Tizanidine hydrochloride medicine solid preparation as well as preparation method and application thereof

Abstract

The invention discloses a tizanidine hydrochloride medicine solid preparation as well as a preparation method and application thereof, and belongs to the technical field of medicines. The technical problem to be solved is to solve the current situation of poor stability of drug tablets in the prior art, and provide a tizanidine hydrochloride drug solid preparation which is consistent with a reference preparation in curative effect, more stable in drug dissolution rate and looser in storage condition, so that the stability of the drug under high-temperature and high-humidity conditions is improved, and the curative effect of the tizanidine hydrochloride drug solid preparation is improved. The influence of the storage environment and the storage time on the dissolution rate and impurities of the medicine is overcome. According to the technical scheme, the tizanidine hydrochloride solid pharmaceutical preparation is characterized by comprising tizanidine hydrochloride, hydroxypropyl methylcellulose acetate succinate, a pH regulator and a filler.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of medicines, in particular to a tizanidine hydrochloride solid preparation and a preparation method and application thereof. BACKGROUND

[0002] For understanding the technical content of the application: Tizanidine hydrochloride is a central-acting skeletal muscle relaxant, which is a central alpha2-adrenergic agonist and mainly acts on the excitatory interneurons at the level of the spinal cord and above to inhibit the excitatory interneurons. The tizanidine hydrochloride is used for the symptomatic relief of muscle rigidity associated with multiple sclerosis or spinal cord injury or disease. The tizanidine hydrochloride is also used for the symptomatic treatment of painful muscle spasm associated with musculoskeletal diseases. In animal models, the tizanidine hydrochloride has no direct effect on skeletal muscle fibers or neuromuscular junctions and has no significant effect on monosynaptic spinal reflexes. The tizanidine hydrochloride is usually orally taken in several times, and the current marketed dosage forms are mainly tablets, capsules and granules.

[0003] The tizanidine hydrochloride is dissolved in water and 0.1 mol / L hydrochloric acid solution and slightly dissolved in 0.1 mol / L sodium hydroxide solution, and the solubility has pH dependence. The tizanidine hydrochloride contains a primary amine group and is easy to have a Maillard reaction with lactose to produce colored impurities. The current traditional prescription, such as the Ternelin tablet (the excipients are lactose, microcrystalline cellulose, stearic acid and silicon dioxide) certified by the Japanese Sun Pharmaceutical Industries Limited company, contains lactose, and the dissolution degree is significantly reduced after being stored under high temperature or high humidity conditions, and the storage conditions of the tablet are required to be higher.

[0004] Hydroxypropyl methylcellulose acetate succinate (HPMC AS) is a mixture of acetic ester and succinic ester of hydroxypropyl methylcellulose (HPMC), and the HPMC AS has amphiphilicity, in which the acetyl group provides hydrophobicity and the succinyl group provides hydrophilicity, and the HPMC AS has low hygroscopicity. As a drug carrier, the HPMC AS can effectively improve the solubility of a poorly soluble drug.

[0005] The pH regulator is an acidic or alkaline excipient, which adjusts the acid-base environment of the preparation, improves the solubility of the drug and increases the stability of the drug. Moisture plays a crucial role in the stability of the main drug, and mannitol is the excipient with the lowest hygroscopicity among the commonly used fillers.

[0006] The searched relevant patent documents are as follows: The document discloses a kind of enteric coated solid dispersion of fruit sequence alcohol extract of Liquidambar formosana Hance, and acetic acid hydroxypropyl methyl cellulose succinate is used as carrier, fruit sequence alcohol extract of Liquidambar formosana Hance is dispersed on acetic acid hydroxypropyl methyl cellulose succinate carrier to form amorphous solid dispersion;Reduce the damage of digestive system, improve the in-vitro dissolution of fruit sequence alcohol extract of Liquidambar formosana Hance, enhance the treatment effect, improve the solubility and chemical stability of fruit sequence alcohol extract of Liquidambar formosana Hance by acetic acid hydroxypropyl methyl cellulose succinate, reduce metabolic clearance rate.

[0007] The document discloses a kind of enteric coated solid dispersion of fruit sequence alcohol extract of Liquidambar formosana Hance, and acetic acid hydroxypropyl methyl cellulose succinate is used as carrier, fruit sequence alcohol extract of Liquidambar formosana Hance is dispersed on acetic acid hydroxypropyl methyl cellulose succinate carrier to form amorphous solid dispersion;Reduce the damage of digestive system, improve the in-vitro dissolution of fruit sequence alcohol extract of Liquidambar formosana Hance, enhance the treatment effect, improve the solubility and chemical stability of fruit sequence alcohol extract of Liquidambar formosana Hance by acetic acid hydroxypropyl methyl cellulose succinate, reduce metabolic clearance rate.

[0008] The document discloses a kind of enteric coated solid dispersion of fruit sequence alcohol extract of Liquidambar formosana Hance, and acetic acid hydroxypropyl methyl cellulose succinate is used as carrier, fruit sequence alcohol extract of Liquidambar formosana Hance is dispersed on acetic acid hydroxypropyl methyl cellulose succinate carrier to form amorphous solid dispersion;Reduce the damage of digestive system, improve the in-vitro dissolution of fruit sequence alcohol extract of Liquidambar formosana Hance, enhance the treatment effect, improve the solubility and chemical stability of fruit sequence alcohol extract of Liquidambar formosana Hance by acetic acid hydroxypropyl methyl cellulose succinate, reduce metabolic clearance rate.

[0009] The document discloses a kind of enteric coated solid dispersion of fruit sequence alcohol extract of Liquidambar formosana Hance, and acetic acid hydroxypropyl methyl cellulose succinate is used as carrier, fruit sequence alcohol extract of Liquidambar formosana Hance is dispersed on acetic acid hydroxypropyl methyl cellulose succinate carrier to form amorphous solid dispersion;Reduce the damage of digestive system, improve the in-vitro dissolution of fruit sequence alcohol extract of Liquidambar formosana Hance, enhance the treatment effect, improve the solubility and chemical stability of fruit sequence alcohol extract of Liquidambar formosana Hance by acetic acid hydroxypropyl methyl cellulose succinate, reduce metabolic clearance rate.

[0010] The document discloses a kind of enteric coated solid dispersion of fruit sequence alcohol extract of Liquidambar formosana Hance, and acetic acid hydroxypropyl methyl cellulose succinate is used as carrier, fruit sequence alcohol extract of Liquidambar formosana Hance is dispersed on acetic acid hydroxypropyl methyl cellulose succinate carrier to form amorphous solid dispersion;Reduce the damage of digestive system, improve the in-vitro dissolution of fruit sequence alcohol extract of Liquidambar formosana Hance, enhance the treatment effect, improve the solubility and chemical stability of fruit sequence alcohol extract of Liquidambar formosana Hance by acetic acid hydroxypropyl methyl cellulose succinate, reduce metabolic clearance rate. Journal name: Chinese Modern Doctor, document name: Research Progress of Tizanidine Hydrochloride in Clinical Application, volume number: the fourth volume, publication date: 2013.05.21, which discloses that tizanidine hydrochloride can inhibit adrenaline at the level of brain stem and spinal cord by activating alpha2 adrenergic receptor, reduce the release of excitatory neurotransmitters in spinal cord and reduce the effect of excitatory neurotransmitters, reduce polysynaptic spinal reflex, increase segmental inhibition, reduce the muscle tension of flexor and extensor, relieve muscle spasm, inhibit the transmission of nociceptive stimulation in the posterior horn of spinal cord, facilitate the inhibition of neurons, and reduce the discharge of nociceptive neurons to achieve analgesic effect.

[0011] The prior art represented by the foregoing documents at least has the following unsolved technical problems or defects: (1) The filler contains lactose, which reduces the storage stability, and the relevant evidence is: document no. CN112370431A does not investigate the stability of the preparation, and the micronized lactose has a larger contact area with the drug substance, which may increase the risk of preparation stability.

[0012] (2) The flexibility of dissolution control is poor, and the relevant evidence is: document no. CN112370431A only controls the dissolution by micronizing part of the lactose, which is relatively single, and it may be difficult to accurately meet the requirements of drugs with high or special dissolution requirements, such as tizanidine hydrochloride of the present application. SUMMARY

[0013] The purpose of the present application is to provide: A tizanidine hydrochloride pharmaceutical solid preparation and related technologies to solve the technical problems of improving the stability of the drug under high temperature and high humidity conditions, overcoming the influence of storage environment and storage time on the dissolution and related substances of the drug, and combinations thereof.

[0014] Term explanation: Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all documents, patents, patent applications, publications, and the like cited herein are hereby incorporated by reference in their entirety. If there is a plurality of definitions for a term herein, the definition in this section prevails.

[0015] It should be understood that the above brief summary and the following detailed description are exemplary and are intended to explain, but not limit, the subject matter of the present application. In the present application, the use of singular also includes plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, "or" and "or" used herein means "and / or". In addition, the term "include" and other forms, such as "contain", "comprise" and "comprise", are not restrictive.

[0016] Definitions of standard chemical terms can be found in the references Chinese Pharmacopoeia 2025 edition and Complete Explanation of Pharmacological Terminology.

[0017] Unless otherwise stated, conventional methods within the scope of the art, such as drug dissolution testing, accelerated stability testing under extreme conditions, and long-term stability testing, shall be used.

[0018] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0019] The term "tizanidine hydrochloride" used in this article refers to the hydrochloride form of tizanidine (the commonly used pharmaceutical form in clinical practice, which can improve drug solubility and stability). It is a centrally acting muscle relaxant that relieves muscle overexcitation and spasms by acting on the central nervous system rather than directly on the muscles, unlike peripheral muscle relaxants (such as succinylcholine, which acts directly on the neuromuscular junction).

[0020] The term "hydroxypropyl methylcellulose acetate succinate" as used in this article refers to a derivative obtained by chemically modifying (hydroxypropylation, methylation, acetylation, succinylation) the natural polymer cellulose. It has four different groups (hydroxypropyl, methyl, acetyl, and succinylation) introduced into its molecular structure. It belongs to the cellulose ether ester excipient class and is a semi-synthetic cellulose derivative that is widely used in the formulation process of oral solid dosage forms (such as tablets and capsules).

[0021] The term "pH adjuster" as used in this article refers to pharmaceutical excipients used to adjust the pH value of liquid preparations, semi-solid preparations, or dissolution / release media. Their core functions are to ensure drug stability (such as preventing penicillin from hydrolyzing in acidic environments), improve drug solubility (such as increasing the dissociation degree of weakly acidic drugs in alkaline environments), and reduce gastrointestinal irritation (making the pH of oral preparations close to the pH of body fluids). Common types include acid adjusters (hydrochloric acid, citric acid), alkaline adjusters (sodium hydroxide, sodium bicarbonate), and buffer adjusters (phosphate buffer pairs, acetate buffer pairs).

[0022] The term "drug carrier" as used herein refers to a pharmaceutical excipient or material that can encapsulate, disperse or adsorb drugs to improve their physicochemical properties (solubility, stability) and in vivo behaviors (absorption, targeting), which can achieve solubilization (e.g., solid dispersion carrier disperses insoluble drugs into molecular level), targeted delivery (e.g., liposome carrier targets tumor tissues) and protection of drugs (e.g., microsphere carrier avoids enzymatic degradation of polypeptide drugs), and common types include polymeric carriers (hydroxypropyl methyl cellulose, povidone), particulate carriers (liposomes, microspheres, nanoparticles) and inorganic carriers (mesoporous silica, calcium carbonate), which are applied to oral solid preparations, injections, topical preparations, etc.

[0023] The term "filler" as used herein refers to a diluent, which is an excipient used in oral solid preparations (tablets, capsules, granules) to increase the volume of the preparation and improve the flowability and compressibility of the drug, which can make a small amount of drug powder into a preparation that meets the specifications (easy to swallow and tabletting), and needs to have the characteristics of chemical inertness, good flowability and compressibility, and no physiological activity, and common types include starches (corn starch, pregelatinized starch), sugars (lactose, sucrose), alcohols (mannitol) and inorganic salts (calcium hydrogen phosphate), which are almost applied to all oral tablets, capsules and granules.

[0024] The term "lubricant" as used herein refers to an excipient that reduces the friction between the drug powder (or granules) and the surface of the equipment and the interior of the particles, which can improve the flowability of the powder (ensure that the tablet weight difference is qualified), prevent sticking (avoid damage to the surface of the tablet), and improve the disintegration (reduce the internal binding force of the tablet), and common types include hydrophobic lubricants (magnesium stearate, calcium stearate), water-soluble lubricants (polyethylene glycol 4000 / 6000, sodium dodecyl sulfate) and glidants (microfine silica, talc), which are mainly used for powder mixing before tabletting and granule processing before capsule filling.

[0025] The term "colloidal silicon dioxide" as used herein refers to microfine silica, colloidal silicon dioxide, which is a superfine silica powder with high specific surface area and high porosity, and belongs to the glidant and anti-adhesive in pharmaceutical excipients, which is a white amorphous powder, insoluble in water and most organic solvents, chemically stable, can adsorb water and air on the surface of the powder to reduce the adhesion between particles, can improve the flowability of the drug powder, prevent the powder from adhering to the equipment parts, and can also increase the viscosity of the suspension to prevent sedimentation and prevent caking in the powder, which is applied to oral tablets, capsules, suspensions and powders.

[0026] The term "stearic acid" as used herein refers to a saturated fatty acid (octadecanoic acid) in white or off-white powder form as pharmaceutical grade, which can reduce the friction between powder and punch in tablet production as lubricant and glidant, prevent sticking to punch, but the effect is weaker than magnesium stearate and may react with basic drugs; as a semi-solid formulation matrix component, it can react with emulsifiers to form emulsion matrix in cream and ointment, improve spreadability and stability; as a coating material excipient, it can act as a plasticizer or anti-sticking agent in film coating, but excessive use may delay tablet disintegration and drug dissolution.

[0027] The term "succinic acid" as used herein refers to a dibasic organic acid (chemical formula C4H6O4) in white crystalline powder form as pharmaceutical grade, which can be used as pH adjuster, cosolvent or stabilizer in formulations, form buffer pair with basic substances to adjust the pH of oral solutions and injections (suitable for maintaining a weak acidic environment), form soluble salts with some alkaloid drugs to improve solubility, inhibit oxidative degradation of drugs in liquid formulations, and act as effervescent disintegrant component in effervescent tablets (react with sodium bicarbonate to generate carbon dioxide), which should be stored separately from acid source and base source to prevent premature reaction.

[0028] The term "mannitol" as used herein refers to a six-membered alcohol (hexane alcohol) in white crystalline powder or granule form as pharmaceutical grade, which is sweet and odorless, widely used as a filler in oral tablets and capsules (especially suitable for direct compression) due to its good flowability, compressibility and non-hygroscopicity, and can improve the medication experience in chewable tablets and buccal tablets; as a lyophilization protectant, it can form a glass structure to protect drug molecules in lyophilized formulations for injection (such as protein and polypeptide drugs); as a sweetener, it can replace sucrose in oral solutions and suspensions, which is suitable for diabetic patients, and in addition, as a drug (mannitol injection), it has osmotic diuretic effect.

[0029] The term "pulverization" as used herein refers to a unit operation in the fields of pharmaceutical formulations, chemical industry, food industry, etc., which uses mechanical force (such as impact, grinding, shearing, extrusion) or physical and chemical methods to break and refine solid materials (such as active pharmaceutical ingredients, excipients) from larger particle sizes to smaller particle sizes (such as coarse powder, fine powder, ultrafine powder) that meet process requirements, the core purpose is to improve the physicochemical properties (such as solubility, flowability) and processing performance (such as mixing uniformity, formability) of the materials, and provide suitable material morphology for subsequent formulation production (such as mixing, granulation, tabletting) or analysis and testing.

[0030] The term "milling" as used herein refers to a pre-formulation process step to reduce particle size by mechanical force (impact, attrition, shear) to achieve a suitable particle size, the purpose is to reduce particle size, to increase the interaction between drug and excipients, to improve the solubility and dissolution rate of poorly soluble drugs, to make the drug and excipient particle size uniform for subsequent mixing and tabletting, to grind bulk or agglomerated powder into fine powder to improve flowability. Common equipment includes ball mill (fine powder milling), universal pulverizer (medium and coarse powder milling), jet mill (ultra-fine powder milling). Low-temperature milling is required for heat-sensitive drugs, and inert gas protection is required for flammable and explosive drugs.

[0031] The term "mixing" as used herein refers to a core step in the production of oral solid preparations to uniformly disperse two or more drug powders, excipient powders (or particles) by mechanical methods, the purpose is to ensure that the drug content in each tablet / particle meets the specifications (to avoid dose deviation), and to ensure that the excipients (lubricants, disintegrants) are uniformly distributed to ensure consistent tablet disintegration and dissolution.

[0032] The term "tabletting" as used herein refers to a core process in the production of oral tablets, in which uniformly mixed drug powders (or particles) are compressed into tablets of fixed shape, weight, and hardness by a tablet press die under a certain pressure. The main steps include feeding (filling the die hole with materials), pre-pressing (compacting the materials to reduce air residues), main pressing (applying main pressure to shape the materials), and tablet ejection (pushing the tablets into the next process). Common equipment includes single-punch tablet presses (for small-scale laboratory production) and rotary tablet presses (for large-scale industrial production). Key quality indicators include tablet weight variation, hardness, friability, disintegration time, and dissolution rate.

[0033] The term "die tabletting" as used herein refers to a tabletting process that uses a die (a core component of a tablet press, consisting of an upper punch, a lower punch, and a die ring) to shape tablets. In a broad sense, it can be understood as a tablet production method that relies on the structure and pressure of the die. The die ring determines the shape, diameter, and volume of the tablet. The upper and lower punches apply pressure to the material in the die ring to compress and shape it. The lower punch can also adjust the amount of material filled to control the weight of the tablet. By replacing different specifications of the die (different diameters, shapes, and notched punches), customized tablets (notched tablets for easy dose splitting, and irregularly shaped tablets for easy identification) can be produced. The precision of the die directly affects the quality of the tablets, and it needs to be regularly maintained and calibrated.

[0034] The term "dissolution" as used herein refers to the rate and extent of drug release from oral solid dosage forms under specified conditions, which is a key in vitro index for evaluating the quality of oral solid dosage forms, predicting the in vivo absorption (bioavailability) of drugs, ensuring batch consistency (reflecting the stability of the production process), correlating the in vivo efficacy (the dissolution of poorly soluble drugs is the rate-limiting step of absorption), screening the preparation process (optimizing the formula), and testing methods refer to the pharmacopoeia (common basket method, paddle method, small cup method). The dissolution is calculated by determining the drug concentration in the dissolution solution by UV-visible spectrophotometry or high performance liquid chromatography (expressed as a percentage of the labeled amount), and the pass criteria vary depending on the drug.

[0035] The term "total impurities" as used herein refers to drug-related substances that are structurally different from the main drug (active pharmaceutical ingredient) and are produced or introduced during the production and storage of the drug.

[0036] The term "high temperature" as used herein refers to stability test conditions. In drug stability tests, it refers to simulating high temperature environments (usually 60°C, 40°C) to investigate the changes in physical, chemical, and biological properties of drugs or preparations under high temperature. It is a core environmental parameter of influence factor tests and accelerated tests, and the purpose is to expose the intrinsic stability of the drug (identify degradation pathways and products, such as influence factor tests at 60±2°C), predict storage stability, screen packaging materials (determine whether special packaging is needed), and investigate indicators including appearance, content, related substances, dissolution, pH, etc.

[0037] The term "high humidity" as used herein refers to stability test conditions. In drug stability tests, it refers to simulating high humidity environments (usually relative humidity RH75±5%, RH92.5±5%) to investigate the hygroscopicity and stability changes of drugs or preparations under high humidity. It is a key environmental parameter of accelerated tests and influence factor tests together with high temperature, and the purpose is to evaluate the hygroscopicity of drugs or excipients, investigate hydrolytic stability, and verify the moisture resistance of packaging. The humidity is usually controlled by a constant humidity box or saturated salt solution, and the investigation indicators include moisture absorption weight gain, content, related substances, appearance, etc.

[0038] The term "reference preparation" as used herein refers to a drug used as a "standard control" in the process of drug research and development, production, quality control, and evaluation. Its quality, safety, and effectiveness have been verified through sufficient clinical research or authoritative institutions, and it is a core benchmark for measuring the quality consistency and efficacy equivalence of other drugs (such as generic drugs, modified new drugs). It plays an irreplaceable "ruler" role in drug regulation, research and development, and clinical application.

[0039] The term "similarity factor" as used herein refers to: usually represented by f2, is a key statistical parameter used to quantify the consistency of dissolution behavior between test formulation (such as generic drug, self-researched formulation) and reference formulation in the in vitro dissolution comparison of oral solid preparations (such as tablets, capsules), to judge whether the in vitro dissolution curves are "similar" by calculating the dissolution difference of the two at multiple time points, and then indirectly predict the bioequivalence of in vivo bioavailability, which is a key tool for the evaluation of quality and efficacy consistency of generic drugs and the optimization of preparation process In a first aspect, the present application provides: a tizanidine hydrochloride pharmaceutical solid preparation, comprising: tizanidine hydrochloride, hydroxypropyl methyl cellulose acetate succinate, a pH adjusting agent and a filler.

[0040] Among them, the technical features include: hydroxypropyl methyl cellulose acetate succinate, a pH adjusting agent, a filler.

[0041] The pH adjusting agent is preferably at least one of succinic acid, malic acid, tartaric acid, citric acid, fumaric acid, phosphoric acid, and acetic acid. The pH adjusting agent is preferably at least one of succinic acid, malic acid, tartaric acid, citric acid, fumaric acid, and phosphoric acid. The pH adjusting agent is further preferably at least one of succinic acid, malic acid, fumaric acid, and phosphoric acid. The pH adjusting agent is more preferably succinic acid. The filler is preferably at least one of microcrystalline cellulose, starch, pregelatinized starch, and mannitol. The filler is preferably at least one of microcrystalline cellulose, pregelatinized starch, and mannitol. The filler is further preferably at least one of microcrystalline cellulose and mannitol. The filler is more preferably mannitol.

[0042] Preferably, the tizanidine hydrochloride pharmaceutical solid preparation further comprises a lubricant.

[0043] Further preferably, the lubricant is at least one of stearic acid, magnesium stearate, calcium stearate, glyceryl behenate, sodium stearyl fumarate, and colloidal silicon dioxide. More preferably, the lubricant is at least one of stearic acid, magnesium stearate, and colloidal silicon dioxide. More preferably, the lubricant is a combination of stearic acid and colloidal silicon dioxide. Most preferably, the mass ratio of stearic acid to colloidal silicon dioxide in the lubricant is 1:3.

[0044] Preferably, the particle size of the tizanidine hydrochloride is less than 15 μm. Preferably, the tizanidine hydrochloride drug solid preparation comprises 1 part of tizanidine hydrochloride, 30-40 parts of hypromellose acetate succinate, 3-8 parts of pH adjuster, 40-60 parts of filler and 2-5 parts of lubricant by weight; For example: 1 part of tizanidine hydrochloride; 30-35 parts, 36-40 parts, 31-38 parts, 33-37 parts, 32-39 parts or 34-40 parts of the drug carrier composition; 3-7 parts, 4-7 parts, 3-5 parts, 6-7 parts, 5-8 parts or 4-8 parts of the pH adjuster; 2-4 parts, 3-5 parts, 2-3 parts, 4-5 parts of the lubricant; and 40-50 parts, 50-60 parts, 45-55 parts, 40-58 parts, 50-55 parts or 48-60 parts of the filler.

[0045] For further example: 1 part of tizanidine hydrochloride; 30 parts, 31 parts, 32 parts, 33 parts, 34 parts, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts or 40 parts of the drug carrier composition; 3 parts, 4 parts, 5 parts, 6 parts, 7 parts or 8 parts of the pH adjuster; 2 parts, 3 parts, 4 parts, 5 parts of the lubricant; and 40 parts, 41 parts, 42 parts, 43 parts, 44 parts, 45 parts, 46 parts, 47 parts, 48 parts, 49 parts, 50 parts, 51 parts, 52 parts, 53 parts, 54 parts, 55 parts or 60 parts of the filler.

[0046] Further preferably, the tizanidine hydrochloride drug solid preparation comprises 1 part of tizanidine hydrochloride, 33-38 parts of hypromellose acetate succinate, 4-7 parts of pH adjuster, 50-60 parts of filler and 3-5 parts of lubricant; More preferably, the tizanidine hydrochloride drug solid preparation comprises 1 part of tizanidine hydrochloride, 35 parts of hypromellose acetate succinate, 5 parts of pH adjuster, 55 parts of filler and 4 parts of lubricant.

[0047] The tizanidine hydrochloride drug solid preparation dosage form is selected from at least one of tablets, granules, capsules, powders, combinations; preferably tablets.

[0048] In pharmaceutical preparations, the term includes products comprising the active ingredient and inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of two or more ingredients, or from dissociation, from decomposition, or from other types of reactions or interactions of one or more ingredients. Thus, pharmaceutical solid preparations of the present application include any composition prepared by mixing tiazanolide hydrochloride, hypromellose acetate succinate, pH adjusting agent, filler and pharmaceutically acceptable excipients.

[0049] The tiazanolide hydrochloride solid dosage forms, such as capsules, tablets, troches, lozenges, granules and powders, are orally administered. The gelatin capsules contain the active ingredient in admixture with a powder or granule carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be manufactured to provide slow or controlled release of the drug in the gastrointestinal tract. The compressed tablets can be sugar coated or film coated to mask any unpleasant taste and to protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract. Useful pharmaceutical dosage forms for administration of the compounds of the present application include, but are not limited to, hard and soft gelatin capsules, tablets.

[0050] Based on further solving or simultaneously solving multiple technical problems of the technical problem of the present application, in the technical solution provided by the first aspect of the present application, the preferred solution includes: The first preferred solution: the pH adjusting agent is selected from at least one of succinic acid, malic acid, tartaric acid, citric acid, fumaric acid, phosphoric acid, acetic acid; preferably at least one of succinic acid, malic acid, citric acid, fumaric acid; further preferably at least one of succinic acid, malic acid, fumaric acid; more preferably succinic acid. This technical solution, on the basis of solving the technical problem of "improving the stability of the pharmaceutical preparation", further solves the technical problem of "further improving the stability of the pharmaceutical preparation".

[0051] The second preferred solution: the lubricant is selected from at least one of stearic acid, magnesium stearate, calcium stearate, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide; preferably at least one of stearic acid, magnesium stearate, colloidal silicon dioxide; further preferably stearic acid and colloidal silicon dioxide are used in combination; more preferably the mass ratio of stearic acid and colloidal silicon dioxide in the lubricant is 1:3. This technical solution, on the basis of solving the technical problem of "improving the stability of the pharmaceutical preparation", further solves the technical problem of "further improving the stability of the pharmaceutical preparation".

[0052] The third preferred solution: the filler is selected from at least one of microcrystalline cellulose, starch, pregelatinized starch, mannitol; preferably at least one of microcrystalline cellulose, pregelatinized starch, mannitol; further preferably at least one of microcrystalline cellulose, mannitol; more preferably mannitol. This technical solution, on the basis of solving the technical problem of "improving the stability of the pharmaceutical preparation", further solves the technical problem of "further improving the stability of the pharmaceutical preparation".

[0053] The fourth preferred solution: the tazanolast hydrochloride pharmaceutical solid preparation comprises 1 part of tazanolast hydrochloride, 30-40 parts of hypromellose acetate succinate, 3-8 parts of pH adjuster, 40-60 parts of filler and 2-5 parts of lubricant; preferably, the tazanolast hydrochloride pharmaceutical solid preparation comprises 1 part of tazanolast hydrochloride, 33-38 parts of hypromellose acetate succinate, 4-7 parts of pH adjuster, 50-60 parts of filler and 3-5 parts of lubricant; further preferably, the tazanolast hydrochloride pharmaceutical solid preparation comprises 1 part of tazanolast hydrochloride, 35 parts of hypromellose acetate succinate, 5 parts of pH adjuster, 55 parts of filler and 4 parts of lubricant. This technical solution, on the basis of solving the technical problem of "improving the stability of the pharmaceutical preparation", further solves the technical problem of "further improving the stability of the pharmaceutical preparation".

[0054] In the second aspect, the present application provides a preparation method of the tazanolast hydrochloride pharmaceutical solid preparation, comprising the steps of: grinding and crushing tazanolast hydrochloride, hypromellose acetate succinate and pH adjuster, and then mixing the filler and the lubricant to obtain the tazanolast hydrochloride pharmaceutical solid preparation.

[0055] The grinding and crushing and the mixing are included.

[0056] The grinding and crushing lasts for 10-60 minutes; more preferably 30 minutes. Preferably, the crushed particles pass through an 80-mesh screen.

[0057] The mixing mode is selected from at least one of stirring mixing, shearing mixing, oscillation mixing and stepwise mixing. Preferably, the mixing mode is a combination of stirring mixing and stepwise mixing. Further preferably, the mixing mode is: grinding and mixing tazanolast hydrochloride, hypromellose acetate succinate and pH adjuster to obtain a mixture, and then mixing the mixture with the lubricant and the filler. More preferably, grinding and mixing tazanolast hydrochloride, hypromellose acetate succinate and pH adjuster to obtain a mixture, mixing the obtained mixture with the filler once, and then mixing the mixture with the lubricant twice.

[0058] More preferably, the first mixing time is 5-30 min; most preferably, 10 min. More preferably, the first mixing is followed by a sieving step. Most preferably, the first mixing is followed by a sieving through a 40-mesh sieve.

[0059] More preferably, the second mixing time is 3-10 min; most preferably, 5 min.

[0060] Preferably, the method for preparing the tizanidine hydrochloride pharmaceutical solid preparation comprises the steps of: (1) grinding tizanidine hydrochloride, hydroxypropyl methyl cellulose acetate succinate, and a pH regulator for 30 min, and then sieving through an 80-mesh sieve to obtain a mixture for standby use; (2) mixing the mixture obtained in (1) with a filler for 10 min, and then sieving through a 40-mesh sieve to obtain a first mixture for standby use; (3) mixing the first mixture obtained in (2) with the lubricant composition for 5 min to obtain an intermediate granule; (4) molding the intermediate granule to obtain the tizanidine hydrochloride pharmaceutical solid preparation.

[0061] Based on further solving or simultaneously solving multiple technical problems of the technical problem of the present application, in the technical solution provided in the second aspect of the present application, the preferred solution comprises: The first preferred solution: the grinding time is 10-60 min; more preferably, 30 min; preferably, the ground granule is required to pass through an 80-mesh sieve. This technical solution, on the basis of solving the technical problem of "improving the stability of the pharmaceutical preparation", further solves the technical problem of "further improving the stability of the pharmaceutical preparation".

[0062] The second preferred solution: the mixing method is selected from at least one of stirring mixing, shearing mixing, oscillation mixing, and stepwise mixing; preferably, the mixing method is a combination of stirring mixing and stepwise mixing; further preferably, the mixing method is: the tizanidine hydrochloride is mixed with the hypromellose acetate succinate and the pH adjuster by grinding to obtain a mixture, and then the mixture is mixed with the lubricant and the filler; further preferably, the tizanidine hydrochloride is mixed with the hypromellose acetate succinate and the pH adjuster by grinding to obtain a mixture, and then the mixture is mixed with the filler for the first time and then mixed with the lubricant for the second time. Further preferably, the first mixing time is 5-30 min; most preferably, 10 min; further preferably, the first mixing is followed by a sieving step; most preferably, the first mixing is followed by sieving through a 40-mesh sieve. Further preferably, the second mixing time is 3-10 min; most preferably, 5 min. This technical solution further improves the stability of the drug preparation on the basis of solving the technical problem of "improving the stability of the drug preparation".

[0063] In a third aspect, the present application provides: use of the tizanidine hydrochloride solid drug preparation in the preparation of a drug for treating central skeletal muscle relaxation diseases.

[0064] The application of the tizanidine hydrochloride solid drug preparation is included.

[0065] Preferably, the central skeletal muscle relaxation disease is at least one of multiple sclerosis, spinal cord injury, disease-related muscle rigidity, and painful muscle spasm associated with musculoskeletal diseases. Preferably, the application of the tizanidine hydrochloride solid drug preparation is embodied in that the tizanidine hydrochloride tablets prepared by using HPMC AS, a pH adjuster, and a low-hygroscopic filler have a dissolution curve comparable to that of a reference preparation and good stability under high-temperature and high-humidity conditions.

[0066] Further preferably, the tizanidine hydrochloride solid drug preparation can disperse or encapsulate the drug in an amorphous / microcrystalline state in the form of a solid dispersion, hinder the crystallization and agglomeration of the drug to maintain the physical form stability, isolate oxygen, moisture, and other degradation inducers, adjust the local microenvironment pH, and isolate the drug from incompatible excipients to reduce oxidation and hydrolysis and other chemical degradation; can also improve the solubility of poorly soluble drugs through solubilization, inhibit the recrystallization of the drug during the dissolution process, regulate the release rate through a matrix or membrane control mechanism to avoid burst release or delayed release, and can also improve the dispersion uniformity of the drug in the preparation to ensure the consistency of the dissolution rate within and between batches, ultimately achieving the goal of stable physical and chemical properties of the preparation and efficient and uniform drug release.

[0067] The embodiments 1-3 in the present application at least support the protection scope of claims 1-7.

[0068] For claims 1-7, the following are involved: hydroxypropyl methyl cellulose acetate succinate, pH adjuster, etc.

[0069] The technical feature "pH adjuster" is generalized by the aforementioned explanation herein and / or the corresponding technical feature "the pH adjuster is selected from at least one of succinic acid, malic acid, tartaric acid, citric acid, fumaric acid, phosphoric acid, and acetic acid" in embodiments 1-3. Therefore, a person skilled in the art can reasonably determine that the technical feature "pH adjuster", its subordinate concept, its substantially equivalent technical means, and technical means that can replace "pH adjuster" within the scope of conventional technical means and common knowledge based on the existing technical level, should all belong to the protection scope of claims 1-7, for example, replacing "pH adjuster" with "malic acid", "fumaric acid", etc. still belongs to the protection scope of claims 1-7 of the present application.

[0070] The technical feature "the tazanolast hydrochloride pharmaceutical solid preparation comprises 1 part of tazanolast hydrochloride, 30-40 parts of hydroxypropyl methyl cellulose acetate succinate, 3-8 parts of a pH adjuster, 40-60 parts of a filler, and 2-5 parts of a lubricant by weight" is generalized by the aforementioned explanation herein and / or the corresponding technical feature "the tazanolast hydrochloride pharmaceutical solid preparation comprises 1 part of tazanolast hydrochloride, 33-38 parts of hydroxypropyl methyl cellulose acetate succinate, 4-7 parts of a pH adjuster, 50-60 parts of a filler, and 3-5 parts of a lubricant" and "the tazanolast hydrochloride pharmaceutical solid preparation comprises 1 part of tazanolast hydrochloride, 35 parts of hydroxypropyl methyl cellulose acetate succinate, 5 parts of a pH adjuster, 55 parts of a filler, and 4 parts of a lubricant" in embodiments 1-3. Therefore, a person skilled in the art can reasonably determine that the technical feature "the tazanolast hydrochloride pharmaceutical solid preparation comprises 1 part of tazanolast hydrochloride, 30-40 parts of hydroxypropyl methyl cellulose acetate succinate, 3-8 parts of a pH adjuster, 40-60 parts of a filler, and 2-5 parts of a lubricant by weight", its subordinate concept, its substantially equivalent technical means, and technical means that can replace it within the scope of conventional technical means and common knowledge based on the existing technical level, should all belong to the content recorded therein.

[0071] The technical feature "lubricant" is summarized by the common feature "an excipient that can reduce the friction between the drug powder (or granules) and the surface of the equipment and the interior of the granules, improve the flowability of the powder (ensure that the tablet weight difference is qualified), prevent sticking (avoid tablet surface defects), and improve disintegration" from the aforementioned explanations and / or the corresponding technical features "stearic acid, magnesium stearate, calcium stearate, glycerol behenate, sodium stearyl fumarate, colloidal silicon dioxide" in Examples 1-3. Therefore, based on reasonable inference, one skilled in the art can determine that the technical feature "lubricant", its subordinate concepts, its substantially equivalent technical means, and technical means that can replace "lubricant" based on the existing technical level within conventional technical means and common knowledge, should all fall within the protection scope of claims 1-7, for example, replacing "lubricant" with "magnesium stearate", "sodium stearyl fumarate", etc. while keeping other technical features unchanged, still falls within the protection scope of claims 1-7 of the present application.

[0072] The technical feature "filler" is summarized by the common feature "an excipient used in oral solid preparations (tablets, capsules, granules) to increase the volume of the preparation, improve the flowability and compressibility of the drug" from the aforementioned explanations and / or the corresponding technical features "microcrystalline cellulose, starch, pregelatinized starch, mannitol" in Examples 1-3. Therefore, based on reasonable inference, one skilled in the art can determine that the technical feature "filler", its subordinate concepts, its substantially equivalent technical means, and technical means that can replace "filler" based on the existing technical level within conventional technical means and common knowledge, should all fall within the protection scope of claims 1-7, for example, replacing "filler" with "starch", "microcrystalline cellulose", etc. while keeping other technical features unchanged, still falls within the protection scope of claims 1-7 of the present application.

[0073] Examples 1-3 in the present application support at least the protection scope of claims 8-9.

[0074] For claims 8-9, grinding and mixing are involved.

[0075] The technical feature "grinding pulverization" is summarized by the common feature "unit operation of breaking and refining solid materials (such as raw materials and excipients) from larger particle size to smaller particle size (such as coarse powder, fine powder, and ultrafine powder) that meets the process requirements by using a grinding method" from the aforementioned explanation and / or the corresponding technical features "the grinding pulverization time is 10-60 min; further preferably 30 min" in embodiments 1-3. Therefore, the skilled person can reasonably infer that the technical feature "grinding pulverization", its subordinate concepts, its basically equivalent technical means, and technical means that can replace "grinding pulverization" based on the existing technical level within conventional technical means and common knowledge should all belong to the protection scope of claims 8-9. For example, "grinding pulverization" is replaced by "crushing", "grinding", etc. without changing other technical features, which still belongs to the protection scope of claims 8-9 of the present application.

[0076] The technical feature "mixing" is summarized by the common feature "a core step of producing oral solid preparations by uniformly dispersing two or more drug powders and excipient powders (or granules) through mechanical methods" from the aforementioned explanation and / or the corresponding technical features "stirring mixing, shearing mixing, oscillation mixing, and step-by-step mixing" in embodiments 1-3. Therefore, the skilled person can reasonably infer that the technical feature "mixing", its subordinate concepts, its basically equivalent technical means, and technical means that can replace "mixing" based on the existing technical level within conventional technical means and common knowledge should all belong to the protection scope of claims 8-9. For example, "mixing" is replaced by "mixing and dispersing", etc. without changing other technical features, which still belongs to the protection scope of claims 8-9 of the present application.

[0077] Embodiments 1-3 in the present application support at least the protection scope of claim 10.

[0078] For the application of the tizanidine hydrochloride drug solid preparation involved in claim 10.

[0079] The technical feature "application of the tizanidine hydrochloride drug solid preparation" is derived from the foregoing explanations and / or the corresponding technical features "tizanidine hydrochloride tablets prepared by using HPMC AS, a pH regulator and a low-hygroscopic filler have dissolution curves comparable to those of the reference preparation and good stability under high-temperature and high-humidity conditions" in embodiments 1-3, which are summarized as follows: the drug can be dispersed or coated in an amorphous / microcrystalline state in the form of a solid dispersion to hinder drug crystallization and aggregation to maintain physical form stability, isolate oxygen, moisture and other degradation inducers, adjust the local microenvironment pH, isolate the drug from incompatible excipients, reduce chemical degradation such as oxidation and hydrolysis, increase the solubility of poorly soluble drugs through solubilization, inhibit drug recrystallization during the dissolution process, control the release rate through a matrix or membrane control mechanism to avoid burst release or delayed release, improve drug dispersion uniformity in the preparation to ensure consistent dissolution within and between batches, and ultimately achieve the goals of stable physical and chemical properties of the preparation and efficient and uniform drug release. Therefore, a person skilled in the art can reasonably infer that the technical feature "application of the tizanidine hydrochloride drug solid preparation", its subordinate concepts, its substantially equivalent technical means, and technical means that can replace the technical means of "application of the tizanidine hydrochloride drug solid preparation" based on the existing technical level within conventional technical means and common general knowledge should all fall within the protection scope of claim 10.

[0080] The present application has the following advantages: The present application has the following advantages: 1. Compared with the prior art, the tizanidine hydrochloride drug solid preparation prepared by using HPMC AS, a pH regulator and a filler has dissolution curves comparable to those of the reference preparation and good stability under high-temperature and high-humidity conditions. According to experimental tests, the present application improves the similarity of the dissolution curves to those of the reference preparation from a similarity factor of 50 or less in the prior art to 60 or more. According to experimental tests, the present application improves the dissolution stability under high-temperature conditions for 30 days from about 45% in the prior art to 83% or more. According to experimental tests, the present application improves the dissolution stability under high-humidity conditions for 30 days from about 70% in the prior art to 85% or more.

[0081] 2. The preparation process only needs grinding, mixing and tabletting, which is simple to operate and suitable for industrial large-scale production for clinical use and storage.

[0082] 3. The use of lactose and other excipients that can cause incompatibility is avoided, the risk of impurity generation is reduced, and the shelf life of the preparation is prolonged.

[0083] In addition, based on the present application: 1. Based on the comparison of Example 1 and Comparative Examples 1-2, 3-4, the present application has achieved better technical effects in the range of 30-40 parts by mass of HPMC AS drug carrier and 3-8 parts by mass of pH adjuster in the solid preparation of tizanidine hydrochloride, the similarity factor of the dissolution curve of the tizanidine hydrochloride solid preparation obtained by the present application in pH 6.8 phosphate buffer is greater than 50, which is similar to the reference preparation, and the dissolution rate after 30 days of storage under high temperature or high humidity conditions is greater than 80% compared with that at 0 day, which meets the requirements of the preparation, and the related substances after 30 days of storage have no significant increase compared with those at 0 day, and the total impurities are less than 0.20%.

[0084] 2. Based on the comparison of Example 1 and Comparative Example 5, the present application has achieved better technical effects by adding a grinding step, the similarity factor of the dissolution curve of the tizanidine hydrochloride solid preparation obtained by the present application in pH 6.8 phosphate buffer is greater than 50, which is similar to the reference preparation, and the dissolution rate after 30 days of storage under high temperature or high humidity conditions is greater than 80% compared with that at 0 day, which meets the requirements of the preparation, and the related substances after 30 days of storage have no significant increase compared with those at 0 day, and the total impurities are less than 0.20%.

[0085] 3. Based on the comparison of Example 1 and Comparative Examples 6-9, the present application has achieved new technical effects by using the specific combination of HPMC AS, pH adjuster and filler, which improves the stability of the drug under high temperature and high humidity conditions and overcomes the influence of storage environment and storage time on the dissolution rate and related substances of the drug. The technical effect after combination is more superior than the sum of the effects of each technical means.

[0086] 4. Based on the comparison of Example 3 and Comparative Examples 10-11, the present application has achieved unexpected technical effects of further improving the stability of the solid preparation of the drug under high temperature and high humidity conditions by selecting a narrow range of auxiliary materials not mentioned in the prior art from the wide range of "starch, cellulose derivative HPMC, polyethylene glycol, povidone, polylactic acid-glycolic acid copolymer, calcium carbonate and other auxiliary materials" disclosed in the prior art. BRIEF DESCRIPTION OF DRAWINGS

[0087] Figure 1 The dissolution curves of different samples. DETAILED DESCRIPTION

[0088] The following non-limiting examples can enable those skilled in the art to have a more comprehensive understanding of the present application, but do not limit the present application in any way. The following content is only an exemplary description of the scope of the present application, and those skilled in the art can make various changes and modifications to the present application based on the disclosed content, which should also belong to the scope of the present application claimed.

[0089] The present application is further described in the following specific examples. The various instruments, devices, equipment, reagents, products, etc. used in the examples of the present application were obtained from commercial sources unless otherwise stated.

[0090] The specific raw material information is shown in Table 1: Table 1. Raw material information

[0091] Examples 1-3 and Comparative Examples 1-4 are based on the same preparation method, and the weight fractions of the components are different, which constitute Examples 1-3 and Comparative Examples 1-4. The specific weight fraction parameters (all for 1000 tablets) are shown in the following table: Table 2. Specific weight fractions of components

[0092] (Note: Tizanidine in this product exists in the form of Tizanidine Hydrochloride, and Tizanidine Hydrochloride D90 < 15 μm.) The preparation method of the Tizanidine Hydrochloride drug tablet of Example 1-3 includes the following steps: (1) Tizanidine Hydrochloride, HPMC AS, and succinic acid are ground for 30 min and then passed through an 80-mesh sieve to obtain a mixture for standby; (2) The mixture obtained in (1) is mixed with mannitol for 10 min, and then passed through a 40-mesh sieve to obtain a first mixture for standby; (3) The first mixture obtained in (2) is mixed with the lubricant composition (stearic acid and colloidal silicon dioxide in a mass ratio of 1:3) for 5 min to obtain an intermediate granule; (4) The intermediate granule is pressed into tablets using a punch, and the Tizanidine Hydrochloride drug tablet preparation is obtained.

[0093] Comparative Example 1 The difference between Example 1 and Comparative Example 1 is that the mass of HPMC AS is changed to 25 g, and the rest is the same.

[0094] Comparative Example 2 The difference between Example 1 and Comparative Example 2 is that the mass of HPMC AS is changed to 45 g, and the rest is the same.

[0095] Comparative Example 3 The difference between Example 1 and Comparative Example 3 is that the mass of succinic acid is changed to 2 g, and the rest is the same.

[0096] Comparative Example 4 The difference between Example 1 and Comparative Example 4 is that the mass of succinic acid is changed to 9 g, and the rest is the same.

[0097] Comparative Example 5 The preparation method of the Tizanidine Hydrochloride drug tablet includes the following steps: (1) Mix tizanidine hydrochloride, HPMC AS, succinic acid and mannitol for 10 minutes, and then pass through a 40-mesh sieve, and reserve; (2) Mix the mixture obtained in (1) with colloidal silicon dioxide and stearic acid for 5 minutes to obtain intermediate granules; (3) Use a punch to press the intermediate granules to obtain tablets.

[0098] The difference from Example 1 is that the grinding operation in step (1) of Example 1 is omitted, and the rest is the same.

[0099] Comparative Example 6 The difference from Example 1 is that succinic acid is not added during the preparation process, and the rest is the same.

[0100] Comparative Example 7 The difference from Example 1 is that HPMC AS is not added during the preparation process, and the rest is the same.

[0101] Comparative Example 8 The difference from Example 1 is that mannitol is not added during the preparation process, and the rest is the same.

[0102] Comparative Example 9 The difference from Example 1 is that mannitol and succinic acid are not added during the preparation process, and the rest is the same.

[0103] Comparative Example 10 The difference from Example 1 is that hydroxypropyl methyl cellulose acetate succinate is replaced by polyethylene glycol, and the rest is the same.

[0104] Comparative Example 11 The difference from Example 1 is that hydroxypropyl methyl cellulose acetate succinate is replaced by diethyl phthalate, and the rest is the same.

[0105] Test Example 1. Dissolution curve investigation Tizanidine hydrochloride has low solubility in a pH 6.8 medium, so it is selected as the medium for prescription screening, which is easy to distinguish product quality. The dissolution curves of the reference preparation (trade name Ternelin, batch number 9XB09S), Examples 1-3 and Comparative Examples 1-11 were determined: the dissolution device was a paddle method, 50 rpm, the dissolution medium was pH 6.8 phosphate buffer, the volume of the dissolution medium was 900 ml, the dissolution temperature was 37 ± 0.5°C, and the dissolution was operated according to the law, and the dissolution was determined at 5 min, 10 min, 15 min, 20 min, 30 min. The results are shown in the following table.

[0106] Table 3. Dissolution curve results table

[0107] Table 4. Dissolution curve results table

[0108] The results of the above table show that the dissolution profiles of Examples 1-3 using HPMC AS 30-40 parts, succinic acid 3-8 parts, and subjected to grinding treatment are similar to the reference formulation in pH 6.8 phosphate buffer with a similarity factor of greater than 50. The dissolution profiles of Comparative Examples 1-2 using HPMC AS not in the range of 30-40 parts, Comparative Examples 3-4 using succinic acid not in the range of 3-8 parts, Comparative Example 5 not subjected to grinding treatment, Comparative Examples 7, 10, 11 not using HPMC AS, Comparative Examples 6, 9 not using succinic acid, and Comparative Examples 8-9 not using mannitol are not similar to the reference formulation in pH 6.8 phosphate buffer with a similarity factor of less than 50.

[0109] Test Example 2. Stability Investigation The reference formulation (trade name Ternelin, batch number 9XB09S), samples prepared in Examples 1-3 and Comparative Examples 1-11 were subjected to aluminum plastic packaging and then stored at high temperature (60℃) and high humidity (92.5% RH) for 30 days. The dissolution rates of the samples at 0 days, high temperature for 30 days, and high humidity for 30 days were measured: the dissolution device was a paddle method at 50 rpm, the dissolution medium was hydrochloric acid solution (9→1000), the volume of the dissolution medium was 900 ml, the dissolution temperature was 37±0.5℃, and the dissolution rate was measured by sampling at 15 min according to the procedure. The required limit in the Chinese Pharmacopoeia 2020 Edition for tizanidine hydrochloride tablets is not less than 80% of the labeled amount, and the results are shown in the following table.

[0110] Table 5. Dissolution stability results table

[0111] Table 6. Dissolution stability results table

[0112] The dissolution stability results show that Examples 1-3 using HPMC AS 30-40 parts, succinic acid 3-8 parts, and subjected to grinding treatment have a dissolution rate of greater than 80% after being stored at high temperature or high humidity for 30 days compared to 0 days, which meets the requirements. The dissolution rates of the reference formulation, Comparative Examples 1-2 using HPMC AS not in the range of 30-40 parts, Comparative Examples 3-4 using succinic acid not in the range of 3-8 parts, Comparative Example 5 not subjected to grinding treatment, Comparative Examples 7, 10, 11 not using HPMC AS, Comparative Examples 6, 9 not using succinic acid, and Comparative Examples 8-9 not using mannitol significantly decreased after being stored at high temperature or high humidity for 30 days, which are less than 80%, and do not meet the requirements.

[0113] Table 7. Material stability results table

[0114] Table 8. Related substance stability results

[0115] The related substance stability results show that Examples 1-3 using HPMC AS 30-40 parts, succinic acid 3-8 parts, and grinding treatment have no significant increase in related substances after 30 days of high temperature or high humidity conditions compared with 0 days, and the total impurities are less than 0.20%. The comparative examples 1-2 using HPMC AS not in the range of 30-40 parts, comparative examples 3-4 using succinic acid not in the range of 3-8 parts, comparative example 5 not grinding treatment, comparative examples 7, 10, 11 not using HPMC AS, comparative examples 6, 9 not using succinic acid, and comparative examples 8-9 not using mannitol have an increase in total impurities of more than 0.20% after 30 days of high temperature conditions.

[0116] Verification of technical effects and / or analysis of solving technical problems The solid preparation of tizanidine hydrochloride prepared by using HPMC AS and a pH regulator, and in combination with a low hygroscopicity filler has a dissolution curve comparable to the reference preparation, and has good stability under high temperature and high humidity conditions. The present prescription has a simple production process, is suitable for industrialized production and clinical use, and storage.

[0117] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A pharmaceutical solid preparation of tizanidine hydrochloride, characterized by, The solid dosage form of the drug includes: tizanidine hydrochloride, hydroxypropyl methylcellulose acetate succinate, pH adjuster, and filler.

2. The pharmaceutical solid preparation according to claim 1, characterized by The pH adjuster is selected from at least one of succinic acid, malic acid, tartaric acid, citric acid, fumaric acid, phosphoric acid, and acetic acid; preferably at least one of succinic acid, malic acid, citric acid, and fumaric acid; more preferably at least one of succinic acid, malic acid, and fumaric acid; and even more preferably succinic acid.

3. The pharmaceutical solid preparation according to claim 1, characterized by The filler is selected from at least one of microcrystalline cellulose, starch, pregelatinized starch, and mannitol; preferably at least one of microcrystalline cellulose, pregelatinized starch, and mannitol; more preferably at least one of microcrystalline cellulose and mannitol; and even more preferably mannitol.

4. The pharmaceutical solid preparation according to any one of claims 1 to 3, characterized in that, The tizanidine hydrochloride solid dosage form also includes a lubricant; The lubricant is selected from at least one of stearic acid, magnesium stearate, calcium stearate, glyceryl behenate, sodium stearate fumarate, and colloidal silica; preferably at least one of stearic acid, magnesium stearate, and colloidal silica; more preferably a combination of stearic acid and colloidal silica; and even more preferably, the mass ratio of stearic acid to colloidal silica in the lubricant is 1:

3.

5. The pharmaceutical solid preparation according to any one of claims 1 to 4, characterized in that, The particle size range of the tizanidine hydrochloride is less than 15 μm.

6. The pharmaceutical solid preparation according to any one of claims 1 to 5, characterized in that, According to parts by weight, the tizanidine hydrochloride solid dosage form comprises 1 part tizanidine hydrochloride, 30-40 parts hydroxypropyl methylcellulose succinate, 3-8 parts pH adjuster, 40-60 parts filler and 2-5 parts lubricant. Preferably, the tizanidine hydrochloride solid dosage form comprises 1 part tizanidine hydrochloride, 33-38 parts hydroxypropyl methylcellulose succinate, 4-7 parts pH adjuster, 50-60 parts filler, and 3-5 parts lubricant. More preferably, the tizanidine hydrochloride solid dosage form comprises 1 part tizanidine hydrochloride, 35 parts hydroxypropyl methylcellulose succinate, 5 parts pH adjuster, 55 parts filler, and 4 parts lubricant.

7. The pharmaceutical solid preparation according to any one of claims 1 to 6, characterized in that, The solid dosage form of tizanidine hydrochloride is selected from at least one of tablets, granules, capsules, powders, and mixtures; preferably tablets.

8. The method for preparing a solid pharmaceutical dosage form according to any one of claims 1-7, characterized in that, The steps include: grinding tizanidine hydrochloride, hydroxypropyl methylcellulose acetate succinate, and a pH adjuster, then mixing them with a filler and a lubricant to obtain the tizanidine hydrochloride solid dosage form.

9. The preparation method according to claim 8, characterized in that, The grinding and pulverizing time is 10-60 minutes; preferably 30 minutes. Preferably, the particles after grinding and pulverizing are required to pass through an 80-mesh sieve; The mixing method is selected from at least one of stirring mixing, shearing mixing, oscillating mixing, and stepwise mixing; preferably, the mixing method is a combination of stirring mixing and stepwise mixing; more preferably, the mixing method is: tizanidine hydrochloride, hydroxypropyl methylcellulose acetate succinate, and a pH adjuster are ground and mixed to obtain a mixture, and then the mixture is mixed with a lubricant and a filler; even more preferably, tizanidine hydrochloride, hydroxypropyl methylcellulose acetate succinate, and a pH adjuster are ground and mixed to obtain a mixture, and then the obtained mixture is first mixed with a filler, and then mixed a second time with a lubricant; The first mixing time is 5-30 minutes, preferably 10 minutes; the second mixing time is 3-10 minutes, preferably 5 minutes. The mixing process further includes a sieving step; preferably, the mixture is sieved through a 40-mesh sieve after the first mixing.

10. The use of the solid dosage form of the drug according to any one of claims 1-7 in the preparation of a drug for treating central skeletal muscle relaxation disorders.

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