Metronidazole particles, preparation containing metronidazole particles and preparation method

Abstract

The invention discloses metronidazole particles, a preparation containing the metronidazole particles and a preparation method of the metronidazole particles. The metronidazole particle comprises a drug core and a coating layer, wherein the coating layer is coated on the outer surface of the drug core; the medicine core comprises metronidazole; the coating layer comprises a film-forming material, and the film-forming material comprises gastric-soluble acrylic resin and ethyl cellulose. The metronidazole granule has low dissolution rate in water and a medium with high pH (such as pH 6.8), especially the dissolution rate in 15 minutes is less than or equal to 10%, the dissolution rate at low pH (such as pH 1.2-4.5) is consistent with the dissolution rate of commercially available tablets, and the metronidazole granule is rapidly dissolved out.

Description

Technical Field

[0001] This invention relates to metronidazole granules, preparations containing metronidazole, and preparation methods thereof. Background Technology

[0002] Metronidazole is used to treat and prevent infections caused by anaerobic bacteria. It has inhibitory activity against a variety of pathogenic microorganisms, particularly Bacteroides, Fusobacterium, Clostridium, eubacteria, Peptococci, anaerobic cocci, and Gardnerella vaginalis. Metronidazole also has therapeutic effects against Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia, Balantidium coli, and Draconis medina. Currently, metronidazole has clearly defined indications and dosages in pediatric populations.

[0003] Metronidazole has an extremely bitter taste. Currently available tablet and capsule formulations have poor taste and strong bitterness, causing nausea and vomiting after administration. Patients find it difficult to accept, resulting in poor compliance and affecting continued medication and clinical efficacy. Furthermore, the tablet and capsule formulations available in China are not suitable for children under 6 years old. Therefore, there is an urgent need to develop a formulation with good taste masking effect that is suitable for oral administration in children, thus solving the problem of oral medication compliance in children.

[0004] In 2023, metronidazole oral suspension (trade name: LIKMEZ) was launched in the United States. It reduces unpleasant taste by adding large amounts of sucrose, sucralose, and other flavoring agents to interfere with taste buds. While the method is simple, its effect on improving taste is limited. Furthermore, LIKMEZ is a liquid formulation, requiring the use of preservatives, and the types of excipients used are unsafe.

[0005] Currently, the main material used for taste-masking coatings is gastric-soluble acrylic resin, which dissolves in acidic gastric juice with a pH less than 5, but is insoluble in neutral saliva and water. This type of material can be used to coat drugs to mask their taste, making the drugs dissolve slowly or not at all in water or saliva, but dissolve rapidly in gastric juice, thus masking the taste. At the same time, after oral administration, the drugs are rapidly dissolved and absorbed in the stomach.

[0006] According to current reports, existing patents have disclosed cases of using gastric-soluble materials to prepare taste-masking formulations. For example, CN1273133C and CN103169669A. CN1273133C discloses the use of an ethanol solution of gastric-soluble acrylic resin Eudragit EPO or E100 to coat berberine hydrochloride particles; CN103169669A targets agomelatine, which can be dispersed in the mouth and is not suitable for metronidazole.

[0007] Therefore, how to select a suitable taste-masking coating based on the dissolution properties of metronidazole so that it can have a good taste-masking effect and be suitable for children's use is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the defects of metronidazole preparations in the prior art, such as poor taste masking effect and unsuitability for children, and to provide metronidazole granules, preparations containing them, and preparation methods.

[0009] During the research and development of this invention, attempts were made to use metronidazole crystal particles for taste-masking coating. While this achieved a good taste-masking effect, it required control over the particle size and size distribution of the metronidazole crystal particles. Due to the difficulty in obtaining large quantities of metronidazole crystal particles that meet the particle size distribution requirements, and the limited availability of the raw material, this process route is difficult to scale up for industrial production. Therefore, this invention provides metronidazole particles, formulations containing them, and a preparation method. The metronidazole particles are prepared by first mixing metronidazole powder and excipients to obtain a drug core, which is then coated. The metronidazole drug core in this invention can be taste-masked using a mature fluidized bed Wuster coating process. The taste-masking coating layer uses a gastric-soluble acrylic resin mixed with an organic solvent system of ethyl cellulose as the coating solution to coat the drug core. The resulting particles have a good taste-masking effect, are suitable for pediatric use, and do not affect the rapid dissolution of the drug in gastric juice.

[0010] This invention provides metronidazole granules, the metronidazole granules comprising a drug core and a coating layer, the coating layer covering the outer surface of the drug core;

[0011] The drug core includes metronidazole;

[0012] The coating layer includes a film-forming material, which includes gastrosoluble acrylic resin and ethyl cellulose.

[0013] In this invention, the chemical formula of metronidazole is C6H9N3O3, and the CAS number is 443-48-1.

[0014] In this invention, the D90 particle size of metronidazole in the drug core can be <100μm.

[0015] In a preferred embodiment of the present invention, the drug core comprises the following components, by mass percentage in the drug core:

[0016] Metronidazole 50-90%;

[0017] Diluent 10-30%;

[0018] Flow aid 0-5%;

[0019] Adhesive 1-15%.

[0020] In a preferred embodiment of the present invention, the drug core comprises the following components, by mass percentage in the drug core:

[0021] Metronidazole 60-80%;

[0022] Diluent 10-30%;

[0023] Flow aid 0-5%;

[0024] Adhesive 1-15%.

[0025] In some embodiments of the present invention, the content of metronidazole is 60-80%, for example 70-80%, for example 70%, 70.4% or 80%, the percentage being the mass percentage in the drug core.

[0026] In this invention, the drug content in the drug core affects the particle shapeability of the metronidazole drug core. Generally, the higher the drug content, the worse the particle shapeability, which is not conducive to masking the taste.

[0027] In some embodiments of the present invention, the diluent includes microcrystalline cellulose and / or lactose.

[0028] In this invention, microcrystalline cellulose can be purchased from JRS, model Vivapur 101.

[0029] In some embodiments of the present invention, the diluent is selected from microcrystalline cellulose, or microcrystalline cellulose and lactose.

[0030] In some embodiments of the present invention, the content of the diluent is 10-25%, for example 13.0%, 22.5% or 24%, the percentage being the mass percentage in the drug core.

[0031] In some embodiments of the present invention, the content of the microcrystalline cellulose is 5-20%, for example 5.6%, 12.5%, 16.0% or 13%, the percentage being the mass percentage in the drug core.

[0032] In some embodiments of the present invention, the lactose content is 0-20%, for example 8.0%, 12.5% ​​or 16.9%, the percentage being the mass percentage in the drug core.

[0033] In some embodiments of the present invention, the flow aid is selected from silica, such as colloidal silica.

[0034] In this invention, colloidal silica can be purchased from Evonik Specialty Chemicals (shanghai) Co., Ltd., model AEROSIL 200 Pharma.

[0035] In some embodiments of the present invention, the content of the gliding agent is 0.5-1.0%, for example 0.8% or 1.0%, and the percentage is the mass percentage in the drug core.

[0036] In some embodiments of the present invention, the adhesive includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone solution.

[0037] In some embodiments of the present invention, the adhesive is selected from hydroxypropyl methylcellulose. The viscosity of the hydroxypropyl methylcellulose may be 5-50 mPa·s, for example 5-30 mPa·s, or even 15 mPa·s. The grade of the hydroxypropyl methylcellulose may be E15.

[0038] In this invention, hydroxypropyl methylcellulose can be purchased from Shanghai Calcare Coating Technology Co., Ltd., model E15, with a viscosity of 15 mPa·s.

[0039] In some embodiments of the present invention, the content of the adhesive is 5-10%, for example 5.0%, 6.0% or 6.2%, the percentage being the mass percentage in the drug core.

[0040] In a preferred embodiment of the present invention, the drug core comprises the following components:

[0041] Metronidazole 60-80%;

[0042] Diluent 10-25%; the diluent is selected from microcrystalline cellulose, or microcrystalline cellulose and lactose;

[0043] Flow aid 0-5%;

[0044] 5-15% adhesive; the adhesive is selected from hydroxypropyl methylcellulose.

[0045] In a preferred embodiment of the present invention, the drug core comprises the following components:

[0046] Metronidazole 70.4%

[0047] Hydroxypropyl methylcellulose 6.2%

[0048] Microcrystalline cellulose 5.6%

[0049] Lactose 16.9%

[0050] Colloidal silica 0.8%.

[0051] In a preferred embodiment of the present invention, the drug core comprises the following components:

[0052] Metronidazole 70%

[0053] 5% hydroxypropyl methylcellulose

[0054] 16% microcrystalline cellulose

[0055] 8% lactose

[0056] 1% colloidal silica.

[0057] In a preferred embodiment of the present invention, the drug core comprises the following components:

[0058] Metronidazole 70%

[0059] 5% hydroxypropyl methylcellulose

[0060] Microcrystalline cellulose 12.5%

[0061] Lactose 12.5%.

[0062] In a preferred embodiment of the present invention, the drug core comprises the following components:

[0063] Metronidazole 70%

[0064] 5% hydroxypropyl methylcellulose

[0065] 16% microcrystalline cellulose

[0066] 8% lactose

[0067] 1% colloidal silica.

[0068] In a preferred embodiment of the present invention, the drug core comprises the following components:

[0069] Metronidazole 80%

[0070] Hydroxypropyl methylcellulose 6%

[0071] Microcrystalline cellulose 13%

[0072] 1% colloidal silica.

[0073] In some embodiments of the present invention, the particle size of the drug core is 180-500 μm, for example 180-270 μm or 180-380 μm; or for example less than 270 μm.

[0074] In some embodiments of the present invention, the bulk density of the drug core is 0.2-0.5 g / mL, for example 0.28 g / mL or 0.41 g / mL.

[0075] In this invention, the gastric-soluble acrylic resin is a high molecular compound, usually based on polyacrylic acid, which forms a network structure through a cross-linking reaction. Its molecular structure contains a large number of carboxyl groups (-COOH), which can form salts with ions or organic bases, and then swell in aqueous solution, giving it good solubility and permeability. It can be used for moisture protection and odor masking, effectively masking odors and ensuring rapid release of active ingredients in the stomach.

[0076] In some embodiments of the present invention, the gastrointestinal soluble acrylic resin is selected from a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate. The molar ratio of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate may be 1:2:1.

[0077] In some embodiments of the present invention, the gastrosoluble acrylic resin is selected from one or more of Eudragit E100, Eudragit EPO, and Eudragit L100, preferably Eudragit E100.

[0078] Eudragit E100 is a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (e.g., butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate in a molar ratio of 1:2:1).

[0079] Eudragit E100 is generally insoluble in near-neutral environments (pH 5-7), but dissolves rapidly in media below pH 5. In the oral cavity, where the pH is higher (pH 6.2 or higher), Eudragit E100 dissolves slowly, but dissolves rapidly in the stomach where the pH is lower.

[0080] In this invention, Eudragit E100 can be purchased from Evonik Operations GmbH.

[0081] In this invention, the ethyl cellulose can be purchased from Shanghai Carrefour Coating Technology Co., Ltd., and the ethyl cellulose can be of the following grades: ETHOCEL Standard 4 Premium Ethylcellulose, ETHOCEL Standard 7 Premium Ethylcellulose, ETHOCEL Standard 10 Premium Ethylcellulose, ETHOCEL Standard 20 Premium Ethylcellulose, ETHOCEL Standard 45 Premium Ethylcellulose, or ETHOCEL Standard 100 Premium Ethylcellulose.

[0082] In some embodiments of the present invention, the indicated viscosity of the ethyl cellulose is 4-100 mPa·s, for example 4 mPa·s, 7 mPa·s, 10 mPa·s, 20 mPa·s, 45 mPa·s or 100 mPa·s.

[0083] In this invention, the viscosity test method for ethyl cellulose is as follows: Take 5.0 g of ethyl cellulose (based on dried product), accurately weigh it, place it in a stoppered conical flask, accurately add 95 g of ethanol-toluene (1:4, g / g) solution, shake until completely dissolved, adjust the temperature to 25℃±0.1℃, and determine the dynamic viscosity (Chinese Pharmacopoeia 2020 Edition, General Chapter 0633, Method 1, select capillary tubes of different inner diameters so that the outflow time is greater than 200 seconds). If the labeled viscosity is greater than 6 mPa·s, the viscosity should be 80.0-120.0% of the labeled viscosity; if the labeled viscosity is less than or equal to 6 mPa·s, the viscosity should be 75.0%-140.0% of the labeled viscosity.

[0084] In some embodiments of the present invention, the mass ratio of the gastrosoluble acrylic resin to the ethyl cellulose is 1:(1-3), for example 1:1, 1:3 or 2:3.

[0085] In some embodiments of the present invention, the mass ratio of the film-forming material to the drug core in the coating layer is ≥0.20:1, which can be (0.20-0.50):1, for example (0.20-0.40):1, or (0.25-0.40):1, or even 0.25:1, 0.30:1, 0.35:1, or 0.40:1.

[0086] In some embodiments of the present invention, the coating layer further includes surfactants and / or anti-sticking agents.

[0087] In some embodiments of the present invention, the coating layer does not contain plasticizers.

[0088] In this invention, plasticizer is a type of small molecule substance. When it is added to a polymer (film-forming material), it will penetrate into the polymer chains, reduce the intermolecular or intramolecular forces, and make the network structure of the polymer loose. Adding an appropriate amount of plasticizer facilitates film formation.

[0089] In some embodiments of the present invention, the content of the anti-adhesive is 1-25%, for example 1.38%, 1.59%, 8.9%, 11.5%, 13.0%, 9.1%, 18.8% or 20.6%; the percentage refers to the mass percentage in the metronidazole granules.

[0090] In some embodiments of the present invention, the anti-adhesion agent is one or more of glyceryl monostearate, PlasACRYL T20, magnesium stearate, talc, and micronized silica gel, such as one or more of glyceryl monostearate, PlasACRYL T20, and talc.

[0091] In some embodiments of the present invention, the anti-adhesion agent is selected from glyceryl monostearate.

[0092] In some embodiments of the present invention, the anti-adhesion agent is selected from glyceryl monostearate, and the content of the anti-adhesion agent is 0.1-5%, for example 1.38% or 1.59%; the percentage refers to the mass percentage of the metronidazole granules.

[0093] In some embodiments of the present invention, the anti-adhesion agent is selected from PlasACRYL T20, which is a premix comprising glyceryl monostearate, triethyl citrate and Tween-80.

[0094] In this invention, PlasACRYL T20 is available from Emerson Resources Inc.; PlasACRYL T20 is a premix of glyceryl monostearate, triethyl citrate and Tween-80, with a solid content concentration of 20%.

[0095] In some embodiments of the present invention, the anti-adhesion agent is PlasACRYL T20, and the content of the anti-adhesion agent is 1-25%, for example 8.9%, 11.5%, 13.0%, 9.1%, 18.8% or 20.6%; the percentage refers to the mass percentage in the metronidazole granules.

[0096] In some embodiments of the present invention, the surfactant is Tween-80.

[0097] In some embodiments of the present invention, the content of the surfactant is 0.1-1%, for example 0.39% or 0.72%; the percentage refers to the mass percentage of the metronidazole granules.

[0098] In some embodiments of the present invention, the coating layer further includes glyceryl monostearate and Tween-80.

[0099] In some embodiments of the present invention, the coating layer further includes PlasACRYL T20.

[0100] In some embodiments of the present invention, the metronidazole granules comprise:

[0101] (1) Drug core:

[0102] The drug core includes metronidazole powder, a diluent (e.g., microcrystalline cellulose and / or lactose), a flow aid (e.g., silica), and a binder (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone solution).

[0103] In the obtained drug core, the content of metronidazole powder can be ≥70%, for example, 80%;

[0104] (2) Coating layer: The coating layer covers the surface of the drug core;

[0105] The coating layer includes Eudragit E100, a gastrosoluble butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate copolymer (e.g., butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate in a molar ratio of 1:2:1), and ethyl cellulose;

[0106] The mass ratio of the gastrointestinal soluble acrylic resin to the ethyl cellulose can be 1:(1-3), for example, 1:1, 1:3 or 2:3;

[0107] Preferably, the coating layer further includes an anti-adhesive (e.g., glyceryl monostearate and / or triethyl citrate) and / or the surfactant Tween 80.

[0108] In some embodiments of the present invention, the metronidazole granules comprise:

[0109] The drug core 200 g

[0110] The coating layer comprises: Eudragit E100 25 g, ethyl cellulose 25 g, glyceryl monostearate 3.5 g, and Tween-80 1 g.

[0111] In some embodiments of the present invention, the metronidazole granules comprise:

[0112] The drug core weighs 170 g.

[0113] The coating layer comprises: Eudragit E100 10.4 g, ethyl cellulose 32.1 g, and PlasACRYL T202 1.25 g.

[0114] In some embodiments of the present invention, the metronidazole granules comprise:

[0115] The drug core 200 g

[0116] The coating layer comprises: Eudragit E100 24 g, ethyl cellulose 36 g, and PlasACRYL T20 60 g.

[0117] In some embodiments of the present invention, the metronidazole granules comprise:

[0118] The drug core 200 g

[0119] The coating layer comprises: Eudragit E100 28 g, ethyl cellulose 42 g, and PlasACRYL T20 70 g.

[0120] In some embodiments of the present invention, the metronidazole granules comprise:

[0121] The drug core weighs 286 g.

[0122] The coating layer comprises: Eudragit E100 28 g, ethyl cellulose 43 g, and PlasACRYL T20 35 g.

[0123] In some embodiments of the present invention, the metronidazole granules comprise:

[0124] The drug core weighs 286 g.

[0125] The coating layer comprises: Eudragit E100 40 g, ethyl cellulose 60 g, and PlasACRYL T20 50 g.

[0126] In some embodiments of the present invention, the metronidazole granules comprise:

[0127] The drug core weighs 286 g.

[0128] The coating layer comprises: Eudragit E100 46 g, ethyl cellulose 69 g, and PlasACRYL T20 60 g.

[0129] In some embodiments of the present invention, the metronidazole granules comprise:

[0130] The drug core 200 g

[0131] The coating layer comprises: Eudragit E100 28 g, ethyl cellulose 42 g, and PlasACRYL T20 70 g.

[0132] The present invention also provides a method for preparing the metronidazole granules, which includes the following steps:

[0133] (1) The raw materials and solvent in the coating layer are mixed to obtain a coating solution;

[0134] (2) The coating solution is coated on the outer surface of the drug core and dried to obtain the metronidazole granules.

[0135] In some embodiments of the present invention, the method for preparing the metronidazole granules includes the following steps:

[0136] (1) After mixing the metronidazole, the diluent, the binder and the flow aid to obtain a material, the material is granulated to obtain the drug core;

[0137] (2) The raw materials and solvent in the coating layer are mixed to obtain a coating solution;

[0138] (3) The coating solution is coated on the outer surface of the drug core and dried to obtain the metronidazole granules.

[0139] In some embodiments of the present invention, the adhesive is dissolved in solvent A to obtain an adhesive solution, which is then mixed with the metronidazole, the diluent, and the flow aid for granulation.

[0140] Solvent A may be a conventional solvent in the art that can dissolve the adhesive, such as water.

[0141] The adhesive solution contains an adhesive with a mass concentration of 1-10%, for example, 5-6%.

[0142] In some embodiments of the present invention, the granulation process employs a top-spray or side-spray fluidized bed granulation process. For example, in a top-spray or side-spray fluidized bed reactor, the metronidazole, the diluent, and the flow aid are mixed, and then the binder solution is top-sprayed or side-sprayed for granulation.

[0143] In the top spray or side spray fluidization process, the inlet air temperature can be 50-70℃.

[0144] In the top spray or side spray fluidization process, the air intake volume can be 25-40 m³ / h.

[0145] In the top-spray or side-spray fluidization process, the fan frequency can be 10-20Hz, for example, 15-20Hz or 13Hz.

[0146] In the top spray or side spray fluidization process, the atomization pressure can be 1.5-2.0 bar, for example, 1.5-1.8 bar.

[0147] In the top-spray or side-spray fluidization process, atomization can be stopped after granulation is completed.

[0148] In some embodiments of the present invention, the granulation process maintains the material temperature at 35-45°C.

[0149] In some embodiments of the present invention, after granulation, drying continues for 15-30 minutes until the moisture content drops to less than 2.0%, where the percentage refers to the mass percentage in the drug core.

[0150] In some embodiments of the present invention, the particle size of the drug core is less than 500 μm.

[0151] In some embodiments of the present invention, the particle size of the drug core is 180-500 μm, for example 180-270 μm or 180-380 μm; or for example less than 270 μm.

[0152] In some embodiments of the present invention, the bulk density of the drug core is 0.2-0.5 g / mL, 0.28 g / mL, or 0.41 g / mL.

[0153] In some embodiments of the present invention, the granulation process is carried out using a Wuster fluidized bed. In the present invention, the amount of fine powder produced when the drug core is coated with a Wuster fluidized bed to mask the taste is small, the sample yield is high, the particle size change after coating is not obvious, and after being made into dry suspensions or granules, there is no obvious foreign body sensation when tasted.

[0154] In this invention, the solvent may be a conventional solvent in the art that can at least dissolve gastric-soluble acrylic resins, such as ethanol and / or water.

[0155] In some embodiments of the present invention, the solvent is ethanol and water, and the mass ratio of ethanol to water is (1-8):1, for example 5.36:1, 5.33:1, 2.33:1.

[0156] In some embodiments of the present invention, the film-forming material is dissolved in the solvent to obtain the coating solution.

[0157] In some embodiments of the present invention, the preparation method of the coating solution includes the following steps:

[0158] First, the gastrointestinal soluble acrylic resin and the solvent are mixed and dissolved to obtain mixture A1. Then, mixture A1 and ethyl cellulose are mixed and dissolved to obtain the coating solution.

[0159] In some embodiments of the present invention, when the raw material of the coating layer further includes one or more of surfactants and / or anti-adhesives, the preparation method of the coating solution includes the following steps:

[0160] The film-forming material is dissolved in a portion of the solvent (e.g., ethanol) to obtain mixture A2;

[0161] The surfactant and / or the anti-adhesion agent are dissolved in the remaining portion of the solvent (e.g., water) and homogenized by high-speed shearing to obtain mixture A3;

[0162] Mix the mixture A2 and the mixture A3 to obtain the coating solution.

[0163] In the preparation of the mixture A3, the heating or non-heating conditions can be selected according to the solubility of the added raw materials.

[0164] For example, when the raw materials of the coating layer include film-forming materials, anti-adhesion agents, and surfactants:

[0165] The solvent (e.g., water) is heated to above 70°C, then mixed with the anti-adhesion agent (e.g., glyceryl monostearate) and the surfactant (e.g., Tween-80), and then subjected to high-speed shear homogenization.

[0166] The high-speed shearing and homogenization time can be a conventional time in the art, such as 30 minutes.

[0167] The rotational speed of the high-speed shearing homogenization can be a conventional rotational speed in the art, such as 4000-10000 rpm.

[0168] In some embodiments of the present invention, the mixture A2 is added to the mixture A3.

[0169] In some embodiments of the present invention, the mixture A3 is added to the mixture A2.

[0170] In some embodiments of the present invention, when the raw materials of the coating layer include film-forming materials, surfactants, and anti-adhesion agents, the preparation method of the coating solution includes the following steps:

[0171] The film-forming material is dissolved in the solvent to obtain mixture A4;

[0172] The surfactant, the anti-adhesion agent, and the mixture A4 are mixed to obtain the coating solution.

[0173] In this invention, the process of coating the drug core with the coating solution can be a conventional coating process in the art, such as bottom spray fluidization coating, or coating in a Wuster fluidized bed.

[0174] In some embodiments of the present invention, the coating process controls the material temperature to be 25-35°C.

[0175] In some embodiments of the present invention, after the coating is completed, atomization is stopped and drying continues for 15-30 minutes until the moisture content drops to less than 2.0%, where the percentage refers to the mass percentage of the metronidazole granules.

[0176] In some embodiments of the present invention, the preparation method of the coating solution includes the following steps:

[0177] ① Add Eudragit E100 to ethanol and stir until completely dissolved. Then add ethyl cellulose and continue stirring until completely dissolved.

[0178] ② Heat pure water to above 70°C, add glyceryl monostearate and Tween-80 to the hot water, and shear at high speed until emulsified and dispersed;

[0179] ③ Add the emulsified and dispersed glyceryl monostearate solution to the Eudragit E100 and ethyl cellulose mixed solution, and stir until homogeneous to obtain the coating solution.

[0180] In some embodiments of the present invention, the preparation method of the coating solution includes the following steps:

[0181] ① After mixing ethanol and water evenly, add Eudragit E100 and stir continuously until completely dissolved. Then add ethyl cellulose and stir continuously until completely dissolved.

[0182] ② Add PlasACRYL T20 to the solution in ① and stir continuously until it is evenly dispersed to obtain the coating solution.

[0183] The present invention also provides a metronidazole formulation comprising the metronidazole granules.

[0184] In some embodiments of the present invention, the metronidazole preparation is an oral metronidazole dosage form.

[0185] In some embodiments of the present invention, the metronidazole oral dosage forms include dry suspensions, dispersible tablets, and chewable tablets.

[0186] In some embodiments of the present invention, the metronidazole dry suspension contains 40-50% by mass, for example 45.0% of the metronidazole particles.

[0187] In some embodiments of the present invention, the metronidazole dry suspension comprises the metronidazole granules and conventional excipients. The excipients may include one or more of the following: flavoring agents, suspending agents, diluents, disintegrants, binders, flow aids, surfactants, and colorants.

[0188] In some embodiments of the present invention, the flavoring agent in the metronidazole dry suspension is selected from one or more of sucralose, cyclamate, aspartame, xylitol, sorbitol and orange flavoring.

[0189] In this invention, the orange flavoring can be purchased from Sensient.

[0190] In some embodiments of the present invention, the flavoring agent in the metronidazole dry suspension has a mass content of 0%-5%, for example 0.05%-0.5%, or for example 0.06%.

[0191] In some embodiments of the present invention, the suspending agent in the metronidazole dry suspension is selected from one or more of microcrystalline cellulose, xanthan gum, sodium carboxymethyl cellulose, and sodium carboxymethyl cellulose.

[0192] In this invention, xanthan gum can be purchased from CP Kolco US, Inc., model XANTURAL 75.

[0193] In some embodiments of the present invention, the mass content of the suspending agent in the metronidazole dry suspension is 1%-10%, for example 1.27%.

[0194] In some embodiments of the present invention, the diluent in the metronidazole dry suspension is selected from sucrose and / or microcrystalline cellulose.

[0195] In some embodiments of the present invention, the mass content of the diluent in the metronidazole dry suspension is 50%-80%, for example 50.63%.

[0196] In some embodiments of the present invention, the disintegrant in the metronidazole dry suspension is selected from croscarmellose sodium and / or croscarmellose polyvinylpyrrolidone.

[0197] In this invention, croscarmellose sodium carboxymethyl cellulose can be purchased from DFE Pharma BV.

[0198] In some embodiments of the present invention, the mass content of the disintegrant in the metronidazole dry suspension is 0.5%-6%, for example 1.27%.

[0199] In some embodiments of the present invention, the binder in the metronidazole dry suspension is selected from hydroxypropyl methylcellulose.

[0200] In some embodiments of the present invention, the mass content of the binder in the metronidazole dry suspension is 0.5%-5%, for example 0.51%.

[0201] In some embodiments of the present invention, the flow aid is selected from one or more of silica, polyethylene glycol 6000, and magnesium stearate, such as colloidal silica.

[0202] In some embodiments of the present invention, the mass content of the glidant in the metronidazole dry suspension is 0.5%-5%, for example 1.27%.

[0203] In some embodiments of the present invention, the surfactant in the metronidazole dry suspension is selected from Tween-80.

[0204] In some embodiments of the present invention, the colorant is selected from lemon yellow pigment and / or β-carotene.

[0205] In this invention, the lemon yellow pigment can be purchased from Sensient.

[0206] In some embodiments of the present invention, the colorant content in the metronidazole dry suspension is 0.05%-0.5% by mass, for example 0.06%.

[0207] In some embodiments of the present invention, the metronidazole dry suspension comprises the following components:

[0208] 355 parts of the metronidazole granules

[0209] 300 parts sucrose

[0210] 4 parts hydroxypropyl methylcellulose

[0211] 100 parts of microcrystalline cellulose

[0212] 10 parts xanthan gum

[0213] 10 parts of croscarmellose sodium cellulose

[0214] 10 parts of colloidal silica

[0215] 0.5 parts orange flavoring

[0216] 0.5 parts lemon yellow pigment.

[0217] In some embodiments of the present invention, the preparation method of the metronidazole dry suspension includes the following steps:

[0218] The suspension-aiding granules and the metronidazole granules were mixed to obtain the following:

[0219] The raw materials of the suspending granules include at least a suspending agent, and also one or more of the following: flavoring agent, diluent, disintegrant, binder, flow aid, and colorant.

[0220] The method for preparing the suspending particles may include the following steps:

[0221] The suspending agent, the flavoring agent, the flow aid and the coloring agent are mixed and sieved for the first time to obtain mixture 1;

[0222] Mixture 1 is mixed with the binder, the diluent, and the disintegrant, and then sieved a second time to obtain mixture 2;

[0223] Add an atomizing solvent (e.g., water) to the mixture 2, wet granulate, and dry to obtain the suspension particles.

[0224] The first sieving can be through a 60-mesh sieve.

[0225] The first sieving can be through a 40-mesh sieve.

[0226] The mixture 2, after sieving and before granulation, can be subjected to high-shear mixing. The stirring speed for high-shear mixing can be 300 rpm. The shear speed for high-shear mixing can be 1000 rpm. The mixing time for high-shear mixing can be 10 minutes.

[0227] The granulation time can be a conventional time in the art, such as 1-3 minutes.

[0228] The drying process can be carried out in a fluidized bed or an oven.

[0229] The drying process can be described as drying to a moisture content of less than 2.0%.

[0230] After drying, the particles can be granulated using a 1.0mm sieve. After granulation, the particles pass through a 40-mesh sieve to remove the portion above the sieve and collect the particles below the sieve.

[0231] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0232] The reagents and raw materials used in this invention are all commercially available.

[0233] The positive and progressive effects of this invention are as follows:

[0234] The metronidazole granules of this invention exhibit low dissolution in water and high pH media (such as pH 6.8), especially with a dissolution rate of ≤10% in 15 minutes, while the dissolution rate at low pH (such as pH 1.2~4.5) is consistent with that of commercially available tablets, indicating rapid dissolution.

[0235] Specifically, the metronidazole masking granules or related formulations of this invention have a solubility of ≤10% in pure water within 15 minutes, and a solubility of greater than 85% in hydrochloric acid solution at pH 1.2 and acetate medium at pH 4.5 within 15 minutes. This is for rapid release and is similar to the solubility of commercially available tablets of the same specifications. Therefore, the masking coating will not affect the bioavailability of the drug. Detailed Implementation

[0236] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0237] In the following embodiments:

[0238] Information on commercially available tablets: Metronidazole tablets, 0.2g, manufactured by Grand Pharmaceutical (China) Co., Ltd.

[0239] Metronidazole: chemical formula C6H9N3O3, CAS number 443-48-1, exists in powder form, powder particle size D90 < 100μm;

[0240] Hydroxypropyl methylcellulose was purchased from Shanghai Calcare Coating Technology Co., Ltd., model E15, viscosity 15 mPa·s;

[0241] Microcrystalline cellulose was purchased from JRS, Vivapur 101;

[0242] Colloidal silica was purchased from Evonik Specialty Chemicals (shanghai) Co., Ltd., model AEROSIL 200 Pharma;

[0243] The Eudragit E100 was purchased from Evonik Operations GmbH.

[0244] Ethyl cellulose was purchased from Shanghai Calcare Coating Technology Co., Ltd., using the model ETHOCEL Standard 7 Premium Ethylcellulose, with a labeled viscosity of 7 mPa·s;

[0245] Glyceryl monostearate: CAS No. 123-94-4;

[0246] Twain-80: CAS No. 9005-65-6;

[0247] PlasACRYL T20, a water-based anti-adhesive and plasticizer mixed emulsion, was purchased from Emerson Resources Inc. It is a premix of glyceryl monostearate, triethyl citrate, and Tween-80, with a total solids content of 20%.

[0248] Xanthan gum was purchased from CP Kolco US, Inc., model XANTURAL 75;

[0249] Crosslinked sodium carboxymethyl cellulose was purchased from DFE Pharma BV, model Primellose;

[0250] The orange flavoring was purchased from Sensient.

[0251] Lemon yellow pigment was purchased from Sensient.

[0252] The viscosity test method for hydroxypropyl methylcellulose is as follows: Add water at 90℃ to prepare a 2.0% (g / g) solution, stir thoroughly for about 10 minutes until the particles are completely and uniformly dispersed and wetted and there are no undissolved sample particles on the inner wall of the bottle. Cool in an ice bath, continue stirring during cooling to remove air bubbles. If necessary, adjust the weight with cold water to remove all foam. At 20℃±0.1℃, with a flow time of not less than 200 seconds, select an Ubbelohde viscometer with an appropriate inner diameter to determine the kinematic viscosity (v) of the solution (Chinese Pharmacopoeia 2020 Edition, General Chapter 0633, Method I). Under the same conditions, determine the density (ρ) of the solution and calculate the dynamic viscosity = ρv.

[0253] Ethyl cellulose viscosity test method: Accurately weigh 5.0 g of this product (based on dried product), place it in a stoppered conical flask, accurately add 95 g of ethanol-toluene (1:4, g / g) solution, shake until completely dissolved, adjust the temperature to 25℃±0.1℃, and determine the dynamic viscosity (Chinese Pharmacopoeia 2020 Edition, General Chapter 0633, Method 1, select capillary tubes of different inner diameters so that the outflow time is greater than 200 seconds). If the labeled viscosity is greater than 6 mPa·s, the viscosity should be 80.0-120.0% of the labeled viscosity; if the labeled viscosity is less than or equal to 6 mPa·s, the viscosity should be 75.0%-140.0% of the labeled viscosity.

[0254] Bulk density determination method: Take an appropriate amount of the test sample suspending particles and slowly pour them into a glass graduated cylinder until the particle level reaches the 100ml mark. Weigh the sample and calculate the density.

[0255] Example 1 (Top-spray granulation)

[0256] (1) Preparation of metronidazole drug core

[0257] Table 1

[0258]

[0259] According to the prescription shown in Table 1, the preparation method of metronidazole drug core is as follows:

[0260] Metronidazole was mixed with microcrystalline cellulose, lactose, and colloidal silica and sieved. The mixture was then added to a top-spray granulation fluidized bed reactor. The reactor was started, and granulation was performed using a hydroxypropyl methylcellulose solution (aqueous solution, 6% mass concentration). The inlet air temperature was 50-70℃, the inlet air volume was 25-40 m³ / h, and the atomization pressure was 1.5 bar. The material temperature was maintained at 35-45℃ during the granulation process. After granulation, atomization was stopped, and the material was dried for another 15-30 minutes until the moisture content dropped to less than 2.0%. The reactor was then stopped, the material was removed, and the bulk density of the granules was measured to be 0.28 g / mL. The material was sieved, and granules with a mesh size of 32-80 mesh (180-500 μm) were used for flavor-masking coating.

[0261] (2) Metronidazole drug core masking coating

[0262] The flavor-masking coating formulation for metronidazole drug core is shown in Table 2. The mass ratio of Eudragit E100 to ethyl cellulose is 1:1, and the coating weight gain is 25%. The coating weight gain is calculated based on the mass of "Eudragit E100 and ethyl cellulose" and their mass ratio relative to the mass of the metronidazole drug core.

[0263] Table 2

[0264]

[0265] According to the prescription shown in Table 2, the preparation method of metronidazole drug core masking coating is as follows:

[0266] ① Add Eudragit E100 to ethanol and stir until completely dissolved. Then add ethyl cellulose and continue stirring until completely dissolved.

[0267] ② Heat pure water to above 70°C, add glyceryl monostearate and Tween-80 to the hot water, and shear at high speed until emulsified and dispersed.

[0268] ③ Add the emulsified and dispersed glyceryl monostearate solution to the mixed solution of Eudragit E100 and ethyl cellulose, and stir until homogeneous to obtain the coating solution.

[0269] ④ Add the metronidazole drug core to the Wuster fluidized bed, and use the coating solution to coat the drug core to mask the taste. During the coating process, control the material temperature at 25-35℃. After the coating is completed, stop atomization and continue drying for 15-30 minutes, and control the moisture content to be less than 2.0%.

[0270] Take an appropriate amount of the metronidazole masking granules obtained above and determine their dissolution and release according to the method of determination of dissolution and release (Chinese Pharmacopoeia (2020 edition, General Chapter 0931, Method II), with a rotation speed of 75 rpm, using pure water and pH 4.5 acetate buffer as media, with a media volume of 900 ml.

[0271] The dissolution results in pure water are shown in Table 3 below.

[0272] Table 3

[0273]

[0274] The dissolution results in pH 4.5 acetate buffer are shown in Table 4 below.

[0275] Table 4

[0276]

[0277] Comparative Example 1 (Side-spray granulation)

[0278] (1) Preparation of metronidazole drug core

[0279] Table 5

[0280]

[0281] According to the prescription shown in Table 5, the preparation method of metronidazole drug core is as follows:

[0282] Metronidazole was mixed with microcrystalline cellulose, lactose, and colloidal silica and sieved. The mixture was then added to a side-spray granulation fluidized bed reactor. Granulation was performed using a hydroxypropyl methylcellulose solution (6% by mass concentration). The inlet air temperature was 50-70℃, the fan frequency was 15-20Hz, and the atomization pressure was 2 bar. The material temperature was maintained at 35-45℃ during granulation. After granulation, atomization was stopped, and drying continued for 15-30 minutes, with the moisture content controlled to be less than 2.0%. The granule bulk density was 0.41 g / mL, and the granules were relatively compact. The mixture was sieved, and granules with a mesh size of 50-80 mesh (180-270 μm) were used for the next step of flavor-masking coating.

[0283] (2) Metronidazole drug core masking coating

[0284] The formulations for the metronidazole drug core masking coating are shown in Table 6. The weight gain of the masking coating, calculated using Eudragit E100, is 20%, 25%, and 30%, respectively. The weight gain is calculated as the ratio of the mass of "Eudragit E100" to the mass of the metronidazole drug core.

[0285] Table 6

[0286]

[0287] According to the prescription shown in Table 6, the preparation method of metronidazole drug core masking coating is as follows:

[0288] ① Add Eudragit E100 to ethanol and stir until completely dissolved.

[0289] ② Heat pure water to above 70℃, add glyceryl monostearate and Tween-80 to the hot water, and shear at high speed of 4000-10000 rpm until emulsified and dispersed.

[0290] ③ Add the emulsified and dispersed glyceryl monostearate solution to the Eudragit E100 solution and stir until homogeneous to obtain the coating solution.

[0291] ④ Add the metronidazole drug core to the Wuster fluidized bed, and use the coating solution described in ③ to coat the drug core to mask the taste. During the coating process, control the material temperature at 25-35℃. After the coating is completed, stop atomization and continue drying for 15-30 minutes, and control the moisture content to be less than 2.0%.

[0292] Take an appropriate amount of the metronidazole masking granules obtained above and determine their dissolution and release according to the method of determination of dissolution and release (Chinese Pharmacopoeia (2020 edition, General Chapter 0931, Method II), with a rotation speed of 75 rpm, using pure water and pH 4.5 acetate buffer as media, with a media volume of 900 ml.

[0293] The dissolution results in pure water are shown in Table 7 below.

[0294] Table 7

[0295]

[0296] The dissolution results in pH 4.5 acetate buffer are shown in Table 8 below.

[0297] Table 8

[0298]

[0299] Conclusion: When the flavor-masking coating contains Eudragit E100 but does not contain ethyl cellulose, within the range of 20%-30% weight gain of the flavor-masking coating, the solubility of the flavor-masking particles in water does not show a significant trend with increasing coating weight gain. Within 15 minutes, the solubility is greater than 10% within the range of 20%-30% weight gain of the coating, and a significant flavor-masking effect cannot be achieved within the weight gain range.

[0300] Example 2

[0301] (1) Preparation of metronidazole drug core

[0302] Table 9

[0303]

[0304] According to the prescription shown in Table 9, the preparation method of metronidazole drug core is as follows:

[0305] Metronidazole, microcrystalline cellulose, and lactose were mixed and sieved, then added to a side-spray granulation fluidized bed reactor. The reactor was started, and granulation was performed using a 5% (w / w) hydroxypropyl methylcellulose solution. The inlet air temperature was 50-70℃, the fan frequency was 13Hz, and the atomization pressure was 1.5 bar. The material temperature was maintained at 35-45℃ during granulation. After granulation, atomization was stopped, and drying continued for 15-30 minutes, with the moisture content controlled to be less than 2.0%. The mixture was then sieved, and 50-80 mesh (180-270μm) particles were used for the next step of flavor-masking coating.

[0306] (2) Metronidazole drug core masking coating

[0307] The formula for the metronidazole drug core masking coating is shown in Table 10, where the mass ratio of Eudragit E100 to ethyl cellulose is 1:3, the weight gain of the masking coating is 25%, and the weight gain of the coating is calculated based on the mass of "Eudragit E100 and ethyl cellulose" and their mass ratio relative to the mass of the metronidazole drug core.

[0308] Table 10

[0309]

[0310] According to the prescription shown in Table 10, the preparation method of metronidazole drug core masking coating is as follows:

[0311] ① After mixing ethanol and water evenly, add Eudragit E100 and stir continuously until completely dissolved. Then add ethyl cellulose and stir continuously until completely dissolved.

[0312] ② The water-based anti-adhesive and plasticizer mixed emulsion PlasACRYL T20 is a premix of glyceryl monostearate, triethyl citrate and Tween-80 with a concentration of 20%. PlasACRYL T20, the premix of glyceryl monostearate, triethyl citrate and Tween-80, is added to the solution in ① and stirred continuously until it is evenly dispersed to obtain a coating solution.

[0313] ③ Add the metronidazole drug core to the Wuster fluidized bed, and use the coating solution to coat the drug core to mask the taste. During the coating process, control the material temperature at 25-35℃. After the coating is completed, stop atomization and continue drying for 15-30 minutes, and control the moisture content to be less than 2.0%.

[0314] Take an appropriate amount of the metronidazole masking granules obtained above and determine their dissolution and release according to the method of determination of dissolution and release (Chinese Pharmacopoeia (2020 edition, General Chapter 0931, Method II), with a rotation speed of 75 rpm, using pure water and pH 4.5 acetate buffer as media, with a media volume of 900 ml.

[0315] The dissolution results in pure water are shown in Table 11 below.

[0316] Table 11

[0317]

[0318] The dissolution results in pH 4.5 acetate buffer are shown in Table 12 below.

[0319] Table 12

[0320]

[0321] Example 3 Preparation of dry suspension

[0322] (1) Preparation of metronidazole drug core

[0323] Table 13

[0324]

[0325] According to the prescription shown in Table 13, the preparation method of metronidazole drug core is as follows:

[0326] Metronidazole was mixed with microcrystalline cellulose, lactose, and colloidal silica and sieved. The mixture was then added to a side-spray granulation fluidized bed reactor. Granulation was performed using a 6% (w / w) aqueous solution of hydroxypropyl methylcellulose. The inlet air temperature was 50-70℃, the fan frequency was 15-20Hz, and the atomization pressure was 1.5-1.8 bar. The material temperature was maintained at 35-45℃ during granulation. After granulation, atomization was stopped, and drying continued for 15-30 minutes, with the moisture content controlled to be less than 2.0%. The mixture was then sieved, and 40-80 mesh (180-380μm) particles were used for the next step of flavor-masking coating.

[0327] (2) Metronidazole drug core masking coating

[0328] The formula for the metronidazole drug core masking coating is shown in Table 14, where the mass ratio of Eudragit E100 to ethyl cellulose is 2:3, and the masking coating increases the weight by 30% and 35% respectively. The weight increase of the coating is calculated based on the mass of "Eudragit E100 and ethyl cellulose" and their mass ratio relative to the metronidazole drug core.

[0329] Table 14

[0330]

[0331] According to the prescription shown in Table 14, the preparation method of metronidazole drug core masking coating is as follows:

[0332] ① After mixing ethanol and water evenly, add Eudragit E100 and stir continuously until completely dissolved. Then add ethyl cellulose and stir continuously until completely dissolved.

[0333] ② Add PlasACRYL T20 to the solution in ① and stir continuously until it is evenly dispersed to obtain the coating solution.

[0334] ③ Add the metronidazole drug core to the Wuster fluidized bed, and use the coating solution to coat the drug core to mask the taste. During the coating process, control the material temperature at 25-35℃. After the coating is completed, stop atomization and continue drying for 15-30 minutes, and control the moisture content to be less than 2.0%.

[0335] Take an appropriate amount of the metronidazole masking granules obtained above and determine their dissolution and release according to the method of determination of dissolution and release (Chinese Pharmacopoeia (2020 edition, General Chapter 0931, Method II), with a rotation speed of 75 rpm, using pure water and pH 4.5 acetate buffer as media, with a media volume of 900 ml.

[0336] The dissolution results in pure water are shown in Table 15 below.

[0337] Table 15

[0338]

[0339] The dissolution results in pH 4.5 acetate buffer are shown in Table 16 below.

[0340] Table 16

[0341]

[0342] (3) Preparation of metronidazole suspension granules

[0343] Table 17

[0344]

[0345] The preparation method of metronidazole suspension granules according to the prescription shown in Table 17 (1000 dosage units of suspension granules) is as follows:

[0346] ① Add equal amounts of flavoring, coloring, colloidal silica and microcrystalline cellulose through a 60-mesh sieve and mix. Then mix with the remaining excipients and pass through a 40-mesh sieve.

[0347] ② Add the mixed auxiliary materials into the high-shear wet granulation machine, stir at 300 rpm and shear at 1000 rpm, and mix for 10 minutes.

[0348] ③ Atomize an appropriate amount of pure water and spray it into the container for wet granulation, granulation for 1-3 minutes.

[0349] ④ Add the wet granules to a fluidized bed or oven for drying until the moisture content is below 2.0%. Discharge the material and dry-size it using a 1.0mm sieve. After sizing, pass the granules through a 40-mesh sieve, remove the portion above the sieve, and take the granules below the sieve.

[0350] ⑤ Pack the metronidazole taste-masking granules and suspension-aiding granules into bags in a certain ratio (containing 200mg of metronidazole per bag) to obtain metronidazole dry suspension. Pour the dry suspension into a cup, add 10ml of warm water (30-50℃) to each bag, stir well, and the suspension-aiding granules will quickly disintegrate and disperse.

[0351] Take an appropriate amount of the metronidazole dry suspension granules obtained above and determine their dissolution and release according to the method of determination of dissolution and release (Chinese Pharmacopoeia (2020 edition, General Chapter 0931, Method II), with a rotation speed of 75 rpm and pure water and pH 4.5 acetate buffer as the medium, with a medium volume of 900 ml.

[0352] The dissolution results in pure water are shown in Table 18 below.

[0353] Table 18

[0354]

[0355] The dissolution results in pH 4.5 acetate buffer are shown in Table 19 below.

[0356] Table 19

[0357]

[0358] Example 4

[0359] Metronidazole drug cores were prepared according to the formulation in Example 3 (1). The drug cores were coated with the masking coating formulation in Table 20. The changes in dissolution were investigated when the coating weight gain was 25%, 35%, and 40%.

[0360] Table 20

[0361]

[0362] Take appropriate amounts of samples with different weight gains (all corresponding to a specification of 200 mg) and determine their dissolution and release according to the method of determination of dissolution and release (Chinese Pharmacopoeia (2020 edition, General Chapter 0931, Method II), with a rotation speed of 75 rpm and pure water as the medium, with a medium volume of 900 ml. The dissolution results are shown in Table 21 below.

[0363] Table 21

[0364]

[0365] Conclusion: Within the weight gain range of 25%-40% for the odor-masking coating, the solubility of the odor-masking particles in water gradually decreases with increasing coating weight, especially after 15 minutes. However, within 15 minutes, the solubility within the 25%-40% weight gain range is not higher than 10%, and a significant odor-masking effect can be achieved within this weight gain range.

[0366] Example 5

[0367] (1) Preparation of metronidazole drug core (API 80%, side spray granulation)

[0368] Table 22

[0369]

[0370] According to the prescription shown in Table 22, the preparation method of metronidazole drug core is as follows:

[0371] Metronidazole was mixed with microcrystalline cellulose and colloidal silica and sieved. The mixture was then added to a side-spray granulation fluidized bed reactor. Granulation was performed using a 6% hydroxypropyl methylcellulose aqueous solution. The inlet air temperature was 50-70℃, the fan frequency was 15-20Hz, and the atomization pressure was 1.5-1.8 bar. The material temperature was maintained at 35-45℃ during granulation. After granulation, atomization was stopped, and drying continued for 15-30 minutes, maintaining a moisture content of less than 2.0%. The mixture was then sieved, and 50-80 mesh (180-270μm) particles were used for the next step of flavor-masking coating.

[0372] (2) Metronidazole drug core masking coating

[0373] The formula for the metronidazole drug core masking coating is shown in Table 23, where the mass ratio of Eudragit E100 to ethyl cellulose is 2:3, the weight gain of the masking coating is 35%, and the weight gain of the coating is calculated based on the mass of "Eudragit E100 and ethyl cellulose" and their mass ratio relative to the mass of the metronidazole drug core.

[0374] Table 23

[0375]

[0376] According to the prescription shown in Table 23, the preparation method of metronidazole drug core masking coating is as follows:

[0377] ① After mixing ethanol and water evenly, add Eudragit E100 and stir continuously until completely dissolved. Then add ethyl cellulose and stir continuously until completely dissolved.

[0378] ② Add PlasACRYL T20 to the above solution and stir continuously until evenly dispersed to obtain the coating solution.

[0379] ③ Add the metronidazole drug core to the Wuster fluidized bed, and use the coating solution to mask the taste of the drug core. During the coating process, control the material temperature at 25-35℃. After the coating is completed, stop atomization and continue drying for 15-30 minutes until the moisture content drops to less than 2.0%. Then, stop the machine and remove the material.

[0380] Take an appropriate amount of the metronidazole dry suspension granules obtained above and determine their dissolution and release according to the method of determination of dissolution and release (Chinese Pharmacopoeia (2020 edition, General Chapter 0931, Method II), with a rotation speed of 75 rpm and pure water and pH 4.5 acetate buffer as the medium, with a medium volume of 900 ml.

[0381] The dissolution results in pure water are shown in Table 24 below.

[0382] Table 24

[0383]

[0384] The dissolution results in pH 4.5 acetate buffer are shown in Table 25 below.

[0385] Table 25

[0386]

[0387] Example 1

[0388] The metronidazole-masked dry suspension prepared in Example 3, along with control solutions (metronidazole aqueous solutions of different concentrations), was subjected to oral testing by 30 adult volunteers. The testing method was as follows: volunteers first tasted the control drug at different concentrations and scored it according to its bitterness level. Half an hour later, each volunteer poured one packet of metronidazole dry suspension into a cup, added 10 ml of warm water (35℃-45℃), and shook it to disperse and suspend it. Within 15 minutes, the volunteers tasted the suspension and evaluated its bitterness, gritty texture, and odor.

[0389] Table 26

[0390]

[0391] The above experiments show that metronidazole masking dry suspension has a good taste, completely masking the characteristic bitterness of metronidazole, without obvious gritty feeling or unpleasant odor, and is more easily accepted by pediatric patients.

[0392] Example 2

[0393] Method for checking the settling volume ratio:

[0394] The metronidazole dry suspension prepared in Example 3 was tested according to the sedimentation volume ratio requirements under General Chapter 0123 Oral Suspension in Part IV of the 2020 Chinese Pharmacopoeia. 30 bags of sample were added to 200ml of pure water to prepare a suspension. 50ml was measured using a stoppered graduated cylinder, sealed tightly, and shaken vigorously for 1 minute. The initial height H0 of the suspension was recorded. After standing for 3 hours, the final height H of the suspension was recorded. The sedimentation volume ratio = H / H0, and the sedimentation volume ratio should not be less than 0.90.

[0395] Table 27

[0396]

[0397] The above experiments show that the sedimentation volume ratio of metronidazole masking dry suspension is not less than 0.90, indicating good stability.

Claims

1. A metronidazole granule, characterized in that, The metronidazole granules comprise a drug core and a coating layer, wherein the coating layer covers the outer surface of the drug core; The drug core includes metronidazole; The coating layer includes a film-forming material, which includes gastrosoluble acrylic resin and ethyl cellulose.

2. The metronidazole granules as described in claim 1, characterized in that, The drug core comprises the following components by weight percentage: Metronidazole 50-90%; Diluent 10-30%; Flow aid 0-5%; Adhesive 1-15%.

3. The metronidazole granules as described in claim 2, characterized in that, The drug core satisfies one or more of the following conditions: The content of metronidazole is 60-80%, and may be 70-80%, for example 70%, 70.4% or 80%, where the percentage is the mass percentage in the drug core; The diluent includes microcrystalline cellulose and / or lactose; The diluent content is 10-25%, for example 13.0%, 22.5% or 24%, the percentage being the mass percentage in the drug core; The flow aid is selected from silica, such as colloidal silica; The content of the gliding agent is 0.5-1.0%, for example 0.8% or 1.0%, where the percentage is the mass percentage in the drug core; The adhesive comprises one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyvinylpyrrolidone solution; the adhesive may be selected from hydroxypropyl methylcellulose, the viscosity of which may be 5-50 mPa·s, for example 5-30 mPa·s, or even 15 mPa·s; and The adhesive content is 5-15%, for example 5.0%, 6.0% or 6.2%, which is the mass percentage in the drug core.

4. The metronidazole granules as described in claim 2, characterized in that, The drug core comprises the following components: Metronidazole 60-80%; Diluent 10-25%; the diluent is selected from microcrystalline cellulose, or microcrystalline cellulose and lactose; Flow aid 0-5%; 5-15% adhesive; the adhesive is selected from hydroxypropyl methylcellulose; Preferably, the drug core comprises the following components: Metronidazole 70.4% Hydroxypropyl methylcellulose 6.2% Microcrystalline cellulose 5.6% Lactose 16.9% Colloidal silica 0.8%; Preferably, the drug core comprises the following components: Metronidazole 70% 5% hydroxypropyl methylcellulose 16% microcrystalline cellulose 8% lactose 1% colloidal silica; Preferably, the drug core comprises the following components: Metronidazole 70% 5% hydroxypropyl methylcellulose Microcrystalline cellulose 12.5% Lactose 12.5%; Preferably, the drug core comprises the following components: Metronidazole 70% 5% hydroxypropyl methylcellulose 16% microcrystalline cellulose 8% lactose 1% colloidal silica; Preferably, the drug core comprises the following components: Metronidazole 80% Hydroxypropyl methylcellulose 6% Microcrystalline cellulose 13% 1% colloidal silica.

5. The metronidazole granules according to any one of claims 1-4, characterized in that, The metronidazole granules meet one or more of the following conditions: ⑧ The particle size of the drug core is 180-500 μm, for example 180-270 μm or 180-380 μm; ⑨ The bulk density of the drug core is 0.2-0.5 g / mL, for example 0.28 g / mL or 0.41 g / mL; ⑩ The gastrointestinal soluble acrylic resin is selected from a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate, wherein the molar ratio of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate can be 1:2:1; the gastrointestinal soluble acrylic resin can be selected from one or more of Eudragit E100, Eudragit EPO, and Eudragit L100, preferably Eudragit E100; The ethyl cellulose has a labeled viscosity of 4-100 mPa·s, for example, 4 mPa·s, 7 mPa·s, 10 mPa·s, 20 mPa·s, 45 mPa·s or 100 mPa·s; The mass ratio of the gastrointestinal soluble acrylic resin to the ethyl cellulose is 1:(1-3), for example, 1:1, 1:3 or 2:3; The mass ratio of the film-forming material to the drug core in the coating layer is ≥0.20:1, and can be (0.20-0.50):1, for example (0.20-0.40):1, or (0.25-0.40):1, or even 0.25:1, 0.30:1, 0.35:1, or 0.40:

1. The coating layer also includes surfactants and / or anti-sticking agents.

6. The metronidazole granules as described in claim 5, characterized in that, The metronidazole granules meet one or more of the following conditions: The content of the anti-adhesive is 1-25%, for example 1.38%, 1.59%, 8.9%, 11.5%, 13.0%, 9.1%, 18.8% or 20.6%; the percentage refers to the mass percentage in the metronidazole granules; The anti-adhesion agent is one or more of glyceryl monostearate, PlasACRYL T20, magnesium stearate, talc, and micronized silica gel, such as one or more of glyceryl monostearate, PlasACRYL T20, and talc; the anti-adhesion agent can be selected from glyceryl monostearate or PlasACRYL T20. The surfactant is Tween-80; The surfactant content is 0.1-1%, for example 0.39% or 0.72%; the percentage refers to the mass percentage of the metronidazole granules.

7. The metronidazole granules as described in claim 6, characterized in that, The anti-adhesion agent is selected from glyceryl monostearate, and the content of the anti-adhesion agent is 0.1-5%, for example 1.38% or 1.59%; the percentage refers to the mass percentage in the metronidazole granules; Alternatively, the anti-adhesion agent is PlasACRYL T20, and the content of the anti-adhesion agent is 1-25%, for example 8.9%, 11.5%, 13.0%, 9.1%, 18.8% or 20.6%; the percentage refers to the mass percentage in the metronidazole granules; Preferably, the metronidazole granules comprise: (1) Drug core: The drug core includes metronidazole powder, diluent, flow aid, and binder; In the obtained drug core, the content of metronidazole powder can be ≥70%, for example, 80%; (2) Coating layer: The coating layer covers the surface of the drug core; The coating layer includes gastrosoluble acrylic resin and ethyl cellulose; The mass ratio of the gastrointestinal soluble acrylic resin to the ethyl cellulose is 1:(1-3). Preferably, the coating layer further includes an anti-adhesive agent and / or the surfactant Tween 80.

8. A method for preparing metronidazole granules as described in any one of claims 1-7, characterized in that, It includes the following steps: (1) The raw materials and solvent in the coating layer are mixed to obtain a coating solution; (2) The coating solution is coated onto the outer surface of the drug core and dried to obtain the metronidazole granules; Preferably, the method for preparing the metronidazole granules includes the following steps: (1) After mixing the metronidazole, the diluent, the binder and the flow aid to obtain a material, the material is granulated to obtain the drug core; (2) The raw materials and solvent in the coating layer are mixed to obtain a coating solution; (3) The coating solution is coated on the outer surface of the drug core and dried to obtain the metronidazole granules.

9. A metronidazole preparation, characterized in that, It contains metronidazole granules as described in any one of claims 1-7.

10. The metronidazole preparation according to claim 9, characterized in that, In the metronidazole dry suspension, the mass content of the metronidazole particles is 40-50%, for example, 45.0%; And / or, the metronidazole formulation further includes excipients; the excipients include one or more of flavoring agents, suspending agents, diluents, disintegrants, binders, flow aids, surfactants, and colorants; In the metronidazole dry suspension, the flavoring agent may be selected from one or more of sucralose, cyclamate, aspartame, xylitol, sorbitol and orange flavoring; In the metronidazole dry suspension, the flavoring agent may have a mass content of 0%-5%, for example 0.05%-0.5%, or even 0.06%; In the metronidazole dry suspension, the suspending agent may be selected from one or more of microcrystalline cellulose, xanthan gum, sodium carboxymethyl cellulose, and sodium carboxymethyl cellulose. In the metronidazole dry suspension, the mass content of the suspending agent can be 1%-10%, for example 1.27%; In the metronidazole dry suspension, the diluent may be selected from sucrose and / or microcrystalline cellulose; In the metronidazole dry suspension, the mass content of the diluent can be 50%-80%, for example 50.63%; In the metronidazole dry suspension, the disintegrant may be selected from croscarmellose sodium and / or croscarmellose. In the metronidazole dry suspension, the mass content of the disintegrant can be 0.5%-6%, for example 1.27%; In the metronidazole dry suspension, the binder may be selected from hydroxypropyl methylcellulose; In the metronidazole dry suspension, the mass content of the binder can be 0.5%-5%, for example 0.51%; In the metronidazole dry suspension, the flow aid may be selected from one or more of silica, polyethylene glycol 6000, and magnesium stearate, such as colloidal silica; In the metronidazole dry suspension, the mass content of the glidant can be 0.5%-5%, for example 1.27%; In the metronidazole dry suspension, the surfactant may be selected from Tween-80; In the metronidazole dry suspension, the colorant may be selected from lemon yellow pigment and / or β-carotene; In the metronidazole dry suspension, the colorant may have a mass content of 0.05%-0.5%, for example, 0.06%; Preferably, the metronidazole dry suspension comprises the following components: 355 parts of the metronidazole granules 300 parts sucrose 4 parts hydroxypropyl methylcellulose 100 parts of microcrystalline cellulose 10 parts xanthan gum 10 parts of croscarmellose sodium cellulose 10 parts of colloidal silica 0.5 parts orange flavoring 0.5 parts lemon yellow pigment.

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