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WO2022247609A1 - 一种替扎尼定液体制剂及其用途 - Google Patents

一种替扎尼定液体制剂及其用途 Download PDF

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Publication number
WO2022247609A1
WO2022247609A1 PCT/CN2022/091371 CN2022091371W WO2022247609A1 WO 2022247609 A1 WO2022247609 A1 WO 2022247609A1 CN 2022091371 W CN2022091371 W CN 2022091371W WO 2022247609 A1 WO2022247609 A1 WO 2022247609A1
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WO
WIPO (PCT)
Prior art keywords
tizanidine
liquid preparation
sodium
water
sucralose
Prior art date
Application number
PCT/CN2022/091371
Other languages
English (en)
French (fr)
Inventor
陈刚
陈功政
林松
普拉萨德·拉希米·罗希特
沙旺·帕蒂尔·加内什·达塔雷
Original Assignee
四川科瑞德制药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 四川科瑞德制药股份有限公司 filed Critical 四川科瑞德制药股份有限公司
Priority to KR1020237037082A priority Critical patent/KR20240006523A/ko
Priority to JP2023548842A priority patent/JP2024506370A/ja
Priority to EP22810337.0A priority patent/EP4275685A1/en
Priority to CA3221397A priority patent/CA3221397A1/en
Priority to US17/918,130 priority patent/US20230414580A1/en
Priority to AU2022280757A priority patent/AU2022280757A1/en
Publication of WO2022247609A1 publication Critical patent/WO2022247609A1/zh
Priority to US18/395,225 priority patent/US12042484B2/en
Priority to US18/770,456 priority patent/US20240358686A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the invention relates to the technical field of medicine, and more specifically relates to a tizanidine liquid preparation and its application.
  • Tizanidine is a central alpha-2 adrenergic agonist used in the treatment of muscle spasms.
  • tizanidine currently on the market is It is used to treat muscle spasms caused by spinal cord injury or multiple sclerosis.
  • MEPS Medical Expenditure Survey
  • AHRQ Agency for Healthcare Research and Quality
  • MEDICARED the number of people who have prescribed tizanidine is about 2.06 million.
  • MEDICARED the number of people who have prescribed tizanidine is about 1.46 million elderly/disabled/seriously ill patients were prescribed tizanidine in 2018. It can be estimated that the elderly accounted for more than 60%.
  • dysphagia is a common clinical symptom, and diseases of the central nervous system are common diseases that cause dysphagia. Abroad, the incidence of dysphagia in patients with acute stroke is 37%-78%; in China, the incidence of dysphagia is 51%-73%. Although most patients recover swallowing function 1 month after stroke, some patients still have dysphagia 6 months after 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%.
  • Solid oral dosage forms play the largest and most important role in the overall pharmaceutical formulation.
  • tizanidine's listed dosage forms are mostly ordinary tablets, and capsule preparations are also available; because the medicines of ordinary tablet/capsule preparations generally need to be swallowed by drinking water when taking them, therefore, tizanidine hydrochloride ordinary tablet/capsule
  • the preparations have poor compliance for some special populations such as infants, the elderly, patients with dysphagia, patients with certain mental illnesses, and patients whose bed positions are difficult to change, and cannot meet the needs of clinical medication.
  • tablets are often crushed or capsules are opened and given to patients with dysphagia. Crushing/opening/mixing other drugs for administration has the risk of causing adverse reactions and medical errors.
  • oral medicines in various solid forms such as buccal tablets, sublingual tablets, effervescent tablets, chewable tablets, orally disintegrating tablets, and soluble tablets have been developed medically.
  • tizanidine liquid preparations has the advantages of more convenient dose titration adjustment, and it is also easy to improve the dosage of patients such as young children, the elderly, patients with dysphagia, certain mental illness patients and bedridden patients.
  • the medication compliance of patients whose body position is difficult to change meets the clinical needs.
  • the impurity detection of related substances in drugs is an important indicator to measure the chemical stability of drugs.
  • the chemical stability of liquid preparations has greatly affected its clinical promotion and use.
  • the content of impurities in related substances has affected the safety of medication. The more impurities, the greater the risk of medication that may occur.
  • the Pharmacopoeia Since there is no listed product of tizanidine liquid preparation on the market at present, the Pharmacopoeia has not made relevant regulations on the relevant substances of tizanidine liquid preparation, so the relevant substances of tizanidine liquid preparation should be referred to in the Chinese Pharmacopoeia Relevant regulations on related substances of tizanidine tablets - the total amount of impurities in related substances of tizanidine tablets shall not exceed 0.5%.
  • the dosage form of the drug determines the route and method of administration, directly affects the degree of drug absorption, and thus affects the efficacy of the drug; 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 pharmaceutical preparations not only It will affect the production process and the appearance and physical properties of the preparation, and will change the bioavailability of the preparation, thus affecting the efficacy of the preparation.
  • the object of the present invention is to provide a kind of tizanidine liquid preparation, the content of its impurity is few, stability is strong; Compared with tizanidine solid preparation, its untoward reaction rate is little, and food is to drug action speed. The effect is small, the drug action speed is fast under postprandial conditions, and the bioavailability is equivalent to that of tizanidine solid preparation.
  • the liquid preparation of tizanidine comprises active ingredient, disodium EDTA and other pharmaceutical excipients; the active ingredient is a kind of in tizanidine or its pharmaceutically acceptable salt, solvate, hydrate or more.
  • the pH value of the tizanidine liquid preparation is greater than 3.5 and less than 6.5.
  • the pH value of the tizanidine liquid preparation is 4.0-6.1.
  • the liquid preparation of tizanidine includes a solvent, and the solvent is water.
  • other pharmaceutical excipients are one or more of pH regulators, preservatives, solubilizers, thickeners, fragrances, sweeteners and colorants.
  • the pH regulator is 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, hydrogen
  • the co-solvent is one or more of sorbitol, maltitol, mannitol, isomaltose, xylitol, glucose, fructose;
  • Preservatives are sodium benzoate, ethylparaben, propylparaben, sodium methylparaben, sodium ethylparaben, sodium propylparaben, benzoic acid, potassium phenylpropionate, sorbic acid, One or more of sodium sorbate, calcium sorbate, potassium sorbate, dehydroacetic acid, sodium diacetate, calcium propionate;
  • the thickener is one or more of hypromellose, hypromellose, colloidal silicon dioxide, methylcellulose, sodium carboxymethylcellulose, sodium alginate, and cyclodextrin;
  • the fragrance is one of strawberry fragrance, orange fragrance, banana fragrance, cherry fragrance, lemon fragrance, cardamom fragrance, fennel fragrance, mint fragrance, menthol fragrance, vanillin fragrance or more;
  • the sweetener is one or more of sucralose, glycerin, sodium saccharin, glucose, stevioside, stevioside, aspartame, cyclamate, acesulfame potassium, alitame, and neotame;
  • the coloring agent is one or more of amaranth, carmine, erythrosine, new red, tartrazine, sunset yellow, indigo, beet red, lac red, cranberry red, capsicum red, and red rice red.
  • 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;
  • Cosolvent is sorbitol
  • the thickener is a mixture of hydroxypropyl cellulose and colloidal silicon dioxide, or, hydroxypropyl cellulose;
  • Aromatic agent is strawberry aromatic agent
  • the sweetener is sucralose.
  • every 100 mL of the liquid preparation includes the following components: 0.02-1 g of the active ingredient, and 0-0.2 g of disodium EDTA; wherein the content of disodium EDTA is not zero.
  • each 100mL liquid preparation includes the following components:
  • each 100mL liquid preparation includes the following components:
  • each 100mL liquid preparation includes the following components:
  • the tizanidine liquid formulation comprises the following components:
  • tizanidine sodium methylparaben, sodium propylparaben, sorbitol, disodium EDTA, sucralose, citric acid, sodium citrate, strawberry flavor, and water;
  • tizanidine hydroxypropyl cellulose, sodium methylparaben, sodium propylparaben, sorbitol, disodium EDTA, sucralose, citric acid, sodium citrate, strawberry flavor, and water;
  • tizanidine hydroxypropyl cellulose, colloidal silicon dioxide, sodium methylparaben, sodium propylparaben, sorbitol, disodium EDTA, sucralose, citric acid, sodium citrate , strawberry essence and water;
  • tizanidine hydroxypropyl cellulose, sodium benzoate, glycerin, sorbitol, disodium EDTA, sucralose, strawberry flavor, and water.
  • each 100mL liquid preparation includes the following components:
  • tizanidine hydrochloride 0.046g, sodium methylparaben 0.1g, sodium propylparaben 0.01g, 70% sorbitol solution 25g, disodium EDTA 0.1g, sucralose 0.05g, citric acid 0.09g, 0.035g sodium citrate, 0.05g strawberry essence, and the rest is water;
  • tizanidine hydrochloride 0.046g, hydroxypropyl cellulose 2.5g, sodium methylparaben 0.1g, sodium propylparaben 0.01g, 70% sorbitol solution 15g, disodium EDTA 0.1g, three Sucralose 0.05g, citric acid 0.09g, sodium citrate 0.046g, strawberry essence 0.05g, the rest is water;
  • tizanidine hydrochloride 0.046g, hydroxypropyl cellulose 2.5g, colloidal silicon dioxide 0.5g, sodium methylparaben 0.1g, sodium propylparaben 0.01g, 70% sorbose solution 15g, 0.1g disodium EDTA, 0.05g sucralose, 0.09g citric acid, 0.04g sodium citrate, 0.05g strawberry essence, the rest is water;
  • tizanidine hydrochloride 5g of hydroxypropyl cellulose, 0.1g of sodium benzoate, 15g of glycerin, 25g of 70% sorbitol solution, 0.1g of disodium EDTA, 0.05g of sucralose, 0.05g of strawberry essence, and the rest for water.
  • the pharmaceutical active ingredient is preferably tizanidine hydrochloride, and the content of its pharmaceutical active ingredient tizanidine hydrochloride is 0.046g/100mL and the liquid preparation of the present invention also contains EDTA disodium;
  • the liquid preparation is stored at room temperature, its total amount of related substances and impurities is ⁇ 0.2%, and/or, after the liquid preparation is administered, its tizanidine C max mean value, AUC 0-t mean value and/or AUC 0- ⁇ Mean values, respectively, in the range of 80%-120% of tizanidine mean C max , AUC 0-t mean and/or AUC 0- ⁇ mean after administration of equivalent doses of tizanidine in the following liquid preparations:
  • Each 100mL liquid preparation contains 0.046g of tizanidine hydrochloride, 0.1g of sodium methylparaben, 0.01g of propylparaben sodium, 0.1g of disodium EDTA, 0.05g of sucralose, and 0.083g of citric acid , sodium citrate 0.042g, strawberry essence 0.05g, the rest is water; or
  • Each 100mL liquid preparation contains 0.046g of tizanidine hydrochloride, 0.1g of sodium methylparaben, 0.01g of propylparaben sodium, 25g of 70% sorbitol solution, 0.1g of disodium EDTA, and 0.1g of triclosan 0.05g of sucrose, 0.09g of citric acid, 0.035g of sodium citrate, 0.05g of strawberry essence, and the rest is water; or,
  • Each 100mL liquid preparation contains 0.046g of tizanidine hydrochloride, 2.5g of hydroxypropyl cellulose, 0.1g of sodium methylparaben, 0.01g of sodium propylparaben, 15g of 70% sorbitol solution, EDTA Disodium 0.1g, sucralose 0.05g, citric acid 0.09g, sodium citrate 0.046g, strawberry essence 0.05g, the rest is water; or
  • Each 100mL liquid preparation contains 0.046g of tizanidine hydrochloride, 2.5g of hydroxypropyl cellulose, 0.5g of colloidal silicon dioxide, 0.1g of sodium methylparaben, 0.01g of sodium propylparaben, 70 % sorbose solution 15g, disodium EDTA 0.1g, sucralose 0.05g, citric acid 0.09g, sodium citrate 0.04g, strawberry essence 0.05g, the rest is water; or
  • Each 100mL liquid preparation contains 0.046g of tizanidine hydrochloride, 5g of hydroxypropyl cellulose, 0.1g of sodium benzoate, 15g of glycerin, 25g of 70% sorbitol solution, 0.1g of disodium EDTA, 0.05g of sucralose, Strawberry essence 0.05g, the rest is water.
  • the tizanidine liquid preparation of the present invention is stored in airtight conditions at 40°C/75%RH for 0-3 months, and the total amount of impurities of related substances is ⁇ 0.2%, and/or, the tizanidine liquid preparation of the present invention Store in airtight storage at 25°C/60%RH for 0-6 months, and the total amount of impurities of related substances shall be ⁇ 0.2%.
  • liquid preparation of the present invention and The bioavailability equivalent of tizanidine tablet preprandial and postprandial, and/or, liquid preparation of the present invention and The bioavailability of tizanidine capsules before and after meals is equivalent.
  • the 90% confidence interval for AUC 0-t is between 80%-125%
  • the 90% confidence interval for AUC 0- ⁇ is between 80%-125%.
  • the mean T max value of the tizanidine liquid preparation of the present invention under the postprandial condition is smaller than the T max mean value of the tizanidine tablet/capsule under the postprandial condition.
  • the incidence of adverse reactions of the present invention is less than that of tizanidine tablets/capsules.
  • the occurrence rate of the preprandial adverse reaction item-drowsiness of the liquid preparation of the present invention is less than that of the tizanidine tablet/capsule ;
  • the occurrence rate of the postprandial adverse reaction item-drowsiness of the liquid preparation of the present invention is less than that of tizanidine tablet/capsule;
  • the postprandial adverse reaction item-headache incidence rate of liquid preparation of the present invention is less than tizanidine tablet/capsule;
  • the occurrence rate of the postprandial adverse reaction item-vomiting of the liquid preparation of the present invention is less than that of the tizanidine capsule.
  • the invention relates to an application of a tizanidine liquid preparation in preparing a medicine for treating muscle spasm.
  • temperature is one of the important factors affecting the stability of pharmaceutical preparations.
  • the degradation reaction speed is accelerated; light is also the reason that may affect the stability of pharmaceutical preparations, and light can trigger
  • the chain reaction accelerates the degradation rate; the presence of oxygen may also accelerate the oxidation reaction and affect the stability of the drug.
  • Other factors such as environmental humidity, packaging materials, pH value, and excipients may also be the reasons that affect the chemical stability of the drug. Different drugs have different factors affecting their stability.
  • the invention adopts EDTA disodium as a chelating agent, which can combine with metal ions in the tizanidine solution to prepare the tizanidine liquid preparation with strong chemical stability and the impurity content of related substances conforming to the provisions of the Pharmacopoeia.
  • Disodium EDTA can be combined and maintained with minerals and metal ions such as chromium, iron, lead, mercury, copper, aluminum, nickel, zinc, calcium, cobalt, manganese and magnesium after being dissolved in water. When these minerals and metal ions are combined , they no longer have an impact on the chemical stability of the tizanidine solution, which greatly guarantees the chemical stability of the tizanidine liquid preparation of the present invention.
  • the tizanidine liquid preparation of the present invention all has good chemical stability in liquid drug conventional storage glass bottle and polyester bottle, as seen, the present invention is not harsh to storage container requirement, can be according to actual needs in storage and transportation process Select a storage container.
  • the medicinal solution of the invention can be preserved at normal temperature, which is beneficial to reduce storage and transportation costs.
  • the appearance of the tizanidine liquid preparation of the present invention is clear, after long-term placement, no precipitation, turbidity and other phenomena appear, and its physical stability is strong; the impurity content of its related substances is far lower than that of the relevant substances of tizanidine products in the Pharmacopoeia
  • the specified limits meet the requirements for drug declaration and can be popularized and applied clinically.
  • the tizanidine liquid preparation prepared by the invention has lower human adverse reactions, and improves the safety of tizanidine drug use and the compliance of patients taking medicine.
  • the liquid formulation of the present invention is administered through oral administration, preferably oral administration. It has the advantages of accurate dose titration, and is convenient for young children, the elderly, patients with dysphagia, patients with certain mental diseases and patients who are difficult to change their bed positions.
  • the tizanidine liquid preparation prepared by the present invention has achieved the equivalence of pre-meal and post-meal in terms of human bioavailability, with not less than The efficacy of existing solid dosage forms. Moreover, the effect of food on the drug action speed of the liquid preparation of the present invention is less than its impact on the existing solid preparations. Compared with the existing solid preparations, the present invention has a faster onset of drug action under postprandial conditions, and can relieve patients more quickly. pain of.
  • the present invention has obtained the tizanidine liquid preparation with few impurities and strong chemical and physical stability, and its adverse reactions are few and its bioavailability is the same as that of the existing tizanidine solid preparation before meal/after meal Equivalent, at the same time, compared with the existing tizanidine solid preparation, its drug action of the liquid preparation of the present invention takes effect faster under postprandial conditions, meeting the demand for tizanidine oral dosage forms on the market , to meet the clinical needs.
  • the invention provides a stable liquid preparation of tizanidine, the pharmaceutical active ingredient of the liquid preparation is tizanidine or one or more of pharmaceutically acceptable salts, solvates and hydrates thereof.
  • Stable in the terms of the present invention refers to chemical stability and/or physical stability.
  • the embodiments of the present invention preferably use tizanidine hydrochloride as the raw material drug, and carry out various investigations.
  • the largest difference in the total impurities of related substances before and after the freeze-thaw test is the No. 1 sample solution in the above table, and the change of the total impurities of related substances before and after the freeze-thaw test is 0.79%.
  • the pH value of the present invention is preferably selected to be greater than 3.5 and less than 6.5.
  • the glass bottle/polyester bottle is one of the commonly used inner packages for storing solid tablets or liquid preparations.
  • Glass bottles have excellent properties such as good heat resistance and not easy to adsorb, 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 glass may affect the stability of drugs Resistance; 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 its heat resistance is poor, and more additives are added in the production process, which may easily lead to changes in the quality of medicines.
  • Polyester bottles also have disadvantages such as air permeability and easy adsorption, which can also accelerate the rate of oxidative deterioration of medicines and cause deterioration of medicines.
  • the liquid preparation of tizanidine is stored in these two commonly used drug storage containers of glass bottle and polyester bottle, and related substance detection is carried out.
  • test method that stability of the present invention investigates is:
  • the temperature of the stability test chamber is set at 40°C, and the relative humidity is 75%;
  • the temperature of the stability test chamber is set at 25°C, and the relative humidity is 60%;
  • test methods of accelerated test and normal temperature test in all embodiments of the present invention all adopt this method.
  • the liquid preparation of the present invention also includes disodium EDTA and one or more pharmaceutically acceptable excipients in addition to the tizanidine crude drug. Therefore, after adding relevant auxiliary materials, after making tizanidine hydrochloride liquid preparation, the stability and pH value range of this liquid preparation are studied:
  • the invention disclosed in the present application is not limited to a specific preparation volume.
  • the concentration of each component of the liquid preparation is determined, the preparation volume can be changed due to the needs of production and testing. .
  • the related substances were determined by high performance liquid chromatography.
  • Need testing solution get about 10g of tizanidine hydrochloride liquid preparation, accurately weighed (approximately equivalent to tizanidine 4mg), put in 100mL measuring bottle, add diluent [mobile phase A and mobile phase B are in a certain proportion Mix] dilute to the mark, shake well, filter, and take the filtrate.
  • Control solution Accurately measure 1.0mL of the test solution, put it in a 100mL measuring bottle, add diluent to dilute to the mark, and shake well.
  • the chromatographic column uses octadecylsilane bonded silica gel column C18 (4.6 ⁇ 250mm, 5 ⁇ m), with sodium pentanesulfonate solution (take 3.5g of sodium pentanesulfonate, dissolve it in 1000mL water, use phosphoric acid solution or sodium hydroxide
  • the pH of the test solution was adjusted to 3.0) as mobile phase A, acetonitrile as mobile phase B, and gradient elution was carried out according to Table 3; the flow rate was 1.0 mL/min; the detection wavelength was 230 nm; the injection volume was 50 ⁇ L; the column temperature was 30 °C.
  • the sum of the areas of the impurity peaks must not be greater than 0.5 times the area of the main peak of the contrast solution (i.e. the total amount of impurities of the related substances must not exceed 0.5%).
  • This detection method can be used for the detection of the related substances in all the examples in this specification, but the detection method of the related substances of the present invention is not limited to this detection method; those skilled in the art can also adjust the detection method/detection parameters by conventional means. Related substances are tested.
  • Table 5 is the test result of related substances of tizanidine hydrochloride liquid preparation normal temperature test of No. 2 prescription
  • the total impurity of related substances placed in the liquid preparation of this embodiment for 6 months at normal temperature is 0.03% (glass bottle) and 0.03% (polyester bottle), and the total impurity content of related substances is less than 0.2%, far less than the 0.5% stipulated in the Pharmacopoeia.
  • the limit has good chemical stability.
  • test results of the related substances stored in the glass bottle and the polyester bottle of the liquid preparation of this example are not much different. It can be seen that the liquid preparation of this example does not have strict requirements on the storage container, and storage can be selected according to actual needs during storage and transportation. container.
  • the tizanidine liquid preparation of this embodiment did not appear precipitation, turbidity, etc., indicating that the liquid preparation of this embodiment can be used for a long time under accelerated conditions and under normal temperature conditions. It has good physical stability during storage.
  • liquid preparation of this embodiment not only has low impurity content, but also has good chemical/physical stability, meets the requirements of the Pharmacopoeia, and meets the requirements for drug listing, and it has strong durability to storage containers, and can provide a variety of storage containers clinically. choose.
  • an auxiliary material-cosolvent is added to the formulation to investigate the stability.
  • step (4) adding citric acid and sodium citrate to the solution obtained in step (4) while stirring;
  • step (7) adding the strawberry essence to the solution obtained in step (6) under stirring;
  • the pH value of the liquid formulation of this embodiment was measured to be 5.0. Since the pH value of the tizanidine liquid preparation of the present invention changes within the range of 4.0-6.1, the stability of the present invention has no substantial impact, so this embodiment does not investigate the pH value.
  • the liquid preparation of this example has a total impurity content of related substances less than 0.2% in 0, 1, and 3 months, which is far less than the limit of 0.5% stipulated in the Pharmacopoeia. It has good chemical stability and meets the regulations of the Pharmacopoeia.
  • the tizanidine liquid formulation prepared in this example was tested at room temperature.
  • the total impurity of related substances placed in the liquid preparation of this embodiment for 6 months at normal temperature is 0.15% (glass bottle), 0.19% (polyester bottle), all less than 0.2%, far less than the limit of 0.5% stipulated in the Pharmacopoeia, and has good chemical properties. Stability, and complies with Pharmacopoeia regulations.
  • the liquid preparation of this example is stored in glass bottles and polyester bottles, and the detection results of related substances are not much different. It can be seen that the liquid preparation of this example does not have strict requirements on storage containers. Select a storage container.
  • the liquid preparation of this embodiment not only has low impurity content, but also has good long-term stability, meets the requirements of the Pharmacopoeia, and meets the requirements for drug listing.
  • Example 1 Compared with Example 1 in this example, a cosolvent is added to the prescription of the liquid preparation. It can be seen that whether the addition of a cosolvent has no substantial impact on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the marketing and use of drugs .
  • an excipient—thickener is added to the prescription, and the amount of co-solvent is adjusted to investigate the stability.
  • step (3) Add sorbitol with a concentration of 70% to the solution obtained in step (2) under stirring, and stir until clear.
  • the pH value of the liquid preparation prepared in this embodiment was measured to be 5.2. Since the pH value of the tizanidine liquid preparation of the present invention varies within the range of 4.0-6.1, the stability of the present invention has no substantial impact, so this embodiment The pH value was not investigated.
  • the liquid preparation of this embodiment has a total impurity content of related substances less than 0.2% in 0, 1, and 3 months, which is far less than the limit of 0.5% stipulated in the Pharmacopoeia. It has good chemical stability and meets the regulations of the Pharmacopoeia.
  • the tizanidine liquid preparation prepared in the present embodiment was tested at normal temperature.
  • the total impurity of related substances placed in the liquid preparation of this embodiment for 6 months at normal temperature is 0.06% (glass bottle), 0.06% (polyester bottle), all less than 0.2%, far less than the limit of 0.5% stipulated in the Pharmacopoeia, and has good chemical properties. Stability, and complies with Pharmacopoeia regulations.
  • the liquid preparation of this example is stored in glass bottles and polyester bottles, and the detection results of related substances are not much different. It can be seen that the liquid preparation of this example does not have strict requirements on storage containers. Select a storage container.
  • the liquid preparation of this embodiment not only has low impurity content, but also has good long-term stability, meets the requirements of the Pharmacopoeia, and meets the requirements for drug listing.
  • Example 2 Compared with Example 2, this embodiment has added a thickener and reduced the amount of cosolvent added. It can be seen that the present invention changes the viscosity of the liquid preparation and adjusts the addition of the cosolvent to the physical and chemical properties of the liquid preparation of the present invention. Chemical stability has no substantial impact, and will not affect the marketing and use of drugs.
  • the type and amount of the thickener in the prescription are adjusted, and the stability is investigated.
  • step (3) Add sorbitol with a concentration of 70% to the solution obtained in step (2) under stirring, and stir until clear.
  • step (7) Disperse the colloidal silicon dioxide in water, and add it into the solution obtained in step (6) under stirring.
  • the pH value of the liquid preparation of the present embodiment was measured to be 5.1, because the change of the pH value of the liquid preparation of tizanidine of the present invention in the scope of 4.0-6.1 has no substantial impact on the stability of the present invention, so the present embodiment has no substantial impact on the stability of the present invention.
  • the pH value was not investigated.
  • the liquid preparation of this embodiment has a total impurity content of related substances less than 0.2% in 0, 1, and 3 months, which is far less than the limit of 0.5% stipulated in the Pharmacopoeia. It has good chemical stability and meets the regulations of the Pharmacopoeia.
  • the prescription of the present embodiment added colloidal silicon dioxide on the basis of Example 3, and adjusted the formula of the thickener. From the detection and comparison results of the related substances in Table 10 and Table 13, it can be seen that the thickener The change of prescription has no substantial impact on the chemical stability of the present invention; And, by the comparison result of table 7/table 10 and table 13, it can be known that the tizanidine liquid preparation of the present embodiment has not less than embodiment 2/implementation The chemical stability of the tizanidine liquid preparation of example 3, under its accelerated condition, 0-3 month relevant substance impurity content meets the regulation of Pharmacopoeia.
  • test results of the related substances stored in the glass bottle and the polyester bottle of the liquid preparation of this example are not much different. It can be seen that the liquid preparation of this example does not have strict requirements on the storage container, and storage can be selected according to actual needs during storage and transportation. container.
  • the liquid preparation of this example has no precipitation, turbidity, etc., and has good physical stability.
  • step (3) Dissolve disodium EDTA in water and add to the solution obtained in step (2) under stirring.
  • step (4) adding glycerin to the solution obtained in step (4).
  • the total impurities of related substances were not detected in 0, 1, and 3 months, and the total impurities were less than 0.2%, far less than the limit of 0.5% stipulated in the Pharmacopoeia. It has good chemical stability and complies with the regulations of the Pharmacopoeia. .
  • liquid preparation of tizanidine in this embodiment did not appear precipitation, turbidity, etc., and had good physical stability.
  • the pH regulator in this example is deleted, and the pH value of the medicinal solution in this example is 4.9 at day 0, which is within the range of pH 4.0-6.1. From the results of the comparison of the total impurities of the related substances under the accelerated test between this embodiment and Example 2 (Table 15 is compared with Table 7), deleting the pH regulator has no substantial impact on the physical and chemical stability of the liquid preparation of the present invention, and will not Affect the marketing and use of medicines.
  • the present embodiment replaces the antiseptic in the prescription of embodiment 2 with sodium benzoate, by the total miscellaneous comparison result of the related substances of the present embodiment and embodiment 2 under accelerated test as can be known (table 15 compares with table 7), changing the antiseptic has great effect on the present invention
  • the physical and chemical stability of the liquid preparation has no substantial impact, and will not affect the marketing and use of the drug.
  • the present embodiment Compared with the prescription of Example 2, the present embodiment added glycerin as a sweetener, and it can be seen from the results of the comparison of related substances in the accelerated test between the present embodiment and Example 2 (Table 15 is compared with Table 7), and the sweetness is changed.
  • the formulation of the formulation has no substantial impact on the physical and chemical stability of the liquid formulation of the present invention, and will not affect the marketing and use of the drug.
  • the present embodiment Compared with the prescription of Example 2, the present embodiment has added hydroxypropyl cellulose as a thickener, and it can be known from the total impurities of related substances in the accelerated test between this embodiment and Example 2 (Table 15 is compared with Table 7), Adding the thickener has no substantial impact on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the marketing and use of medicines.
  • This embodiment is compared with the prescription of embodiment 2.
  • the active substance of tizanidine hydrochloride except the active substance of tizanidine hydrochloride, only adjuvant sorbitol, disodium EDTA and sucralose and strawberry essence that only play a corrective role are retained.
  • the rest of the accessories are different. It can be seen that, except for sorbitol and disodium EDTA, other auxiliary materials are changed and deleted within the cognition scope of those skilled in the art, and have no substantial impact on the physical and chemical stability of the liquid preparation of the present invention, and will not affect the drug. listing and use.
  • 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.
  • co-solvents sorbitol, maltitol, mannitol, isomaltose, xylitol, glucose, fructose, etc.
  • 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.);
  • thickeners hypomethyllose, hypromellose, colloidal silicon dioxide, methylcellulose, sodium carboxymethylcellulose, sodium alginate, cyclodextrin, etc.
  • fragrances strawberry fragrance, orange fragrance, banana fragrance, cherry fragrance, lemon fragrance, cardamom fragrance, fennel fragrance, mint fragrance, menthol fragrance, vanillin fragrance Wait);
  • sweeteners saccharin, glucose, stevioside, stevioside, aspartame, cyclamate, acesulfame potassium, alitame, neotame, etc.
  • coloring agents of their color enhancing effect only (maranth, carmine, erythrosin, new red, tartrazine, sunset yellow, indigo, beet red, lac red, bilberry red, capsicum red, red rice red Wait).
  • the investigation time of tizanidine liquid formulation stability research design of the present invention is 24 months or more time, the 0-3 month accelerated test of current tizanidine liquid formulation of the present invention and the 0-6 month normal temperature test
  • the data shows that the impurity content of related substances is less than 0.2% at 40°C/75%RH and 25°C/60%RH, which is far less than the limit of 0.5% stipulated in the Pharmacopoeia. This shows that the stability of the liquid formulations of the present invention under drug storage conditions can be expected to be comparable to that obtained by the stability tests described above.
  • the tizanidine liquid preparation of the present invention has added antiseptic, has carried out preservative effectiveness investigation, and has the stability investigation of 24 months or more time, can expect the microbiological index of liquid preparation of the present invention to meet the quality standard of medicine .
  • the administration method of the liquid preparation is: the subject keeps a sitting position, injects 10mL i/ii into the subject's mouth with an oral syringe; the subject swallows it together with 50mL of water, washes the syringe with 10mL of water and injects it into the subject's mouth, Repeat three times, and then give the subject water to ensure that the total amount of water given to the subject during the course of taking the medicine is 240mL; the subject keeps a sitting position within two hours after taking the medicine.
  • Tablets/capsules are administered as follows: Subject remains seated, puts a single dose of III/iv into the subject's mouth, swallows it whole with 240 mL of water (subject must not chew or crush the tablet/capsule) ; The subject remained in a sitting position for two hours after taking the drug.
  • subjects will be treated before administration (0.00h) and after administration 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 were collected blood samples 2.5mL. Calculate relevant pharmacokinetic parameters.
  • T max is the peak time of the drug.
  • Cmax is the peak concentration, that is, the maximum blood concentration measured.
  • AUC 0-t was calculated by the linear trapezoidal method.
  • AUC 0- ⁇ AUC 0-t + Ct/ ⁇ z.
  • t is the sampling time of the last measurable blood drug concentration;
  • Ct is the last measurable sample drug concentration, and
  • ⁇ z is the terminal elimination rate constant.
  • the tizanidine liquid preparation prepared by the present invention can be compared with existing commercially available standard substance under preprandial condition (Tizanidine Hydrochloride) 4mg tablets/capsules are bioequivalent.
  • the incidence rate of adverse reactions (drowsiness, headache, weakness, dizziness) before meals of Embodiment 1/Example 2 of the present invention is 0/12.00%, while the adverse reactions of tablets/capsules (drowsiness , headache, weakness, dizziness) incidence rate is 40.00%/16.00%; Visible, under preprandial condition, the untoward reaction (drowsiness, headache, weakness, dizziness) incidence rate of tizanidine liquid preparation of the present invention is less than Existing solid dosage forms.
  • This experiment was carried out in 27 healthy adult subjects under postprandial conditions, using a randomized, open, crossover, single dose (tizanidine 4 mg), 6 cycles, 3 sequence partial repetition design.
  • the cleaning time of the cycle is 2 days. After fasting for at least 10 hours before the administration, the subjects are prohibited from drinking water (except for 240mL water during the administration period) one hour before and one hour after the administration.
  • a high-calorie, high-fat non-vegetable standard meal was provided for h hours, and the drug was administered within 0.5h after the meal, and a high-calorie, high-fat non-vegetable standard meal was provided 4h, 8h, and 12h after the administration; the subjects were given 48h before each cycle and Abstain from caffeine- and/or xanthine-containing food or beverages (e.g., coffee, tea, and caffeinated soda, cola, etc.) and grapefruit and/or grapefruit juice throughout the trial period, and foods containing poppies.
  • caffeine- and/or xanthine-containing food or beverages e.g., coffee, tea, and caffeinated soda, cola, etc.
  • grapefruit and/or grapefruit juice throughout the trial period, and foods containing poppies.
  • the administration method of the liquid preparation is: the subject keeps a sitting position, injects 10mL i/ii into the subject's mouth with an oral syringe; the subject swallows it together with 50mL of water, washes the syringe with 10mL of water and injects it into the subject's mouth, Repeat three times, and then give the subject water to ensure that the total amount of water given to the subject during the course of taking the medicine is 240mL; the subject keeps a sitting position within two hours after taking the medicine.
  • Tablets/capsules are administered as follows: Subject remains seated, puts a single dose of III/iv into the subject's mouth, swallows it whole with 240 mL of water (subject must not chew or crush the tablet/capsule) ; The subject remained in a sitting position for two hours after taking the drug.
  • subjects will be treated before administration (0.00h) and after administration 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 were collected blood samples 2.5mL. Calculate relevant pharmacokinetic parameters.
  • Cmax is the peak concentration, that is, the maximum blood concentration measured.
  • AUC 0-t was calculated by the linear trapezoidal method.
  • AUC 0- ⁇ AUC 0-t + Ct/ ⁇ z.
  • t is the sampling time of the last measurable blood drug concentration;
  • Ct is the last measurable sample drug concentration, and
  • ⁇ z is the terminal elimination rate constant.
  • the Tmax of the tizanidine hydrochloride liquid preparation of embodiment 1/embodiment 2 of the present invention in the table above is 0.94/1.00 hour; And existing (tizanidine hydrochloride) tablet/capsule Tmax is 1.74/2.02 hour It can be seen that under postprandial conditions, the T max of the liquid preparation of the present invention has been significantly reduced compared to the existing solid preparation, and the drug action is obviously accelerated.
  • the RSABE method can be used for equivalence Evaluation (applied to any or all of AUC 0-t , AUC 0- ⁇ , and C max ); use RSABE method to determine the pharmacokinetic parameters of the test preparation and the reference preparation (AUC 0-t or AUC 0- ⁇ or C max ) has the standard of bioequivalence equivalence: the point estimate of the geometric mean ratio of the calculation parameters (hereinafter referred to as the point estimate) is in the range of 80%-125%, and at the same time, the calculation parameters are one-sided
  • the upper limit of the 95% confidence interval (abbreviated as 95% upper limit of confidence) ⁇ 0 is sufficient. If S WR ⁇ 0.294 (ie ISCV% ⁇ 30%), the ABE method should be used for equivalence Evaluation (applied to any or all of AUC 0-t , AUC 0- ⁇ , and C max ); use RSABE method to determine the pharmacokinetic parameters of the test preparation and the reference preparation
  • the tizanidine liquid preparation prepared by the present invention can be compared with existing commercially available standard substance under postprandial condition (Tizanidine Hydrochloride) 4mg tablets/capsules are bioequivalent.
  • the incidence rate of adverse reactions (drowsiness, vomiting, headache) after meals in Example 1/Example 2 of the present invention is 3.70%/3.70%, while the adverse reactions of tablets/capsules (drowsiness, vomiting) , headache) incidence rate is 29.62%/25.92%; Visible, under postprandial condition, the untoward reaction (drowsiness, vomiting, headache) incidence rate of tizanidine liquid preparation of the present invention is less than existing solid preparation.
  • the incidence of adverse reaction items-drowsiness (Drowsiness) of the tizanidine liquid preparation of the present invention under pre-meal/post-prandial conditions is all less than that of solid Preparations (i.e. tablets and capsule preparations); the incidence of its adverse reaction item-headache (Headache) is less than that of solid preparations (i.e. tablet and capsule preparations) under postprandial conditions; and its adverse reaction item-vomiting ( The incidence of Vomiting) is less than that of capsule preparations in postprandial conditions.
  • the incidence of adverse reactions of the tizanidine liquid preparation of the present invention is less than that of the existing solid preparation no matter under the condition of preprandial or postprandial.
  • the liquid preparation of the present invention changes the pharmaceutical dosage form of tizanidine and related auxiliary materials, so that adverse drug reactions are significantly reduced, which is unexpected by those skilled in the art.
  • the reduction of the adverse reaction rate of the medicine of the present invention improves the safety of the medicine of the present invention and the compliance of patients taking medicine.
  • the tizanidine liquid preparation of the present invention has less impurity content and strong stability; compared with the existing tizanidine solid preparation, its adverse reaction rate is small, food has little influence on the drug action speed, The drug acts quickly under postprandial conditions, and has the same bioavailability as the existing solid preparation, which meets the clinical needs.

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Abstract

一种替扎尼定液体制剂及其在制备治疗肌肉痉挛的药物中的用途，该替扎尼定液体制剂包括活性成分、EDTA二钠及其他药物赋形剂，其中活性成分为替扎尼定或其药学上可接受的盐、溶剂化物、水合物中的一种或多种。

Description

一种替扎尼定液体制剂及其用途
本申请要求于2021年5月26日提交中国专利局、申请号为202110577512.4、发明名称为“一种替扎尼定液体制剂及其用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医药技术领域，更具体地说，涉及一种替扎尼定液体制剂及其用途。
背景技术
替扎尼定是一种中枢α-2肾上腺素能激动剂，用于治疗肌肉痉挛。
替扎尼定的化学结构如下所示：
Figure PCTCN2022091371-appb-000001
替扎尼定目前在市场上的商标是
Figure PCTCN2022091371-appb-000002
用于治疗因脊髓损伤或多发性硬化症引起的肌肉痉挛。
替扎尼定处方用药人群，老年人群占比最大。根据美国医疗照护研究及质量机构(AHRQ)医疗费用调查(MEPS)显示，替扎尼定处方用药人数约206万人。根据美国MEDICARED部分处方药用药数据，2018年约有146万老年/残疾/重疾患者为替扎尼定处方用药的患者。由此可推算，老年人占比超60％。
老年神经系统疾病者，更易患吞咽障碍：吞咽障碍是临床常见的症状，而中枢神经系统疾病是引起吞咽障碍的常见疾病。在国外，急性脑卒中患者吞咽困难的发生率37％-78％；在国内，其吞咽困难的发生率为51％-73％。尽管多数患者在卒中后1个月恢复吞咽功能，但有部分患者在卒中6个月后仍存在吞咽困难。MS患者吞咽困难总体患病率约33-43％，急性颈髓损伤吞咽困难发生率约30.9％，脑损伤吞咽困难发生率为27-30％。
固体口服剂型在整个药物制剂中起着最大和最重要的作用。目前替扎尼定上市剂型多为普通片剂，也有胶囊制剂；由于普通片剂/胶囊制剂的药物在服用时一般都需要借助饮水以帮助吞咽，因此，盐酸替扎尼定普通片剂/胶囊制剂对于一些特殊人群如幼儿、老年人、吞咽困难的患者、某些精神疾病患者及卧床体位难变动的患者依从性差，不能满足临床用药的需要。临床实践中常将片剂压碎或将胶囊打开后给予吞咽困难患者，压碎/打开/混合其他药物给药有引发不良反应及医疗过错的风险。由于有大量的病人吞咽固体口服剂型有困难，因此医学上开发出了含片、舌下片、泡腾片、咀嚼片、口崩片、可溶片等多种固体形式的口服药物。
口服固体制剂在剂量滴定过程中，存在一定的局限性：1)剂量分割不准确；2) 需开发多个规格，企业制剂开发成本变高；3)根据患者病情变化进行剂量滴定期间，规格需求的变化易导致浪费。而液体制剂则在剂量滴定过程中不存在上述问题。
由此可见，与口服固体制剂相比，开发替扎尼定液体制剂具有剂量滴定调整更为方便的优势，同时也易于提高如幼儿、老年人、吞咽困难的患者、某些精神疾病患者及卧床体位难变动的患者服药的依从性，满足临床需要。
众所周知，液体形式的活性药物制剂比固体形式的活性药物制剂更容易受到化学不稳定性的影响，虽然液体形式的活性药物制剂具有明显良好的临床上的优势，但往往因为稳定性问题，而让制剂开发人员望而却步。
药品有关物质杂质检测是衡量药品化学稳定性的重要指标，有关物质杂质含量越高，其化学稳定性越差。而液体制剂的化稳定性极大的影响了其临床上的推广使用，同时有关物质杂质的含量影响了用药的安全性，杂质越多，可能出现的用药风险越大。
由于目前市场上并未有替扎尼定液体制剂的上市产品，药典对替扎尼定液体制剂的有关物质并未做相关规定，因此替扎尼定液体制剂的有关物质应参照于中国药典中关于替扎尼定片有关物质的相关规定—替扎尼定片有关物质的杂质总量不得大于0.5％。
目前替扎尼定上市的普通片剂和胶囊制剂人体服用后具有较大概率发生不良反应，以
Figure PCTCN2022091371-appb-000003
(盐酸替扎尼定)片剂和胶囊为例，其说明书写明，单剂量给药情况下，患者出现的不良反应中，仅‘嗜睡(somnolence)’这一项不良反应的发生率便高达78％(单剂量8mg)/92％(单剂量16mg)。药物不良反应是指药物在正常用法和用量使用当中产生的与用药目的无关或对集体有害的反应，不仅指药物的副作用。药物的质量、剂型、杂质、辅料、含量等都是致使药品不良反应发生的因素之一。替扎尼定的普通片剂和胶囊制剂不良反应极大的影响了替扎尼定药品使用的安全性，与此同时，其不良反应中嗜睡的高发生率也一定程度上影响了服药患者的正常生活，大大减少了患者服药的依从性。因此，如何减少正常使用下替扎尼定药品的不良反应发生率，对于增强药品使用的安全性以及患者服药的依从性是具有重要意义的。
同时，对于肌肉痉挛来说，药物作用的速度越快，越能快速缓解患者的痛苦。而对于口服药物，食物对药物作用速度的影响往往较大，现有的替扎尼定的普通片剂和胶囊制剂在餐后条件下的药物达峰时间明显延长，不利于快速减轻患者的痛苦。因此，如何减小食物对药物达峰时间的影响，加快替扎尼定药品在餐后条件下的药物作用速度，也是需要解决的问题之一。
替扎尼定液体药物新剂型的开发除了稳定性、不良反应以及药物作用速度等因素的考虑以外，剂型的改变对药效的影响，也是必须考虑的因素。药物剂型决定着给药途径和方法，直接影响药物吸收程度，从而对药效造成影响；药物的理化性质将直接影响药物的释放，从而影响药物的治疗效果；药物制剂中赋形剂的选择不仅影响到生产工艺及制剂的外观和物理性质，而且会改变制剂的生物利用度，从而影响制剂的疗 效。
因此，开发出一种杂质的含量少、稳定性强、不良反应率小、食物对药物作用速度影响小、餐后条件下药物作用速度快，且与固体制剂生物利用度等效的替扎尼定液体制剂满足临床需要是亟待解决的问题。
发明内容
有鉴于此，本发明的目的在于提供一种替扎尼定液体制剂，其杂质的含量少、稳定性强；相比于替扎尼定固体制剂，其不良反应率小、食物对药物作用速度影响小、餐后条件下药物作用速度快，且与替扎尼定固体制剂生物利用度等效。
在本发明中，替扎尼定液体制剂包括活性成分、EDTA二钠以及其他药物赋形剂；活性成分为替扎尼定或其药学上可接受的盐、溶剂化物、水合物中的一种或多种。
优选的，替扎尼定液体制剂的pH值大于3.5且小于6.5。
优选的，替扎尼定液体制剂的pH值为4.0-6.1。
优选的，替扎尼定液体制剂包括溶剂，所述溶剂为水。
优选的，其他药物赋形剂为pH调节剂、防腐剂、助溶剂、增稠剂、芳香剂、甜味剂和着色剂中的一种或多种。
优选的，pH调节剂为柠檬酸、抗坏血酸、乙酸、酒石酸、柠檬酸三钠、柠檬酸钠、柠檬酸钾、磷酸钠、磷酸三钙、碳酸钙、碳酸氢钠、磷酸钙、碳酸钙、氢氧化镁、盐酸、氢氧化钠中的一种或多种；
助溶剂为山梨糖醇、麦芽糖醇、甘露醇、异麦芽糖、木糖醇、葡萄糖、果糖中的一种或多种；
防腐剂为苯甲酸钠、尼泊金乙酯、尼泊金丙酯、尼泊金甲酯钠、尼泊金乙酯钠、尼泊金丙酯钠、苯甲酸、苯丙酸钾、山梨酸、山梨酸钠、山梨酸钙、山梨酸钾、脱氢乙酸、双乙酸钠、丙酸钙中的一种或多种；
增稠剂为羟丙甲纤维素、羟丙纤维素、胶态二氧化硅、甲基纤维素、羧甲基纤维素钠、海藻酸钠、环糊精中的一种或多种；
芳香剂为草莓芳香剂、橘子芳香剂、香蕉芳香剂、樱桃芳香剂、柠檬芳香剂、小豆蔻芳香剂、茴香芳香剂、薄荷芳香剂、薄荷脑芳香剂、香兰素芳香剂中的一种或多种；
甜味剂为三氯蔗糖、甘油、糖精钠、葡萄糖、甜菊糖、甜菊甙、阿斯巴甜、甜蜜素、安赛蜜、阿力甜、纽甜中的一种或多种；
着色剂为苋菜红、胭脂红、赤藓红、新红、柠檬黄、日落黄、靛蓝、甜菜红、紫胶红、越桔红、辣椒红、红米红中的一种或多种。
优选的，pH调节剂为柠檬酸和柠檬酸钠的混合物；
防腐剂为尼泊金甲酯钠和尼泊金丙酯钠的混合物，或，苯甲酸钠；
助溶剂为山梨糖醇；
增稠剂为羟丙纤维素和胶态二氧化硅的混合物，或，羟丙纤维素；
芳香剂为草莓芳香剂；
甜味剂为三氯蔗糖。
优选的，每100mL液体制剂中包括以下组分：活性成分0.02-1g、EDTA二钠0-0.2g；其中，EDTA二钠的含量不为0。
优选的，每100mL液体制剂中包括以下组分：
替扎尼定      0.02-1g
EDTA二钠      0.005-0.2g。
优选的，每100mL液体制剂中包括以下组分：
Figure PCTCN2022091371-appb-000004
优选的，每100mL液体制剂中包括以下组分：
Figure PCTCN2022091371-appb-000005
优选的，替扎尼定液体制剂括以下组分：
替扎尼定、尼泊金甲酯钠、尼泊金丙酯钠、EDTA二钠、三氯蔗糖、柠檬酸、柠檬酸钠、草莓香精以及水；
或，替扎尼定、尼泊金甲酯钠、尼泊金丙酯钠、山梨糖醇、EDTA二钠、三氯蔗糖、柠檬酸、柠檬酸钠、草莓香精以及水；
或，替扎尼定、羟丙纤维素、尼泊金甲酯钠、尼泊金丙酯钠、山梨糖醇、EDTA二钠、三氯蔗糖、柠檬酸、柠檬酸钠、草莓香精以及水；
或，替扎尼定、羟丙纤维素、胶态二氧化硅、尼泊金甲酯钠、尼泊金丙酯钠、山梨糖醇、EDTA二钠、三氯蔗糖、柠檬酸、柠檬酸钠、草莓香精以及水；
或，替扎尼定、羟丙纤维素、苯甲酸钠、甘油、山梨糖醇、EDTA二钠、三氯蔗糖、草莓香精以及水。
优选的，每100mL液体制剂包括以下组分：
盐酸替扎尼定0.046g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.083g、柠檬酸钠0.042g、草莓香精0.05g，其余为水；
或，盐酸替扎尼定0.046g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖醇溶液25g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.035g、草莓香精0.05g，其余为水；
或，盐酸替扎尼定0.046g、羟丙纤维素2.5g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖醇溶液15g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.046g、草莓香精0.05g，其余为水；
或，盐酸替扎尼定0.046g、羟丙纤维素2.5g、胶态二氧化硅0.5g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖溶液15g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.04g、草莓香精0.05g，其余为水；
或，盐酸替扎尼定0.046g、羟丙纤维素5g、苯甲酸钠0.1g、甘油15g、70％山梨糖醇溶液25g、EDTA二钠0.1g、三氯蔗糖0.05g、草莓香精0.05g，其余为水。
本发明替扎尼定液体制剂中药物活性成分优选为盐酸替扎尼定，其药物活性成分盐酸替扎尼定的含量为0.046g/100mL且本发明的液体制剂还含有EDTA二钠；所述液体制剂在室温下保存时其有关物质杂质总量≤0.2％，和/或，所述液体制剂给药后，其替扎尼定C max均值、AUC 0-t均值和/或AUC 0-∞均值，分别在下列液体制剂以替扎尼定计同等剂量给药后替扎尼定C max均值、AUC 0-t均值和/或AUC 0-∞均值的80％-120％范围内：
(1)每100mL液体制剂含盐酸替扎尼定0.046g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.083g、柠檬酸钠0.042g、草莓香精0.05g，其余为水；或
(2)每100mL液体制剂含盐酸替扎尼定0.046g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖醇溶液25g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.035g、草莓香精0.05g，其余为水；或，
(3)每100mL液体制剂含盐酸替扎尼定0.046g、羟丙纤维素2.5g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖醇溶液15g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.046g、草莓香精0.05g，其余为水；或
(4)每100mL液体制剂含盐酸替扎尼定0.046g、羟丙纤维素2.5g、胶态二氧化硅0.5g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖溶液15g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.04g、草莓香精0.05g，其余为水；或
(5)每100mL液体制剂含盐酸替扎尼定0.046g、羟丙纤维素5g、苯甲酸钠0.1g、甘油15g、70％山梨糖醇溶液25g、EDTA二钠0.1g、三氯蔗糖0.05g、草莓香精0.05g，其余为水。
本发明的替扎尼定液体制剂在40℃/75％RH的条件下密闭存放0-3个月，其有关物质杂质总量≤0.2％，和/或，本发明的替扎尼定液体制剂在25℃/60％RH的条件下密闭存放0-6个月，其有关物质杂质总量≤0.2％。
本发明的液体制剂与
Figure PCTCN2022091371-appb-000006
替扎尼定片剂餐前、餐后的生物利用度等效，和/或，本发明液体制剂与
Figure PCTCN2022091371-appb-000007
替扎尼定胶囊餐前、餐后的生物利用度等效。
本发明的液体制剂与替扎尼定片剂/胶囊的餐后条件下生物利用度等效的评判标准为：
C max的单侧95％置信区间上限≤0；
AUC 0-t的90％置信区间介于80％-125％之间；
AUC 0-∞的90％置信区间介于80％-125％之间。
本发明的替扎尼定液体制剂餐后条件下的T max均值小于替扎尼定片剂/胶囊的餐后条件下的T max均值。
本发明的替扎尼定液体制剂以替扎尼定计同等剂量给药条件下，本发明的不良反应发生率小于替扎尼定片剂/胶囊的不良反应发生率。
更加具体的，本发明的替扎尼定液体制剂以替扎尼定计同等剂量给药条件下，本发明液体制剂的餐前不良反应项-困倦的发生率小于替扎尼定片剂/胶囊；
和/或，本发明液体制剂的餐后不良反应项-困倦的发生率小于替扎尼定片剂/胶囊；
和/或，本发明液体制剂的餐后不良反应项-头痛的发生率小于替扎尼定片剂/胶囊；
和/或，本发明液体制剂的餐后不良反应项-呕吐的发生率小于替扎尼定胶囊。
一种替扎尼定液体制剂在制备治疗肌肉痉挛的药物中的用途。
影响药物化学稳定性的因素很多，其中温度是影响药物制剂稳定性的重要因素之一，一般说来，温度升高，降解反应速度加快；光也是可能影响药物制剂稳定性的原因，光可以引发链反应，加快降解速度；氧的存在也可能会加速氧化反应，影响药物稳定性，其他比如环境湿度、包材、pH值、辅料等也可能是影响药物化学稳定性的原因。不同的药物，其稳定性的影响因素千差万别。
本发明的制剂研究人员研究过程中发现，溶液中的金属离子对替扎尼定溶液的化学稳定性有影响，金属离子的存在具有加快替扎尼定有关物质降解的作用。本发明采用EDTA二钠作为螯合剂，其可以结合替扎尼定溶液中的金属离子，制备出化学稳定性强且有关物质杂质含量符合药典规定的替扎尼定液体制剂。EDTA二钠溶于水后能与铬、铁、铅、汞、铜、铝、镍、锌、钙、钴、锰和镁等矿物和金属离子结合并保持，当这些矿物和金属离子被结合时，它们对替扎尼定溶液的化学稳定性不再具有影响，极大程度的保证了本发明替扎尼定液体制剂的化学稳定性。
本发明的替扎尼定液体制剂在液体药品常规储存器玻璃瓶和聚酯瓶中都具有良好的化学稳定性，可见，本发明对存储容器要求并不苛刻，存储运输过程中可根据实际需要选择存放容器。本发明的药液可在常温下保存，有利于降低储藏和运输成本。
本发明的替扎尼定液体制剂外观澄清，经过长期放置，未出现沉淀、浑浊等现象，其物理稳定性强；其有关物质的杂质含量远低于药典对替扎尼定产品有关物质杂质含量规定的限度，符合药品申报的要求，可在临床上推广应用。
本发明制备的替扎尼定液体制剂相比于市场上现有的替扎尼定固体制剂，人体不良反应降低，提高了替扎尼定药品使用的安全性和患者服药的依从性。
本发明的液体制剂通过口腔给药方式进行给药，优选为口服给药。具有剂量滴定准确，便于幼儿、老年人、吞咽困难的患者、某些精神疾病患者及卧床体位难变动的患者服药的优势。
与此同时，本发明制备的替扎尼定液体制剂与现有的片剂和胶囊相比，在人体生物利用度方面，本发明均实现了餐前和餐后的等效，具有不低于现有固体制剂的药效。而且，食物对本发明液体制剂药物作用速度的影响小于其对现有固体制剂的影响，本发明相比于现有固体制剂，在餐后条件下药物作用起效更快，能更快速的缓解患者的痛苦。
综上所述，本发明获得了杂质少、化学和物理稳定性强的替扎尼定液体制剂，其不良反应少且其生物利用度与现有的替扎尼定固体制剂餐前/餐后等效，与此同时，本发明的液体制剂相比于现有的替扎尼定固体制剂其药物作用在餐后条件下起效更快，满足市场上对替扎尼定口服药物剂型的需求，满足了临床需求。
具体实施方式
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分优选实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明提供一种稳定的替扎尼定液体制剂，所述液体制剂的药物活性成分为替扎尼定或其药学上可接受的盐、溶剂化物、水合物中的一种或多种。所述本发明术语中的稳定指的是化学稳定和/或物理稳定。
本发明的药物活性成分无论是所述哪一种存在形式，待其溶解后，产生药效作用的是溶解在药液中的替扎尼定。为了方便进行数据对比，本发明的实施例优选以盐酸替扎尼定作为原料药，进行各方面的考察。
对盐酸替扎尼定原料药溶液pH值范围进行考察：
实验方法：
(1)称取盐酸替扎尼定0.323g，溶于400mL纯化水中；
(2)将上步溶液分成四等份，用0.1N HCI及0.1N NaOH调节pH至3.5，4.5，5.5，6.5；
(3)冻融试验—将四份的样品溶液放置于2-8℃、室温、40℃/75％RH各条件下保存24小时，重复3次。
测得盐酸替扎尼定原料药溶液pH及外观和冻融试验的有关物质检测的变化差异如下表：
表1盐酸替扎尼定原料药溶液pH影响考察表
样品 pH值 外观 有关物质总杂％增量(±)
1 3.5 澄清无色溶液 0.79％
2 4.5 澄清无色溶液 0.21％
3 5.5 澄清无色溶液 0.34％
4 6.5 澄清淡黄色溶液 0.22％
物理观察表明，当pH为6.5时，溶液颜色发生变化，由无色变为淡黄色。
冻融实验前后有关物质总杂变化差异最大的是上表中1号样品溶液，其冻融实验前后有关物质总杂变化量为0.79％。
由盐酸替扎尼定原料药溶液外观变化和冻融实验前后有关物质总杂变化差异，可知，盐酸替扎尼定原料药溶液的pH值在大于3.5和小于6.5的区间范围内具有更为优良的稳定性。
因此本发明的pH值优先选择为大于3.5且小于6.5。
接下来通过具体实施例对本发明替扎尼定液体制剂的稳定性进行考察。
由于玻璃瓶/聚酯瓶是现在常用的固体药片或者是液体制剂存放的内包装之一。玻璃瓶具有耐热性较好、不易吸附等优良特质，但其比较脆，容易破碎，不能挤压，给生产和运输带来不便，而且玻璃中含有的微量金属离子有可能会影响药品的稳定性；聚酯瓶不易破碎，破损率为零，价格低廉，生产运输成本低，但其耐热性较差，而且其在生产过程中附加剂添加较多，容易导致药品质量发生变化，同时，聚酯瓶还具有透气、易吸附等缺点，该缺点也可加速药品氧化变质的速度，引起药品变质。
因此，本发明在稳定性考察过程中，将替扎尼定液体制剂存放于玻璃瓶和聚酯瓶这两种常用的药品存放容器，进行有关物质检测。
本发明稳定性考察的试验方法为：
a加速试验步骤：
(1)设置稳定性试验箱的温度为40℃，相对湿度为75％；
(2)取密封装入玻璃瓶和聚酯瓶的液体制剂置于设置好的稳定性试验箱；
(3)取放置后的样品进行有关物质检测。
b常温试验步骤：
(1)设置稳定性试验箱的温度为25℃，相对湿度为60％；
(2)取密封装入玻璃瓶和聚酯瓶的液体制剂置于设置好的稳定性试验箱；
(3)取放置后的样品进行有关物质检测。
本发明所有实施例中的加速试验和常温试验的试验方法均采用该方法。
实施例1
本发明的液体制剂除了替扎尼定原料药，还包括EDTA二钠和其他一种或多种药学上可接受的赋形剂。因此，加入相关辅料，制成盐酸替扎尼定液体制剂后，对该液体制剂的稳定性和pH值范围进行研究：
(一)实验处方：
表2处方表
Figure PCTCN2022091371-appb-000008
对于本申请的处方表，应当理解，本申请所公开的发明不限于特定的配制体积，在其液体制剂各组分浓度确定的情况下，因为生产和试验的需求，其配制体积是可以变化的。
本申请全文所提供的关于液体制剂体积的描述仅出于描述特定实施方案或各组分的浓度的目的而给出，其不旨在限制本发明的范围。
(二)工艺：
按照处方量称量物料备用；
(1)将EDTA二钠溶于适量水中，搅拌均匀；
(2)将三氯蔗糖溶于适量水，加入到步骤(1)所得的溶液中，搅拌均匀；
(3)将尼泊金甲酯钠溶于适量水，加入至步骤(2)所得的溶液中，搅拌均匀；
(4)将尼泊金丙酯钠溶于适量水，加入至步骤(3)所得的溶液中，搅拌均匀；
(5)将柠檬酸溶于适量水，加入步骤(4)所得的溶液中，搅拌均匀；
(6)将柠檬酸钠溶于适量水，加入步骤(5)所得的溶液中，搅拌均匀；
(7)将盐酸替扎尼定溶于适量水，加入步骤(6)所得的溶液中，搅拌均匀；
(8)用0.1N HCl或0.1N NaOH调节步骤(7)溶液的pH值约至4.0或6.0或不进行pH值调节。
(9)在搅拌下将草莓香精加入至步骤(8)所得的溶液中，搅拌均匀；
(10)加入水，调节体积至1000mL，过滤，得到盐酸替扎尼定液体制剂。
(三)有关物质检测方法：
采用高效液相色谱法测定有关物质。
供试品溶液：取盐酸替扎尼定液体制剂约10g，精密称定(约相当于替扎尼定4mg)，置100mL量瓶中，加稀释剂[流动相A与流动相B按一定比例混合]稀释至刻度，摇匀，过滤，取滤液。
对照溶液：精密量取供试品溶液1.0mL，置100mL量瓶中，加稀释剂稀释至刻度，摇匀。
色谱柱选用十八烷基硅烷键合硅胶柱C18(4.6×250mm，5μm)，以戊烷磺酸钠溶液(取戊烷磺酸钠3.5g，溶于1000mL水中，用磷酸溶液或氢氧化钠试液调pH至3.0)为流动相A，乙腈为流动相B，按表3进行梯度洗脱；流速为1.0mL/min；检测波长为230nm；进样体积为50μL；柱温为30℃。
表3梯度洗脱程序
时间(分钟) 流动相A(％) 流动相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
限度：供试品溶液色谱图中如显杂质峰，杂质峰面积总和不得大于对照溶液主峰面积的0.5倍(即有关物质杂质总量不得超过0.5％)。
本检测方法可用于本说明书中所有实施例的有关物质的检测，但本发明有关物质的检测方法不限于本检测方法；本领域技术人员通过常规手段部分调整检测方法/检测参数也可对本发明的有关物质进行检测。
表4不同pH的盐酸替扎尼定液体制剂加速试验有关物质检测结果
Figure PCTCN2022091371-appb-000009
Figure PCTCN2022091371-appb-000010
表4结果表明，在加速条件下，pH为4.0/5.0/6.1时，替扎尼定液体制剂0天、1月、3月的有关物质的总杂含量均小于0.2％，远小于药典规定的0.5％；与此同时，不同pH值的液体制剂均未发生浑浊、沉淀等现象。可见，本发明替扎尼定液体制剂的pH在4.0-6.1范围内变化时候，pH值对制剂的物理和化学稳定性无实质性影响，不会影响药品的上市和使用。
为了进一步验证本实施例的液体制剂长期稳定性，对本实施例所制备的替扎尼定液体制剂进行常温试验。为了节省资源，本次考察仅对表2中未添加HCl或NaOH的2号处方进行考察。
表5为2号处方的盐酸替扎尼定液体制剂常温试验有关物质检测结果
Figure PCTCN2022091371-appb-000011
本实施例的液体制剂常温下放置6月的有关物质总杂为0.03％(玻璃瓶)、0.03％(聚酯瓶)，其有关物质总杂含量均小于0.2％，远小于药典规定的0.5％的限度，具有良好的化学稳定性。
本实施例的液体制剂存储在玻璃瓶和聚酯瓶中的有关物质的检测结果区别不大，可见本实施例的液体制剂对存储容器要求并不苛刻，存储运输过程中可根据实际需要选择存放容器。
与此同时，无论是在加速试验还是在常温试验中，本实施例替扎尼定液体制剂均未出现沉淀、浑浊等现象，说明本实施例的液体制剂在加速条件下和在常温条件下长期储存过程中均具有良好的物理稳定性。
由此可见，本实施例的液体制剂不仅杂质含量低，而且具有良好的化学/物理稳定性，符合药典规定，满足药品上市要求，而且其对存储容器耐用性强，临床上可提供多种存储选择。
实施例2
本实施例在处方中添加辅料—助溶剂，对稳定性进行考察。
(一)实验处方
表6处方表
Figure PCTCN2022091371-appb-000012
(二)工艺：
按照处方量称量物料备用；
(1)将EDTA二钠溶于适量水中，搅拌均匀；
(2)将三氯蔗糖溶于适量水中，加入至步骤(1)所得的溶液中；
(3)在搅拌下，将浓度为70％山梨糖醇加入步骤(2)所得的溶液中；
(4)将尼泊金甲酯钠和尼泊金丙酯钠溶于水，搅拌下加入至步骤(3)所得的溶液中；
(5)将柠檬酸和柠檬酸钠搅拌下加入至步骤(4)所得的溶液中；
(6)将盐酸替扎尼定单独溶于水后，在持续搅拌下加入至步骤(5)所得的溶液中；
(7)在搅拌下将草莓香精加入至步骤(6)得到的溶液中；
(8)加入水，调节体积至1000mL，过滤，得到盐酸替扎尼定液体制剂。
(三)稳定性考察
对本实施例制备的液体制剂进行加速试验。
表7加速试验有关物质检测结果
Figure PCTCN2022091371-appb-000013
0天时，测得本实施例液体制剂的pH值为5.0。由于本发明替扎尼定液体制剂pH值在4.0-6.1的范围内变化对本发明的稳定性无实质性影响，因此本实施例对pH值不做考察。
本实施例的液体制剂在加速条件下，0、1、3月有关物质总杂含量均小于0.2％，均远小于药典规定的0.5％的限度，具有良好的化学稳定性，且符合药典规定。
为了进一步验证本实施例液体制剂长期稳定性，对本实施例所制备的替扎尼定液体制剂进行常温试验。
表8常温试验有关物质检测结果
Figure PCTCN2022091371-appb-000014
本实施例液体制剂常温下放置6月的有关物质总杂为0.15％(玻璃瓶)、0.19％(聚酯瓶)，均小于0.2％，远小于药典规定的0.5％的限度，具有良好的化学稳定性，且符合药典规定。
本实施例的液体制剂存储在玻璃瓶和聚酯瓶中的有关物质总杂的检测结果区别不大，可见本实施例的液体制剂对存储容器要求并不苛刻，存储运输过程中可根据实际需要选择存放容器。
与此同时，无论是在加速试验还是在常温试验中，本实施例替扎尼定液体制剂外观上均未出现沉淀、浑浊等现象，说明本实施例的液体制剂在加速条件下和在常温条件下长期储存过程中也具有良好的物理稳定性。
本实施例的液体制剂不仅杂质含量低，而且具有良好的长期稳定性，符合药典规定，满足药品上市要求。
本实施例与实施例1相比，液体制剂的处方中增加了助溶剂，可见助溶剂的添加与否对本发明液体制剂的物理和化学稳定性无实质性影响，不会影响药品的上市和使用。
实施例3
本实施例处方中添加辅料—增稠剂，并调整助溶剂的加入量，对稳定性进行考察。
(一)实验处方
表9处方表
Figure PCTCN2022091371-appb-000015
Figure PCTCN2022091371-appb-000016
(二)工艺
按照处方量称量物料备用；
(1)将羟丙纤维素加入至适量水中分散，搅拌至澄清。
(2)将EDTA二钠溶于水，搅拌下加入至步骤(1)所得的溶液中。
(3)搅拌下将浓度为70％山梨糖醇加入至步骤(2)所得的溶液中，搅拌至澄清。
(4)将尼泊金甲酯钠和尼泊金丙酯钠溶于水，搅拌下加入至步骤(3)所得的溶液中。
(5)将柠檬酸和柠檬酸钠搅拌下加入至步骤(4)所得的溶液中。
(6)将三氯蔗糖溶溶于水，搅拌下加入步骤(5)所得的溶液中。
(7)将盐酸替扎尼定单独溶于水后，在持续搅拌下加入至步骤(6)所得的溶液中。
(8)草莓香精在持续搅拌下加入至步骤(7)所得的溶液中。
(9)加水调节体积至1000mL，过滤，得到盐酸替扎尼定液体制剂。
(三)稳定性考察
对本实施例制备的液体制剂进行加速试验。
表10加速试验有关物质检测结果
Figure PCTCN2022091371-appb-000017
0天时，测得本实施例制备的药液pH值为5.2，由于本发明替扎尼定液体制剂pH值在4.0-6.1的范围内变化对本发明的稳定性无实质性影响，因此本实施例对pH值不做考察。
本实施例的液体制剂在加速条件下，0、1、3月有关物质总杂含量均小于0.2％，远小于药典规定的0.5％的限度，具有良好的化学稳定性，符合药典规定。
为了进一步验证本实施例液体制剂长期稳定性，对本实施例所制备的替扎尼定液 体制剂进行常温试验。
表11常温试验有关物质检测结果
Figure PCTCN2022091371-appb-000018
本实施例液体制剂常温下放置6月的有关物质总杂为0.06％(玻璃瓶)、0.06％(聚酯瓶)，均小于0.2％，远小于药典规定的0.5％的限度，具有良好的化学稳定性，且符合药典规定。
本实施例的液体制剂存储在玻璃瓶和聚酯瓶中的有关物质总杂的检测结果区别不大，可见本实施例的液体制剂对存储容器要求并不苛刻，存储运输过程中可根据实际需要选择存放容器。
与此同时，无论是在加速试验还是在常温试验中，本实施例替扎尼定液体制剂外观上均未出现沉淀、浑浊等现象，说明本实施例的液体制剂在加速条件下和在常温条件下长期储存过程中也具有良好的物理稳定性。
本实施例的液体制剂不仅杂质含量低，而且具有良好的长期稳定性，符合药典规定，满足药品上市要求。
本实施例与实施例2相比，添加了增稠剂，并减少了助溶剂的添加量，由此可知，本发明改变液体制剂的粘度、调整助溶剂的加入量对本发明液体制剂的物理和化学稳定性无实质性影响，不会影响药品的上市和使用。
实施例4
本实施例调整处方中增稠剂的种类和加入量，对稳定性进行考察。
(一)实验处方
表12处方表
Figure PCTCN2022091371-appb-000019
Figure PCTCN2022091371-appb-000020
(二)工艺
按照处方量称量物料备用；
(1)将羟丙纤维素加入至适量水中分散，搅拌至澄清。
(2)将EDTA二钠溶于水，搅拌下加入至步骤(1)所得的溶液中，搅拌至澄清。
(3)搅拌下将浓度为70％山梨糖醇加入至步骤(2)所得的溶液中，搅拌至澄清。
(4)将尼泊金甲酯钠和尼泊金丙酯钠溶于水，加入至步骤(3)所得的溶液中。
(5)将柠檬酸和柠檬酸钠溶于水，搅拌下加入至步骤(4)所得的溶液中。
(6)将三氯蔗糖溶溶于水，加入步骤(5)所得的溶液中。
(7)将胶态二氧化硅分散在水中，搅拌下加入至步骤(6)所得的溶液中。
(8)将盐酸替扎尼定单独溶于水后，在持续搅拌下加入至步骤(7)所得的溶液中。
(9)将草莓香精在持续搅拌下加入至步骤(8)所得的溶液中。
(10)加水调节体积至1000mL，过滤，得到盐酸替扎尼定液体制剂。
(三)稳定性考察
对本实施例制备的液体制剂进行加速试验。
表13加速试验有关物质检测结果
Figure PCTCN2022091371-appb-000021
0天时，测得本实施例液体制剂的pH值为5.1，由于本发明替扎尼定液体制剂pH值在4.0-6.1的范围内变化对本发明的稳定性无实质性影响，因此本实施例对pH值不做考察。
本实施例的液体制剂在加速条件下，0、1、3月有关物质总杂含量均小于0.2％，远小于药典规定的0.5％的限度，具有良好的化学稳定性，符合药典规定。
本实施例的处方在实施例3的基础上添加了胶态二氧化硅的，对增稠剂的配方进行调整，由表10和表13的有关物质总杂的检测对比结果可知，增稠剂处方的改变对本发明的化学稳定性无实质性影响；且，由表7/表10与表13的对比结果可知，本实施例的替扎尼定液体制剂明显具有不低于实施例2/实施例3的替扎尼定液体制剂的化学稳定性，其加速条件下，0-3月有关物质杂质含量符合药典的规定。
本实施例的液体制剂存储在玻璃瓶和聚酯瓶中的有关物质的检测结果区别不大， 可见本施例的液体制剂对存储容器要求并不苛刻，存储运输过程中可根据实际需要选择存放容器。
与此同时，本实施例的液体制剂未出现沉淀、浑浊等现象，具有良好的物理稳定性。
由此可知，增稠剂的配方的调整对本发明液体制剂的物理和化学稳定性无实质性影响，不会影响药品的上市和使用。
实施例5
本实施例加大辅料调整力度，对稳定性进行考察。
(一)实验处方
表14处方表
Figure PCTCN2022091371-appb-000022
(二)工艺
按照处方量称量物料备用；
(1)将羟丙纤维素加入至适量水中分散，搅拌至澄清。
(2)将苯甲酸钠溶于水中，加入至步骤(1)所得的溶液中。
(3)接着将EDTA二钠溶于水，搅拌下加入至步骤(2)所得的溶液中。
(4)将三氯蔗糖加入至步骤(3)所得的溶液中，搅拌均匀。
(5)将甘油加入至步骤(4)所得的溶液中。
(6)在搅拌下将浓度为70％山梨糖醇加入至步骤(5)所得的溶液中。
(7)将盐酸替扎尼定单独溶于水后，在持续搅拌下加入至步骤(6)所得的溶液中。
(8)将草莓香精在持续搅拌下加入至步骤(7)所得的溶液中。
(9)加水调节体积至1000mL，过滤，得到盐酸替扎尼定液体制剂。
(三)稳定性考察
对本实施例制备的药液进行加速试验。
表15加速试验有关物质检测结果
Figure PCTCN2022091371-appb-000023
本实施例在加速条件下，0、1、3月有关物质总杂未检出，总杂含量均小于0.2％，远小于药典规定的0.5％的限度，具有良好的化学稳定性，符合药典规定。
本实施例存储在玻璃瓶和聚酯瓶中的有关物质的检测结果无区别，可见本实施例对存储容器要求并不苛刻，存储运输过程中可根据实际需要选择存放容器。
与此同时，本实施例替扎尼定液体制剂未出现沉淀、浑浊等现象，具有良好的物理稳定性。
本实施例与实施例2处方相比，删除了pH值调节剂，本实施例药液0天时测得pH值为4.9，在pH值为4.0-6.1的范围内。由本实施例与实施例2在加速试验下的有关物质总杂对比结果可知(表15与表7对比)，删除pH值调节剂对本发明液体制剂的物理和化学稳定性无实质性影响，不会影响药品的上市和使用。
本实施例将实施例2处方中的防腐剂更换为苯甲酸钠，由本实施例与实施例2在加速试验下的有关物质总杂对比结果可知(表15与表7对比)，更换防腐剂对本发明液体制剂的物理和化学稳定性无实质性影响，不会影响药品的上市和使用。
本实施例与实施例2处方相比，添加了甘油作为甜味剂，由本实施例与实施例2在加速试验下的有关物质总杂对比结果可知(表15与表7对比)，变更甜味剂处方对本发明液体制剂的物理和化学稳定性无实质性影响，不会影响药品的上市和使用。
本实施例与实施例2处方相比，添加了羟丙纤维素作为增稠剂，由本实施例与实施例2在加速试验下的有关物质总杂对比结果可知(表15与表7对比)，增加增稠剂对本发明液体制剂的物理和化学稳定性无实质性影响，不会影响药品的上市和使用。
本实施例与实施例2处方对比，本实施例处方中除了盐酸替扎尼定活性物质外，只保留了辅料山梨糖醇、EDTA二钠以及仅起矫味作用的三氯蔗糖、草莓香精，其余辅料均不相同。可见，除山梨糖醇、EDTA二钠以外，其他辅料在本领域技术人员的认知范围内做相应的改变和删除，对本发明液体制剂的物理和化学稳定性无实质性影响，不会影响药品的上市和使用。
与此同时，由实施例1与实施例2对比可知，助溶剂—山梨糖醇的添加与否对本发明液体制剂的物理和化学稳定性无实质性影响，不会影响药品的上市和使用。
可见，本发明除EDTA二钠以外的其他辅料的改变和删除不会对本发明的物理和化学稳定性有实质性的影响，所述其他辅料包括且不限于：
pH调节剂(柠檬酸、抗坏血酸、乙酸、酒石酸、柠檬酸三钠、柠檬酸钠、柠檬酸 钾、磷酸钠、磷酸三钙、碳酸钙、碳酸氢钠、磷酸钙、碳酸钙、氢氧化镁、盐酸、氢氧化钠等)；
和/或，助溶剂(山梨糖醇、麦芽糖醇、甘露醇、异麦芽糖、木糖醇、葡萄糖、果糖中等)；
和/或，防腐剂(苯甲酸钠、尼泊金乙酯、尼泊金丙酯、尼泊金甲酯钠、尼泊金乙酯钠、尼泊金丙酯钠、苯甲酸、苯丙酸钾、山梨酸、山梨酸钠、山梨酸钙、山梨酸钾、脱氢乙酸、双乙酸钠、丙酸钙等)；
和/或，增稠剂(羟丙甲纤维素、羟丙纤维素、胶态二氧化硅、甲基纤维素、羧甲基纤维素钠、海藻酸钠、环糊精等)；
和/或，芳香剂(草莓芳香剂、橘子芳香剂、香蕉芳香剂、樱桃芳香剂、柠檬芳香剂、小豆蔻芳香剂、茴香芳香剂、薄荷芳香剂、薄荷脑芳香剂、香兰素芳香剂等)；
和/或，甜味剂(三氯蔗糖、甘油、糖精钠、葡萄糖、甜菊糖、甜菊甙、阿斯巴甜、甜蜜素、安赛蜜、阿力甜、纽甜等)；
和/或，仅其增色作用的着色剂(苋菜红、胭脂红、赤藓红、新红、柠檬黄、日落黄、靛蓝、甜菜红、紫胶红、越桔红、辣椒红、红米红等)。
本发明的替扎尼定液体制剂稳定性研究设计的考察时间为24个月或更长时间，目前本发明的替扎尼定液体制剂的0-3月加速试验和0-6月常温试验的数据显示在40℃/75％RH、25℃/60％RH下其有关物质杂质含量均小于0.2％，远小于药典规定的0.5％的限度。这表明，可以预期药品贮藏条件下本发明液体制剂的稳定性与如上所述稳定性试验所获得的稳定性相当。
本发明所述替扎尼定液体制剂加入了防腐剂，进行了防腐剂效力考察，并有24个月或更长时间的稳定性考察，可以预期本发明液体制剂的微生物指标符合药品的质量标准。
以下通过临床试验，分餐前(即空腹)和餐后对本发明进行人体药代动力学试验，同时对不良反应发生率进行考察：
实验样品：
ⅰ实施例1制备的盐酸替扎尼定液体制剂；
ⅱ实施例2制备的盐酸替扎尼定液体制剂；
Figure PCTCN2022091371-appb-000024
(盐酸替扎尼定)4mg片剂(标准品1)；
Figure PCTCN2022091371-appb-000025
(盐酸替扎尼定)4mg胶囊(标准品2)。
餐前(空腹)生物等效试验方法及试验结果：
本试验在餐前条件下的25名健康成人受试者中进行，随机、开放、交叉、单剂量(以替扎尼定计4mg)，5周期，5序列的交叉实验设计，周期清洗时间为2天，受试者给药前经过至少10小时禁食，给药前一小时和给药后一小时禁止饮用水(给药期间的240mL水除外)，给药后4h、8h提供标准餐；受试者在每周期前48h以及在整个试验 期间，禁止进食含有咖啡因和/或含黄嘌呤的食物或饮料(例如，咖啡、茶和含有咖啡因的苏打水、可乐等)，同时禁止进食葡萄柚和/或葡萄柚果汁，以及含有罂粟的食物。
给药方式：
液体制剂给药方式为：受试者保持坐姿，用口服注射器将10mLⅰ/ⅱ注入受试者口中；受试者将其与50mL水一同吞下，用10mL水清洗注射器并注入受试者口中，重复三次，接着给予受试者水，保证受试者服药过程中的给水总量为240mL；受试者在服药后两小时内保持坐姿。
片剂/胶囊的给药方式为：受试者保持坐姿，将单剂量的ⅲ/ⅳ放入受试者口中，服用240mL水将其整个吞下(受试者不得咀嚼或粉碎药片/胶囊)；受试者在服药后两小时内保持坐姿。
每周期受试者将在给药前(0.00h)及给药后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和12.00h分别采集血样2.5mL。计算相关的药代动力学参数。
T max为药物的达峰时间。
C max为峰浓度即测得的最大血药浓度。
AUC 0-t为以线性梯形法进行计算。
AUC 0-∞＝AUC 0-t+Ct/λz。t为最后一次可实测血药浓度的采样时间；Ct为末次可测定样本药物浓度，λz为末端消除速率常数。
表16餐前条件下人体药代动力学试验结果
参数(均值) ⅰ ⅱ ⅲ ⅳ
C max(pg/mL) 6891.0570 6700.6869 6214.9907 6884.0184
AUC 0-t(pg·hr/mL) 16452.1907 16750.9623 15326.0384 15937.0213
AUC 0-∞(pg·hr/mL) 16770.7496 17017.0368 15570.9400 16190.1320
T max(hr) 0.80 0.71 0.87 0.87
表17 ⅰ与ⅲ餐前条件下生物等效评价结果
Figure PCTCN2022091371-appb-000026
表18 ⅰ与ⅳ餐前条件下生物等效评价结果
Figure PCTCN2022091371-appb-000027
表19 ⅱ与ⅲ餐前条件下生物等效评价结果
Figure PCTCN2022091371-appb-000028
表20 ⅱ与ⅳ餐前条件下生物等效评价结果
Figure PCTCN2022091371-appb-000029
结论：本发明制备的替扎尼定液体制剂在餐前条件下能与现有市售的标准品
Figure PCTCN2022091371-appb-000030
(盐酸替扎尼定)4mg片剂/胶囊均实现生物等效。
餐前(空腹)不良反应考察试验及试验结果：
在餐前生物等效试验的过程中通过观察、采访和主动上报的方式记录受试者的在整个实验过程中的不良反应。
表21餐前条件下不良反应及其发生率的考察结果
样品 ⅰ ⅱ ⅲ ⅳ
困倦(Drowsiness) 无 8.00％ 40.00％ 16.00％
头痛(Headache) 无 无 无 无
衰弱(Asthenia) 无 无 无 无
晕眩(Vertigo) 无 4.00％ 无 无
不良反应发生率 0 12.00％ 40.00％ 16.00％
由上表实验结果可知，本发明实施例1/实施例2的餐前的不良反应(困倦、头痛、衰弱、晕眩)发生率为0/12.00％，而片剂/胶囊的不良反应(困倦、头痛、衰弱、晕眩)发生率为40.00％/16.00％；可见，在餐前条件下，本发明的替扎尼定液体制剂的不良反应(困倦、头痛、衰弱、晕眩)发生率小于现有的固体制剂。
餐后生物等效试验方法及试验结果：
本试验在餐后条件下的27名健康成人受试者中进行，采用随机、开放、交叉、单剂量(替扎尼定4mg)、6周期、3序列的部分重复试验设计。周期清洗时间为2天，受试者给药前经过至少10小时禁食后，给药前一小时和给药后一小时禁止饮用水(给药期间的240mL水除外)，在给药前0.5h小时提供高热量高脂肪非蔬菜标准餐，在餐后0.5h内给药，并于给药后4h、8h、12h提供高热量高脂肪非蔬菜标准餐；受试者在每周期前48h以及在整个试验期间，禁止进食含有咖啡因和/或含黄嘌呤的食物或饮料(例如，咖啡、茶和含有咖啡因的苏打水、可乐等)，同时禁止进食葡萄柚和/或葡萄柚果汁，以及含有罂粟的食物。
给药方式：
液体制剂给药方式为：受试者保持坐姿，用口服注射器将10mLⅰ/ⅱ注入受试者口中；受试者将其与50mL水一同吞下，用10mL水清洗注射器并注入受试者口中，重复三次，接着给予受试者水，保证受试者服药过程中的给水总量为240mL；受试者在服药后两小时内保持坐姿。
片剂/胶囊的给药方式为：受试者保持坐姿，将单剂量的ⅲ/ⅳ放入受试者口中，服用240mL水将其整个吞下(受试者不得咀嚼或粉碎药片/胶囊)；受试者在服药后两小时内保持坐姿。
每周期受试者将在给药前(0.00h)及给药后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和12.00h分别采集血样2.5mL。计算相关的药代动力学参数。
C max为峰浓度即测得的最大血药浓度。
AUC 0-t为以线性梯形法进行计算。
AUC 0-∞＝AUC 0-t+Ct/λz。t为最后一次可实测血药浓度的采样时间；Ct为末次可测定样本药物浓度，λz为末端消除速率常数。
表22餐后条件下人体药代动力学试验结果
参数(均值) ⅰ ⅱ ⅲ ⅳ
C max(pg/mL) 4879.123 4852.799 5395.440 4832.833
AUC 0-t(pg·hr/mL) 14551.615 14810.490 14943.559 15267.928
AUC 0-∞(pg·hr/mL) 14783.945 15051.702 15180.678 15557.618
T max(hr) 0.94 1.00 1.74 2.02
上表中本发明实施例1/实施例2的盐酸替扎尼定液体制剂的T max为0.94/1.00小时；而现有(盐酸替扎尼定)片剂/胶囊T max为1.74/2.02小时；可见，餐后条件下，本发明的液体制剂相比于现有固体制剂的T max有了明显降低，药物作用明显加快。
由表16与表22的对比结果可知，本发明实施例1/实施例2的盐酸替扎尼定液体制剂餐后条件相比于其餐前条件下的T max仅延长了0.14/0.29小时，而现有片剂/胶囊餐后条件相比于其餐前条件下的T max延长了0.87/1.15小时，可见食物对本发明的T max影响小 于其对现有固体制剂的影响。
由此可知，食物对本发明的盐酸替扎尼定液体制剂药物作用速度的影响小于其对现有固体制剂的影响；餐后条件下，本发明相比于现有固体制剂的药物作用更快。
由于餐后生物等效试验方法采用部分重复试验设计，本领域技术人员所公知的，若S WR(个体内标准差)≥0.294(即ISCV％≥30％)，可采用RSABE方法进行等效性评价(应用于AUC 0-t、AUC 0-∞、C max两者之中任意一个或全部采用)；采用RSABE方法判定受试制剂与参比制剂的药动学参数(AUC 0-t或AUC 0-∞或C max)具有生物等效性等效的标准为：计算参数几何均值比的点估计值(以下简称点估值)在80％-125％范围内，同时，该计算参数单侧95％置信区间上限(简称95％置信上限)≤0即可。若S WR＜0.294(即ISCV％＜30％)，则应采用ABE方法评价生物等效性。
表23-1 ⅰ与ⅲ餐后条件下C max生物等效评价结果
参数 ISCV％ 点估值(％) 95％置信上限 结果
C max 51.62％ 98.60％ -0.1251 等效
表23-2 ⅰ与ⅲ餐后条件下AUC 0-t、AUC 0-∞生物等效评价结果
参数 ISCV％ Lower90％CI Upper90％CI 90％CI等效范围 结果
AUC 0-t 25.75％ 94.27％ 115.44％ 80.00-125.00％ 等效
AUC 0-∞ 25.62％ 94.48％ 115.54％ 80.00-125.00％ 等效
表24-1 ⅰ与ⅳ餐后条件下C max生物等效评价结果
参数 ISCV％ 点估值(％) 95％置信上限 结果
C max 33.64％ 108.39％ -0.0241 等效
表24-2 ⅰ与ⅳ餐后条件下AUC 0-t、AUC 0-∞生物等效评价结果
参数 ISCV％ Lower90％CI Upper90％CI 90％CI等效范围 结果
AUC 0-t 26.04％ 92.62％ 116.22％ 80.00-125.00％ 等效
AUC 0-∞ 25.46％ 92.50％ 115.82％ 80.00-125.00％ 等效
表25-1 ⅱ与ⅲ餐后条件下C max生物等效评价结果
参数 ISCV％ 点估值(％) 95％置信上限 结果
C max 51.62％ 103.73％ -0.122 等效
表25-2 ⅱ与ⅲ餐后条件下AUC 0-t、AUC 0-∞生物等效评价结果
参数 ISCV％ Lower90％CI Upper90％CI 90％CI等效范围 结果
AUC 0-t 25.97％ 104.12％ 123.69％ 80.00-125.00％ 等效
AUC 0-∞ 25.74％ 104.30％ 123.74％ 80.00-125.00％ 等效
表26-1 ⅱ与ⅳ餐后条件下C max生物等效评价结果
参数 ISCV％ 点估值(％) 95％置信上限 结果
C max 33.64％ 114.46％ -0.0041 等效
表26-2 ⅱ与ⅳ餐后条件下AUC 0-t、AUC 0-∞生物等效评价结果
参数 ISCV％ Lower90％CI Upper90％CI 90％CI等效范围 结果
AUC 0-t 25.85％ 103.32％ 122.33％ 80.00-125.00％ 等效
AUC 0-∞ 25.30％ 103.10％ 121.88％ 80.00-125.00％ 等效
结论：本发明制备的替扎尼定液体制剂在餐后条件下能与现有市售的标准品
Figure PCTCN2022091371-appb-000031
(盐酸替扎尼定)4mg片剂/胶囊均实现生物等效。
餐后不良反应考察试验及试验结果：
在餐后生物等效试验的过程中通过观察、采访和主动上报的方式记录受试者的在整个实验过程中的不良反应。
表27餐后条件下不良反应及其发生率的考察结果
样品 ⅰ ⅱ ⅲ ⅳ
困倦(Drowsiness) 3.70％ 3.70％ 25.92％ 22.22％
呕吐(Vomiting) 无 无 无 1.85％
头痛(Headache) 无 无 3.70％ 1.85％
不良反应发生率 3.70％ 3.70％ 29.62％ 25.92％
由上表实验结果可知，本发明实施例1/实施例2的餐后的不良反应(困倦、呕吐、头痛)发生率为3.70％/3.70％，而片剂/胶囊的不良反应(困倦、呕吐、头痛)发生率为29.62％/25.92％；可见，在餐后条件下，本发明的替扎尼定液体制剂的不良反应(困倦、呕吐、头痛)发生率小于现有的固体制剂。
由表21和表27的不良反应及其发生率的考察结果可知，本发明的替扎尼定液体制剂在餐前/餐后条件下其不良反应项-困倦(Drowsiness)的发生率均小于固体制剂(即片剂和胶囊制剂)；其不良反应项-头痛(Headache)的发生率在餐后条件下的发生率小于固体制剂(即片剂和胶囊制剂)；而其不良反应项-呕吐(Vomiting)的发生率在餐后条件小于胶囊制剂。
由此可见，本发明的替扎尼定液体制剂无论在餐前还是餐后条件下，其不良反应发生率小于现有的固体制剂。本发明的液体制剂改变了替扎尼定药物剂型以及相关辅料，使得药物不良反应明显降低，这是本领域技术人员所意料不到的。本发明药物不良反应率的降低，提高了本发明药物使用的安全性和患者服药的依从性。
综上所述，本发明的替扎尼定液体制剂杂质的含量少、稳定性强；相比于现有的替扎尼定固体制剂，其不良反应率小、食物对药物作用速度影响小、餐后条件下药物作用速度快，且与现有固体制剂生物利用度等效，满足了临床需要。
所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (21)

  1. 一种替扎尼定液体制剂，其特征在于，包括活性成分、EDTA二钠以及其他药物赋形剂；所述活性成分为替扎尼定或其药学上可接受的盐、溶剂化物、水合物中的一种或多种。
  2. 根据权利要求1所述的替扎尼定液体制剂，其特征在于，所述液体制剂的pH值大于3.5且小于6.5。
  3. 根据权利要求1所述的替扎尼定液体制剂，其特征在于，所述液体制剂的pH值为4.0-6.1。
  4. 根据权利要求1所述的替扎尼定液体制剂，其特征在于，所述液体制剂包括溶剂，所述溶剂为水。
  5. 根据权利要求1所述的替扎尼定液体制剂，其特征在于，所述其他药物赋形剂为pH调节剂、防腐剂、助溶剂、增稠剂、芳香剂、甜味剂和着色剂中的一种或多种。
  6. 根据权利要求5所述的替扎尼定液体制剂，其特征在于，所述pH调节剂为柠檬酸、抗坏血酸、乙酸、酒石酸、柠檬酸三钠、柠檬酸钠、柠檬酸钾、磷酸钠、磷酸三钙、碳酸钙、碳酸氢钠、磷酸钙、碳酸钙、氢氧化镁、盐酸、氢氧化钠中的一种或多种；
    所述助溶剂为山梨糖醇、麦芽糖醇、甘露醇、异麦芽糖、木糖醇、葡萄糖、果糖中的一种或多种；
    所述防腐剂为苯甲酸钠、尼泊金乙酯、尼泊金丙酯、尼泊金甲酯钠、尼泊金乙酯钠、尼泊金丙酯钠、苯甲酸、苯丙酸钾、山梨酸、山梨酸钠、山梨酸钙、山梨酸钾、脱氢乙酸、双乙酸钠、丙酸钙中的一种或多种；
    所述增稠剂为羟丙甲纤维素、羟丙纤维素、胶态二氧化硅、甲基纤维素、羧甲基纤维素钠、海藻酸钠、环糊精中的一种或多种；
    所述芳香剂为草莓芳香剂、橘子芳香剂、香蕉芳香剂、樱桃芳香剂、柠檬芳香剂、小豆蔻芳香剂、茴香芳香剂、薄荷芳香剂、薄荷脑芳香剂、香兰素芳香剂中的一种或多种；
    所述甜味剂为三氯蔗糖、甘油、糖精钠、葡萄糖、甜菊糖、甜菊甙、阿斯巴甜、甜蜜素、安赛蜜、阿力甜、纽甜中的一种或多种；
    所述着色剂为苋菜红、胭脂红、赤藓红、新红、柠檬黄、日落黄、靛蓝、甜菜红、紫胶红、越桔红、辣椒红、红米红中的一种或多种。
  7. 根据权利要求5所述的替扎尼定液体制剂，其特征在于，所述pH调节剂为柠檬酸和柠檬酸钠的混合物；
    所述防腐剂为尼泊金甲酯钠和尼泊金丙酯钠的混合物，或，苯甲酸钠；
    所述助溶剂为山梨糖醇；
    所述增稠剂为羟丙纤维素和胶态二氧化硅的混合物，或，羟丙纤维素；
    所述芳香剂为草莓芳香剂；
    所述甜味剂为三氯蔗糖。
  8. 根据权利要求6所述的替扎尼定液体制剂，其特征在于，每100mL液体制剂包括以下组分：
    活性成分0.02-1g、EDTA二钠0-0.2g；其中，EDTA二钠的含量不为0。
  9. 根据权利要求6所述的替扎尼定液体制剂，其特征在于，每100mL液体制剂中包括以下组分：
    替扎尼定     0.02-1g
    EDTA二钠     0.005-0.2g。
  10. 根据权利要求6所述的替扎尼定液体制剂，其特征在于，每100mL液体制剂中包括以下组分：
    Figure PCTCN2022091371-appb-100001
  11. 根据权利要求6所述的替扎尼定液体制剂，其特征在于，每100mL液体制剂中包括以下组分：
    Figure PCTCN2022091371-appb-100002
  12. 根据权利要求6所述的替扎尼定液体制剂，其特征在于，所述液体制剂括以下组分：
    替扎尼定、尼泊金甲酯钠、尼泊金丙酯钠、EDTA二钠、三氯蔗糖、柠檬酸、柠檬酸钠、草莓香精以及水；
    或，替扎尼定、尼泊金甲酯钠、尼泊金丙酯钠、山梨糖醇、EDTA二钠、三氯蔗糖、柠檬酸、柠檬酸钠、草莓香精以及水；
    或，替扎尼定、羟丙纤维素、尼泊金甲酯钠、尼泊金丙酯钠、山梨糖醇、EDTA二钠、三氯蔗糖、柠檬酸、柠檬酸钠、草莓香精以及水；
    或，替扎尼定、羟丙纤维素、胶态二氧化硅、尼泊金甲酯钠、尼泊金丙酯钠、山梨糖醇、EDTA二钠、三氯蔗糖、柠檬酸、柠檬酸钠、草莓香精以及水；
    或，替扎尼定、羟丙纤维素、苯甲酸钠、甘油、山梨糖醇、EDTA二钠、三氯蔗糖、草莓香精以及水。
  13. 根据权利要求12所述的替扎尼定液体制剂，其特征在于，所述每100mL液体制剂包括以下组分：
    盐酸替扎尼定0.046g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.083g、柠檬酸钠0.042g、草莓香精0.05g，其余为水；
    或，盐酸替扎尼定0.046g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖醇溶液25g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.035g、草莓香精0.05g，其余为水；
    或，盐酸替扎尼定0.046g、羟丙纤维素2.5g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖醇溶液15g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.046g、草莓香精0.05g，其余为水；
    或，盐酸替扎尼定0.046g、羟丙纤维素2.5g、胶态二氧化硅0.5g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖溶液15g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.04g、草莓香精0.05g，其余为水；
    或，盐酸替扎尼定0.046g、羟丙纤维素5g、苯甲酸钠0.1g、甘油15g、70％山梨糖醇溶液25g、EDTA二钠0.1g、三氯蔗糖0.05g、草莓香精0.05g，其余为水。
  14. 根据权利要求1-13任一项所述的替扎尼定液体制剂，其特征在于，所述液体制剂中盐酸替扎尼定含量为0.046g/100mL并含有EDTA二钠；且，所述液体制剂在室温下保存时其有关物质杂质总量≤0.2％，和/或，所述液体制剂给药后，其替扎尼定C max均值、AUC 0-t均值和/或AUC 0-∞均值，分别在下列液体制剂以替扎尼定计同等剂量给药后替扎尼定C max均值、AUC 0-t均值和/或AUC 0-∞均值的80％-120％范围内：
    (1)每100mL液体制剂含盐酸替扎尼定0.046g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.083g、柠檬酸钠0.042g、草莓香精0.05g，其余为水；或
    (2)每100mL液体制剂含盐酸替扎尼定0.046g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖醇溶液25g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.035g、草莓香精0.05g，其余为水；或
    (3)每100mL液体制剂含盐酸替扎尼定0.046g、羟丙纤维素2.5g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖醇溶液15g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.046g、草莓香精0.05g，其余为水；或
    (4)每100mL液体制剂含盐酸替扎尼定0.046g、羟丙纤维素2.5g、胶态二氧化硅0.5g、尼泊金甲酯钠0.1g、尼泊金丙酯钠0.01g、70％山梨糖溶液15g、EDTA二钠0.1g、三氯蔗糖0.05g、柠檬酸0.09g、柠檬酸钠0.04g、草莓香精0.05g，其余为水；或
    (5)每100mL液体制剂含盐酸替扎尼定0.046g、羟丙纤维素5g、苯甲酸钠0.1g、甘油15g、70％山梨糖醇溶液25g、EDTA二钠0.1g、三氯蔗糖0.05g、草莓香精0.05g，其余为水。
  15. 根据权利要求1-13任一项所述的替扎尼定液体制剂，其特征在于，所述液 体制剂在40℃/75％RH的条件下密闭存放0-3个月，其有关物质杂质总量≤0.2％；
    和/或，所述液体制剂在25℃/60％RH的条件下密闭存放0-6个月，其有关物质杂质总量≤0.2％。
  16. 根据权利要求1-13任一项所述的替扎尼定液体制剂，其特征在于，所述液体制剂与
    Figure PCTCN2022091371-appb-100003
    替扎尼定片剂餐前、餐后的生物利用度等效；
    和/或，所述液体制剂与
    Figure PCTCN2022091371-appb-100004
    替扎尼定胶囊餐前、餐后的生物利用度等效。
  17. 根据权利要求16所述的替扎尼定液体制剂，其特征在于，餐后条件下，所述生物利用度等效的评判标准为：
    C max的单侧95％置信区间上限≤0；
    AUC 0-t的90％置信区间介于80％-125％之间；
    AUC 0-∞的90％置信区间介于80％-125％之间。
  18. 根据权利要求1-13任一项所述的替扎尼定液体制剂，其特征在于，所述液体制剂餐后条件下的T max均值小于替扎尼定片剂/胶囊的餐后条件下的T max均值。
  19. 根据权利要求1-13任一项所述的替扎尼定液体制剂，其特征在于，以替扎尼定计同等剂量给药条件下：
    所述液体制剂的不良反应发生率小于替扎尼定片剂/胶囊的不良反应发生率。
  20. 根据权利要求1-13任一项所述的替扎尼定液体制剂，其特征在于，以替扎尼定计同等剂量给药条件下：
    所述液体制剂的餐前不良反应项-困倦的发生率小于替扎尼定片剂/胶囊；
    和/或，所述液体制剂的餐后不良反应项-困倦的发生率小于替扎尼定片剂/胶囊；
    和/或，所述液体制剂的餐后不良反应项-头痛的发生率小于替扎尼定片剂/胶囊；
    和/或，所述液体制剂的餐后不良反应项-呕吐的发生率小于替扎尼定胶囊。
  21. 一种如权利要求1-20任一项所述的替扎尼定液体制剂在制备治疗肌肉痉挛的药物中的用途。
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