylparaben sodium, 0.01 g of propylparaben sodium, 25 g of 70% sorbitol solution, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.09 g of citric acid, 0.035 g of sodium citrate, 0.05 g of strawberry flavor, and the remainder is water; or (3) Each 100 mL of the liquid preparation contains 0.046 g of tizanidine hydrochloride, 2.5 g of hydroxypropylcellulose, 0.1 g of sodium methylparaben, 0.01 g of sodium propylparaben, 15 g of 70% sorbitol solution, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.09 g of citric acid, 0.046 g of sodium citrate, 0.05 g of strawberry flavor, and the remainder is water; or (4) Each 100 mL of the liquid preparation contains 0.046 g of tizanidine hydrochloride, 2.5 g of hydroxypropylcellulose, 0.5 g of colloidal silicon dioxide, 0.1 g of sodium methylparaben, 0.01 g of sodium propylparaben, 15 g of 70% sorbitol solution, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.09 g of citric acid, 0.04 g of sodium citrate, 0.05 g of strawberry flavor, and the remainder is water; or (5) Each 100 mL of the liquid preparation contains 0.046 g of tizanidine hydrochloride, 5 g of hydroxypropyl cellulose, 0.1 g of sodium benzoate, 15 g of glycerol, 25 g of 70% sorbitol solution, 0.1 g of disodium EDTA, 0.05 g of sucralose, 0.05 g of strawberry flavor, and the remainder is water.

9. according to any one of claims 1-7 described tizanidine liquid preparation, it is characterized in that, The liquid preparation is sealed and stored for 0-3 months under the conditions of 40°C / 75%RH, and the total amount of related impurities is ≤0.2%; And / or, the liquid preparation is stored in a sealed state at 25° C. / 60% RH for 0-6 months, and the total amount of related substance impurities is ≤0.2%.

10. according to any one of claims 1-7 described tizanidine liquid preparation, it is characterized in that, The liquid preparation The bioavailability of tizanidine tablets before and after meals is equivalent; And / or, the liquid preparation and The bioavailability of tizanidine capsules before and after meals is equivalent.

11. Tizanidine liquid preparation according to claim 9, characterized in that, Under postprandial conditions, the criteria for judging the bioavailability equivalence are: C max The upper limit of the one-sided 95% confidence interval is ≤0; AUC 0-t The 90% confidence interval is between 80% and 125%; AUC 0-∞ The 90% confidence interval is between 80% and 125%.

12. according to any one of claims 1-7 described tizanidine liquid preparation, it is characterized in that, The T of the liquid preparation under postprandial conditions max The mean value is less than the T of tizanidine tablets / capsules under postprandial conditions. max Mean.

13. according to any one of claims 1-7 described tizanidine liquid preparation, it is characterized in that, Under the same dosage conditions of tizanidine: The adverse reaction incidence rate of the liquid preparation is less than that of tizanidine tablets / capsules.

14. according to any one of claims 1-7 described tizanidine liquid preparation, it is characterized in that, Under the same dosage conditions of tizanidine: The incidence of the pre-meal adverse reaction item - drowsiness of the liquid preparation is lower than that of tizanidine tablets / capsules; And / or, the incidence of the postprandial adverse reaction item - drowsiness of the liquid preparation is less than that of tizanidine tablets / capsules; And / or, the incidence of the postprandial adverse reaction item - headache of the liquid preparation is less than that of tizanidine tablets / capsules; And / or, the incidence of vomiting, a postprandial adverse reaction item, of the liquid preparation is lower than that of tizanidine capsules.

15. A method of preparing a medicament for treating muscle spasm using a tizanidine liquid preparation as claimed in any one of claims 1 to 14.

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