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 granule A comprises an active ingredient inner core and a first coating layer coating the outer surface of the active ingredient inner core; the active ingredient inner core comprises metronidazole particles; the D90 particle size range of the metronidazole particles is 50 [mu] m to 500 [mu] m; the first coating layer comprises a first film-forming material, and the film-forming material comprises gastric-soluble acrylic resin. According to the metronidazole granules and the preparation containing the metronidazole granules, provided by the invention, metronidazole can be dissolved out slowly or even cannot be dissolved out in water or saliva, but can be dissolved out quickly in gastric juice, so that a taste masking effect is achieved, and meanwhile, the metronidazole granules can be dissolved out and absorbed quickly in the stomach after oral administration. In addition, the settlement volume ratio of the metronidazole dry suspension is not lower than 0.90, and the metronidazole dry suspension is good in stability; moreover, the metronidazole tablet is good in taste, completely shields the special bitter taste of metronidazole, does not have obvious sand feeling and bad smell, and is easier to accept by children patients.

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 tablets and capsules have an unpleasant taste, causing nausea and vomiting after administration, making them difficult for patients to accept, resulting in poor compliance and affecting continued medication and clinical efficacy. Furthermore, domestically available tablets and capsules not only have a bitter taste but also present swallowing difficulties for children, failing to meet clinical needs. Therefore, there is an urgent need to develop a dosage form with good taste masking properties suitable for oral administration in children, addressing the issue 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 excipients to interfere with taste buds. While the method is simple, its effectiveness 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 the use of gastric-soluble materials to prepare taste-masking agents, such as CN1273133C (berberine hydrochloride) and CN103169669A (agomelatine).

[0007] However, CN103169669A discloses a method of first coating a prescribed amount of agomelatine onto a blank pellet core to prepare a drug-containing pellet core, and then coating the drug-containing pellet core with a taste-masking layer to prepare a coated micro-pellet with a taste-masking effect. It is evident that this involves drug loading onto a blank pellet core. Since metronidazole preparations have a high drug content and metronidazole is only slightly soluble in water and ethanol, it cannot be directly replaced with metronidazole.

[0008] Chinese patent C1273133C discloses a preparation process for a berberine hydrochloride taste-masking formulation. The process involves first granulating and drying berberine hydrochloride using a top-spray fluidized bed coating material, followed by a rotary fluidized bed taste-masking coating. The top-spray granulation produced by this process results in relatively loose particles, making it easy for the drug-containing particles to detach during taste-masking coating. Furthermore, the simultaneous use of taste-masking coating liquid for granulation and coating leads to a large amount of taste-masking coating material. This does not meet clinical needs for metronidazole formulations used in children, as the minimum dosage for children is 50 mg. Preparing a dry suspension of metronidazole for children using this patented technology involves a large amount of excipients, posing a risk to the safety of children's medication.

[0009] Therefore, how to provide a metronidazole formulation with good taste masking effect and high safety based on the properties of metronidazole is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0010] 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.

[0011] This invention provides a metronidazole particle A, which includes an active ingredient core and a first coating layer covering the outer surface of the active ingredient core;

[0012] The active ingredient core includes metronidazole particles; the D90 particle size of the metronidazole particles ranges from 50 μm to 500 μm.

[0013] The first coating layer includes a first film-forming material, which includes a gastrosoluble acrylic resin.

[0014] In this invention, the chemical formula of metronidazole is C6H9N3O3, and the CAS number is 443-48-1.

[0015] In some embodiments of the present invention, the D90 particle size of the metronidazole particles ranges from 150 μm to 350 μm, for example, 346 μm.

[0016] In this invention, D90 refers to the particle size value corresponding to the cumulative distribution percentage from smallest to largest reaching 90% in the particle size distribution.

[0017] In some embodiments of the present invention, the D50 particle size of the metronidazole particles ranges from 10 μm to 300 μm, for example 10 μm to 200 μm, or 10 μm to 150 μm, or even 113 μm.

[0018] In this invention, D50 refers to the particle size value corresponding to the cumulative distribution percentage from smallest to largest reaching 50% in the particle size distribution.

[0019] In some embodiments of the present invention, the D10 particle size of the metronidazole particles ranges from 1 μm to 50 μm, for example, 1 μm to 20 μm, and also for example, 16 μm.

[0020] In this invention, D10 refers to the particle size value corresponding to the cumulative percentage of particles from smallest to largest reaching 10% in the particle size distribution.

[0021] In some embodiments of the present invention, the particle size distribution of the metronidazole particles is D90: 346 μm; D50: 113 μm; D10: 16 μm.

[0022] In some embodiments of the present invention, the crystal shape (crystal habit / crystal habit) of the metronidazole granules is columnar, layered, or cubic. The crystal shape of the metronidazole granules affects the coating effect. Generally speaking, columnar, layered, or cubic crystal habits are suitable for coating, while rod-shaped, needle-shaped, or plate-shaped crystals are easily broken into fine powder and are not suitable for coating.

[0023] In some embodiments of the present invention, the mass ratio of the active ingredient core to the first film-forming material in the first coating layer is 1:(0.1-0.5), for example 1:(0.2-0.53), and also for example 1:0.2, 1:0.25, 1:0.3.

[0024] 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.

[0025] In this invention, the gastric-soluble acrylic resin generally refers to a pH-dependent acrylic resin that dissolves and releases the drug at a specific pH (e.g., pH < 5), such as a copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate (the molar ratio of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate can be 1:2:1), or a copolymer of methyl methacrylate and diethylaminoethyl methacrylate (the molar ratio of methyl methacrylate and diethylaminoethyl methacrylate can be 7:3), etc.

[0026] In some embodiments of the present invention, the gastrosoluble acrylic resin is selected from one or more of Eudragit E100, Eudragit EPO, and Kollicoat Smartseal 100P, preferably Eudragit E100.

[0027] Eudragit E100 is a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (the molar ratio of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate can be 1:2:1).

[0028] In some embodiments of the present invention, Eudragit E100 was purchased from Evonik Operations GmbH.

[0029] In some embodiments of the present invention, the first coating layer further includes a surfactant and / or an anti-sticking agent.

[0030] In some embodiments of the present invention, the surfactant is Tween-80.

[0031] In some embodiments of the present invention, the content of the surfactant is 1-10%, for example 2.6%; the percentage refers to the mass percentage in the first coating layer.

[0032] In some embodiments of the present invention, the anti-adhesion agent is one or more of the following: glyceryl monostearate, water-based anti-adhesion and plasticizer mixed emulsion PlasACRYL T20, magnesium stearate, talc, and micronized silica gel, such as one or more of glyceryl monostearate, water-based anti-adhesion and plasticizer mixed emulsion PlasACRYL T20, and talc.

[0033] In some embodiments of the present invention, the aqueous anti-adhesive and plasticizer mixed emulsion PlasACRYL T20 is a mixed emulsion of glyceryl monostearate, triethyl citrate, and Tween-80, with a solid content of up to 20%. In some embodiments of the present invention, the aqueous anti-adhesive and plasticizer mixed emulsion PlasACRYL T20 is purchased from Emerson Resources Inc.

[0034] In this invention, the main component of talc is hydrated magnesium silicate, with the molecular formula Mg3(Si4O3). 10 (OH)2. In some embodiments of the present invention, the talc powder was purchased from Imerys Talc Italy SpA.

[0035] In some embodiments of the present invention, the content of the anti-adhesive is 1-40%, for example 6.4%, 8.7% or 33.3%; the percentage refers to the mass percentage in the first coating layer.

[0036] In some embodiments of the present invention, the anti-adhesive is selected from PlasACRYL T20, a mixed emulsion of water-based anti-adhesive and plasticizer, and the content of the anti-adhesive is 1-10%, for example 8.7%, where the percentage refers to the mass percentage in the first coating layer.

[0037] In some embodiments of the present invention, the anti-adhesion agent is selected from talc powder, and the content of the anti-adhesion agent is 20-40%, for example 33.3%, where the percentage refers to the mass percentage in the first coating layer.

[0038] 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 1-10%, for example 6.4%; the percentage refers to the mass percentage in the first coating layer.

[0039] In some embodiments of the present invention, the first coating layer does not include a plasticizer. A plasticizer is a small molecule substance that, when added to a polymer (film-forming material), penetrates into the polymer chains, reducing intermolecular or intramolecular forces and making the polymer network structure looser. Adding this amount of plasticizer facilitates film formation.

[0040] In this invention, the film-forming material includes a gastrosoluble acrylic resin, such as Eudragit E100, which has good film-forming properties and generally does not require the use of additional plasticizers.

[0041] In one embodiment of the present invention, the metronidazole granules A comprise:

[0042] Metronidazole granules: 200mg

[0043] First coating layer: Eudragit E100: 40mg-80mg, anti-adhesive: 0-8mg, surfactant: 0-0.1mg.

[0044] In one embodiment of the present invention, the metronidazole granules A comprise:

[0045] Metronidazole granules: 200mg

[0046] First coating layer: Eudragit E100: 60mg.

[0047] The present invention also provides metronidazole granules B, which include an active ingredient core, a second coating layer covering the outer surface of the active ingredient core, and a first coating layer covering the outer surface of the second coating layer;

[0048] The active ingredient core includes metronidazole granules; the metronidazole granules have a D... 90 The particle size range is 50μm-500μm;

[0049] The first coating layer includes a first film-forming material, which includes a gastrosoluble acrylic resin;

[0050] The second coating layer includes a second film-forming material.

[0051] In some embodiments of the present invention, the metronidazole granules may be as described above.

[0052] In some embodiments of the present invention, the first coating layer may be as described above.

[0053] In some embodiments of the present invention, the mass ratio of the active ingredient core coating the second coating layer to the first film-forming material in the first coating layer is 1:(0.1-0.5), for example 1:(0.2-0.3), and also for example 1:0.2, 1:0.25, 1:0.3.

[0054] In some embodiments of the present invention, the second film-forming material includes hydroxypropyl methylcellulose and polyethylene glycol.

[0055] In some embodiments of the present invention, the viscosity of the hydroxypropyl methylcellulose is less than 15 mPa·s, for example less than 10 mPa·s.

[0056] In some embodiments of the present invention, the hydroxypropyl methylcellulose was purchased from Shanghai Calcare Coating Technology Co., Ltd.

[0057] In some embodiments of the present invention, the hydroxypropyl methylcellulose is designated as E5.

[0058] In some embodiments of the present invention, the viscosity of the hydroxypropyl methylcellulose is 5 mPa·s.

[0059] In this invention, the viscosity of hydroxypropyl methylcellulose is determined as follows: a 2.0% (g / g) solution is prepared by adding water at 90°C, and the solution is stirred 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. The solution is then cooled in an ice bath, and stirring is continued during the cooling process to remove air bubbles. If necessary, the weight is adjusted with cold water to remove all foam. At 20°C ± 0.1°C, the kinematic viscosity (v) of the solution is determined using an Ubbelohde viscometer with an appropriate inner diameter (Chinese Pharmacopoeia 2020 Edition, General Chapter 0633, Method I) with a flow time of not less than 200 seconds. The density (ρ) of the solution is also determined under the same conditions, and the dynamic viscosity is calculated as ρv.

[0060] In some embodiments of the present invention, the degree of polymerization of the polyethylene glycol is 4000-8000, for example 6000.

[0061] In some embodiments of the present invention, the mass ratio of the active ingredient core to the second film-forming material in the second coating layer is 1:(0.01-0.05), for example 1:0.03.

[0062] In some embodiments of the present invention, the mass ratio of hydroxypropyl methylcellulose to polyethylene glycol in the second coating layer is (1-10):1, for example 5:1.

[0063] In some embodiments of the present invention, the second coating layer further includes a surfactant and / or an anti-sticking agent.

[0064] In some embodiments of the present invention, the surfactant is Tween-80.

[0065] In some embodiments of the present invention, the content of the surfactant is 1-10%, for example 3%; the percentage refers to the mass percentage in the second coating layer.

[0066] In some embodiments of the present invention, the anti-adhesion agent is one or more of the following: glyceryl monostearate, water-based anti-adhesion and plasticizer mixed emulsion PlasACRYL T20, magnesium stearate, talc, and micronized silica gel, such as one or more of glyceryl monostearate, water-based anti-adhesion and plasticizer mixed emulsion PlasACRYL T20, and talc.

[0067] In some embodiments of the present invention, the content of the anti-adhesive is 1-50%, for example 7.4% or 40%; the percentage refers to the mass percentage in the second coating layer.

[0068] In some embodiments of the present invention, the anti-adhesion agent is selected from talc powder, and the content of the anti-adhesion agent is 20-50%, for example 40%, where the percentage refers to the mass percentage in the second coating layer.

[0069] 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 1-10%, for example 7.4%; the percentage refers to the mass percentage in the second coating layer.

[0070] In some embodiments of the present invention, the second coating layer includes hydroxypropyl methylcellulose, polyethylene glycol and talc.

[0071] In some embodiments of the present invention, the second coating layer includes hydroxypropyl methylcellulose, polyethylene glycol, glyceryl monostearate, and Tween-80.

[0072] In one embodiment of the present invention, the metronidazole granules B comprise:

[0073] (1) Particle size range D 90 Metronidazole particles ranging from 150μm to 350μm;

[0074] (2) A second coating layer (isolation coating layer) covering the outer surface of the metronidazole particles, the second coating layer comprising hydroxypropyl methylcellulose, polyethylene glycol 6000, and talc;

[0075] (3) A first coating layer (flavor-masking coating layer) covering the outer surface of the second coating layer, the first coating layer comprising a gastrosoluble butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate copolymer, wherein the molar ratio of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate may be 1:2:1, for example Eudragit E100.

[0076] In one embodiment of the present invention, the metronidazole granules B comprise:

[0077] (1) Metronidazole granules coated with the second coating layer: 200-210mg

[0078] First coating layer: Eudragit E100: 40-63mg, anti-adhesive: 0-31.5mg, surfactant: 0-1.4mg;

[0079] (2) The metronidazole particles coated with the second coating layer include:

[0080] Metronidazole granules: 200mg

[0081] The second coating layer consists of: hydroxypropyl methylcellulose: 5 mg, polyethylene glycol 6000: 1 mg, and talc: 4 mg.

[0082] In one embodiment of the present invention, the metronidazole granules B comprise:

[0083] (1) Metronidazole granules coated with the second coating layer: 200-210mg

[0084] First coating layer: Eudragit E100: 40-63mg, anti-adhesive: 0-31.5mg, surfactant: 0-1.4mg;

[0085] (2) The metronidazole particles coated with the second coating layer include:

[0086] Metronidazole granules: 200mg

[0087] The second coating layer consists of: hydroxypropyl methylcellulose: 5 mg, polyethylene glycol 6000: 1 mg, glyceryl monostearate: 0.5 mg, and Tween-80: 0.2 mg.

[0088] In one embodiment of the present invention, the metronidazole granules B comprise:

[0089] (1) Metronidazole granules coated with the second coating layer: 210mg

[0090] First coating layer: Eudragit E100: 42mg;

[0091] (2) The metronidazole particles coated with the second coating layer include:

[0092] Metronidazole granules: 200mg

[0093] The second coating layer consists of: hydroxypropyl methylcellulose: 5 mg, polyethylene glycol 6000: 1 mg, and talc: 4 mg.

[0094] In one embodiment of the present invention, the metronidazole granules B comprise:

[0095] (1) Metronidazole granules coated with the second coating layer: 210mg

[0096] First coating layer: Eudragit E100: 63 mg, talc: 31.5 mg;

[0097] (2) The metronidazole particles coated with the second coating layer include:

[0098] Metronidazole granules: 200mg

[0099] The second coating layer consists of: hydroxypropyl methylcellulose: 5 mg, polyethylene glycol 6000: 1 mg, and talc: 4 mg.

[0100] In one embodiment of the present invention, the metronidazole granules B comprise:

[0101] (1) Metronidazole granules coated with the second coating layer: 210mg

[0102] First coating layer: Eudragit E100: 63 mg, PlasACRYL T20: 6 mg;

[0103] (2) The metronidazole particles coated with the second coating layer include:

[0104] Metronidazole granules: 200mg

[0105] The second coating layer consists of: hydroxypropyl methylcellulose: 5 mg, polyethylene glycol 6000: 1 mg, and talc: 4 mg.

[0106] In one embodiment of the present invention, the metronidazole granules B comprise:

[0107] (1) Metronidazole granules coated with the second coating layer: 200mg

[0108] First coating layer: Eudragit E100: 50 mg, glyceryl monostearate: 3.5 mg, Tween-80: 1.4 mg;

[0109] (2) The metronidazole particles coated with the second coating layer include:

[0110] Metronidazole granules: 200mg

[0111] The second coating layer consists of: hydroxypropyl methylcellulose: 5 mg, polyethylene glycol 6000: 1 mg, glyceryl monostearate: 0.5 mg, and Tween-80: 0.2 mg.

[0112] The present invention also provides a method for preparing the metronidazole granules A, which includes the following steps:

[0113] (1) The raw material in the first coating layer and the first solvent are mixed to obtain the first coating solution;

[0114] (2) The first coating solution is coated onto the core of the active ingredient and dried to obtain the metronidazole granules A.

[0115] The present invention also provides a method for preparing the metronidazole granules B, which includes the following steps:

[0116] S1: Mix the raw material and the second solvent in the second coating layer to obtain the second coating solution;

[0117] S2: The second coating solution is coated onto the active ingredient core, and then dried to obtain active ingredient core A;

[0118] S3: Mix the raw material in the first coating layer with the first solvent to obtain the first coating solution;

[0119] S4: Coat the active ingredient core A with the first coating solution and dry to obtain the metronidazole granules B.

[0120] In this invention, the first solvent may be a conventional solvent in the art that can at least dissolve gastric-soluble acrylic resins, such as ethanol and / or water.

[0121] In some embodiments of the present invention, the first solvent is an aqueous ethanol solution. The mass concentration of ethanol in the aqueous ethanol solution may be 50-70%, for example 60% or 63%.

[0122] In some embodiments of the present invention, when the raw material of the first coating layer includes a first film-forming material, and further includes the surfactant and / or the anti-adhesion agent, the preparation method of the first coating solution includes the following steps;

[0123] The surfactant and / or the anti-adhesion agent are dissolved or dispersed in a portion of a first solvent (e.g., an aqueous solution of water or ethanol), and then subjected to high-speed shear homogenization or suspension treatment to obtain a mixture A1;

[0124] The first film-forming material is dissolved in the remaining portion of the first solvent to obtain mixture A2;

[0125] Mix the mixture A1 and the mixture A2 to obtain the first coating solution.

[0126] In the preparation of the mixture A1, the heating or non-heating conditions can be selected according to the solubility of the added raw materials.

[0127] For example, when the raw material of the first coating layer includes a first film-forming material, and also includes the anti-adhesion agent and the surfactant:

[0128] The first solvent is heated to 70-80°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.

[0129] The high-speed shearing and homogenization time can be a conventional time in the art, such as 30 minutes.

[0130] In some embodiments of the present invention, the mixture A2 is added to the mixture A1.

[0131] In some embodiments of the present invention, the mixture A1 is added to the mixture A2.

[0132] In some embodiments of the present invention, when the raw material of the first coating layer includes a first film-forming material, and further includes the surfactant and / or the anti-adhesion agent, the preparation method of the first coating solution includes the following steps;

[0133] The first film-forming material is dissolved in a first solvent to obtain mixture A;

[0134] The surfactant and / or the anti-adhesion agent are dissolved in the mixture A to obtain the first coating solution.

[0135] In this invention, the process by which the first coating solution and / or the second coating solution coats the core of the active ingredient can be a conventional process in the art.

[0136] In some embodiments of the present invention, the process of coating the first coating solution onto the core of the active ingredient is fluidized bed bottom spray coating.

[0137] In some embodiments of the present invention, the air intake volume is 25-50 m³ / h during the coating process of the first coating solution.

[0138] In some embodiments of the present invention, the air inlet temperature is 35-40°C during the coating process of the first coating solution.

[0139] In some embodiments of the present invention, during the coating process of the first coating solution, the atomization pressure is 1-3 bar, for example 2 bar.

[0140] In some embodiments of the present invention, the material temperature is maintained at 25-30°C during the coating process of the first coating solution.

[0141] In some embodiments of the present invention, the drying endpoint is when the moisture content drops to below 2.0%, where the percentage refers to the mass percentage of the metronidazole granules A or B.

[0142] In this invention, the second solvent can be a solvent conventional in the art capable of dissolving the raw material of the second coating layer. For example, when the second coating layer includes hydroxypropyl methylcellulose and polyethylene glycol, the second solvent includes ethanol and / or water.

[0143] In some embodiments of the present invention, the second solvent comprises ethanol and water. The mass ratio of the ethanol to the water may be (1.0-5.0):1, for example, 2.8:1.

[0144] In some embodiments of the present invention, when the raw material of the second coating layer includes a second film-forming material, and further includes a surfactant and / or an anti-adhesion agent, the preparation method of the second coating solution includes the following steps;

[0145] The surfactant and / or the anti-adhesion agent are dissolved in a portion of a second solvent (e.g., an aqueous solution of water or ethanol) and homogenized by high-speed shearing to obtain mixture B1;

[0146] The second film-forming material is dissolved in the remaining portion of the second solvent (e.g., ethanol, water, or an aqueous solution of ethanol) to obtain mixture B2;

[0147] Mix the mixture B1 and the mixture B2 to obtain the second coating solution.

[0148] In the preparation of the mixture B1, the heating or non-heating conditions can be selected according to the solubility of the added raw materials.

[0149] For example, when the raw material of the second coating layer includes a film-forming material, and also includes an anti-adhesive agent and a surfactant:

[0150] The second solvent is heated to 70-80°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.

[0151] The high-speed shearing and homogenization time can be a conventional time in the art, such as 30 minutes.

[0152] In the preparation of the mixture B2, the polyethylene glycol can be dissolved in the remaining portion of the second solvent first, and then the hydroxypropyl methylcellulose can be added.

[0153] In some embodiments of the present invention, the mixture B1 is added to the mixture B2.

[0154] In some embodiments of the present invention, the mixture B2 is added to the mixture B1.

[0155] In some embodiments of the present invention, the process of coating the second coating solution onto the core of the active ingredient is fluidized bed bottom spray coating.

[0156] In some embodiments of the present invention, the air intake volume is 25-50 m³ / h during the second coating solution coating process.

[0157] In some embodiments of the present invention, the air inlet temperature is 45-70°C during the second coating solution coating process.

[0158] In some embodiments of the present invention, the atomization pressure is 1.5-2 bar during the second coating solution coating process.

[0159] In some embodiments of the present invention, the material temperature is maintained at 35-45°C during the coating process of the second coating solution.

[0160] In some embodiments of the present invention, during the coating process of the second coating solution, after the coating weight gain reaches 1-10% (e.g., 3% or 5%), fluidized drying is performed.

[0161] The fluidized drying time can be 10-30 minutes.

[0162] In some embodiments of the present invention, the active ingredient kernel A is sieved (e.g., sieved through a 40-mesh sieve) before being coated with the first coating solution.

[0163] The present invention also provides a metronidazole preparation comprising the metronidazole granules A or B.

[0164] In some embodiments of the present invention, the metronidazole preparation is an oral metronidazole dosage form.

[0165] In some embodiments of the present invention, the metronidazole oral dosage forms include dry suspensions, dispersible tablets, and chewable tablets.

[0166] In some embodiments of the present invention, the metronidazole dry suspension comprises metronidazole granules A or B, and conventional excipients. The excipients may include one or more of flavoring agents, suspending agents, fillers, disintegrants, flow aids, and binders.

[0167] In some embodiments of the present invention, the flavoring agent is selected from one or more of sucralose, cyclamate, aspartame, xylitol and sorbitol.

[0168] In some embodiments of the present invention, the content of the flavoring agent is 0%-1%, for example 0.5%, 0.68% or 0.69%, where the percentage refers to the mass percentage in the metronidazole dry suspension.

[0169] In some embodiments of the present invention, the suspending agent is selected from xanthan gum and / or colloidal microcrystalline cellulose.

[0170] In some embodiments of the present invention, xanthan gum was purchased from CP Kolco US, Inc., model XANTURAL 75.

[0171] In some embodiments of the present invention, the colloidal microcrystalline cellulose was purchased from Mingtai Chemical Co., Ltd., model C11.

[0172] In some embodiments of the present invention, the content of the suspending agent is 1%-15%, for example 1.0%, 1.9%, 4.1%, 4.2%, 4.9%, 6.8%, 10.1% or 11.1%, where the percentage refers to the mass percentage in the metronidazole dry suspension.

[0173] In some embodiments of the present invention, the filler is selected from sucrose and / or microcrystalline cellulose.

[0174] In some embodiments of the present invention, the microcrystalline cellulose was purchased from JRS, model Vivapur 101.

[0175] In some embodiments of the present invention, the content of the filler is 50-70%, for example 60.6%, 61.2%, 55.5% or 54.4%, where the percentage refers to the mass percentage in the metronidazole dry suspension.

[0176] In some embodiments of the present invention, the disintegrant is selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, and croscarmellose, for example, croscarmellose sodium.

[0177] In some embodiments of the present invention, croscarmellose sodium carboxymethyl cellulose was purchased from DFE Pharma GmbH & Co. KG.

[0178] In some embodiments of the present invention, the content of the disintegrant is 0.9-4%, for example 1.0%, 0.97%, 1.36% or 1.39%, where the percentage refers to the mass percentage in the metronidazole dry suspension.

[0179] In some embodiments of the present invention, the adhesive is selected from one or more of hydroxypropyl methylcellulose, povidone and hydroxypropyl cellulose, such as hydroxypropyl methylcellulose.

[0180] In some embodiments of the present invention, the content of the adhesive is 0.1-2%, for example 0.3%, 0.4%, 0.5% or 0.8%, where the percentage refers to the mass percentage of the metronidazole dry suspension.

[0181] In some embodiments of the present invention, the flow aid is selected from silica (e.g., colloidal silica) and / or magnesium stearate.

[0182] In some embodiments of the present invention, the colloidal silica was purchased from Evonik Specialty Chemicals (Shanghai) Co., Ltd., model AEROSIL 200 Pharma.

[0183] In some embodiments of the present invention, the content of the glidant is 0.9%-4%, for example 1% or 1.4%, where the percentage refers to the mass percentage in the metronidazole dry suspension.

[0184] In some embodiments of the present invention, the metronidazole dry suspension comprises the following components:

[0185] 252-304.5 parts of the metronidazole granules A or B.

[0186] 300-400 parts sucrose

[0187] 0-5 parts of sucralose

[0188] 10-30 parts xanthan gum

[0189] 0-100 parts of colloidal microcrystalline cellulose

[0190] 100-200 parts of microcrystalline cellulose

[0191] 3-6 parts of hydroxypropyl methylcellulose

[0192] 10 parts of croscarmellose sodium

[0193] 10 parts of colloidal silica.

[0194] In some embodiments of the present invention, the metronidazole dry suspension comprises the following components:

[0195] 252 parts of the metronidazole granules A or B

[0196] 400 parts sucrose

[0197] 5 parts sucralose

[0198] 10 parts xanthan gum

[0199] 100 parts of colloidal microcrystalline cellulose

[0200] 200 parts of microcrystalline cellulose

[0201] 3 parts hydroxypropyl methylcellulose

[0202] 10 parts of croscarmellose sodium

[0203] 10 parts of colloidal silica.

[0204] In some embodiments of the present invention, the metronidazole dry suspension comprises the following components:

[0205] 304.5 parts of the metronidazole granules A or B

[0206] 500 parts of sucrose

[0207] 20 parts xanthan gum

[0208] 50 parts of colloidal microcrystalline cellulose

[0209] 130 parts of microcrystalline cellulose

[0210] 4 parts hydroxypropyl methylcellulose

[0211] 10 parts of croscarmellose sodium

[0212] 10 parts of colloidal silica.

[0213] In some embodiments of the present invention, the metronidazole dry suspension comprises the following components:

[0214] 276 parts of metronidazole granules A or B

[0215] 300 parts sucrose

[0216] 5 parts sucralose

[0217] 30 parts xanthan gum

[0218] 100 parts of microcrystalline cellulose

[0219] 4 parts hydroxypropyl methylcellulose

[0220] 10 parts of croscarmellose sodium

[0221] 10 parts of colloidal silica.

[0222] In some embodiments of the present invention, the metronidazole dry suspension comprises the following components:

[0223] 259 parts of the metronidazole granules A or B

[0224] 300 parts sucrose

[0225] 5 parts sucralose

[0226] 30 parts xanthan gum

[0227] 100 parts of microcrystalline cellulose

[0228] 6 parts hydroxypropyl methylcellulose

[0229] 10 parts of croscarmellose sodium

[0230] 10 parts of colloidal silica.

[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 and formulations containing them provided by this invention allow metronidazole to dissolve slowly or not at all in water or saliva, but to dissolve rapidly in gastric juice, thus masking the taste. Furthermore, after oral administration, it dissolves and is rapidly absorbed in the stomach. In addition, the metronidazole dry suspension has a sedimentation volume ratio of not less than 0.90, exhibiting good stability; and it has a good taste, completely masking the characteristic bitterness of metronidazole, with no obvious gritty feel or unpleasant odor, making it more easily accepted by pediatric patients. Detailed Implementation

[0235] 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.

[0236] In the following embodiments and comparative examples:

[0237] Metronidazole raw material was purchased from Huanggang Yinhe Adi Pharmaceutical Co., Ltd.; the particle size distribution of metronidazole crystals was D90: 346μm; D50: 113μm; D10: 16μm;

[0238] The Eudragit E100 was purchased from Evonik Operations GmbH;

[0239] Hydroxypropyl methylcellulose was purchased from Shanghai Carrefour Coating Technology Co., Ltd., model E5, viscosity: 5 mPa.s;

[0240] Polyethylene glycol 6000: CAS No. 25322-68-3;

[0241] PlasACRYL T20, a water-based anti-adhesive and plasticizer mixed emulsion, was purchased from Emerson Resources Inc.

[0242] The main component of talc is hydrated magnesium silicate, with the molecular formula Mg3(Si4O3). 10 (OH)2, purchased from Imerys Talc Italy SpA;

[0243] Glyceryl monostearate: CAS No. 123-94-4;

[0244] Twain-80: CAS No. 9005-65-6;

[0245] Xanthan gum was purchased from CP Kolco US, Inc., model XANTURAL 75;

[0246] Colloidal microcrystalline cellulose was purchased from Mingtai Chemical, type C11;

[0247] Microcrystalline cellulose was purchased from JRS, model Vivapur 101;

[0248] The croscarmellose sodium was purchased from DFE Pharma GmbH & Co. KG.

[0249] Colloidal silica was purchased from Evonik Specialty Chemicals (shanghai) Co., Ltd., product name AEROSIL 200 Pharma.

[0250] Ethyl cellulose was purchased from Shanghai Calcare Coating Technology Co., Ltd., model Ethocel Standard 10 Premium;

[0251] The commercially available metronidazole tablets were purchased from Grand Pharmaceutical (China) Co., Ltd., with a specification of 200mg / tablet and 100 tablets / bottle.

[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, use 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] The concentration of an ethanol solution refers to the mass concentration of ethanol, specifically the mass of ethanol per unit volume of the solution.

[0254] Example 1

[0255] Preparation method:

[0256] (1) API screening: Metronidazole raw material obtained from the market was screened to obtain the particle size distribution of metronidazole crystals as D90: 346μm; D50: 113μm; D10: 16μm.

[0257] (2) Taste-masking coating: Metronidazole granules were coated with an ethanol-water solution of Eudragit E100, a gastrosoluble copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate (1:2:1). The taste-masking coating formula is shown in Table 1 below.

[0258] Table 1

[0259]

[0260] Prepare 1000 bags according to the prescription shown in Table 1. The flavor-masking coating process is as follows:

[0261] Add Eudragit E100 to a 60% ethanol solution and stir until completely dissolved;

[0262] ② The drug core is coated by bottom spraying in a fluidized bed using the above coating solution. During the coating process, the material temperature is maintained at 25~30℃. After all the coating solution is used up, continue drying for 15-30 minutes. When the moisture content drops below 2.0%, the material is removed to obtain metronidazole taste-masked coated granules.

[0263] Comparative Example 1

[0264] Preparation method:

[0265] (1) API screening: Metronidazole raw material obtained from the market was screened to obtain the particle size distribution of metronidazole crystals as D90: 346μm; D50: 113μm; D10: 16μm.

[0266] (2) Taste-masking coating: Metronidazole granules were coated with an 85% ethanol aqueous solution of ethyl cellulose (Ethocel Standard 10 Premium). The taste-masking coating formula is shown in Table 2 below.

[0267] Table 2

[0268]

[0269] Prepare 1000 bags according to the prescription shown in Table 1. The flavor-masking coating process is as follows:

[0270] Add ethyl cellulose to an 85% ethanol solution and stir until completely dissolved;

[0271] ② Coat the drug core with the above coating solution in a fluidized bed. Maintain the material temperature at 25~35℃ during the coating process. After all the coating solution is used up, continue drying for about 15-30 minutes, controlling the moisture content to be below 2.0%. Remove the material to obtain metronidazole taste-masked coated granules.

[0272] Example 2

[0273] The first step is to prepare metronidazole isolation-coated particles:

[0274] (1) API sieving: Metronidazole raw material was sieved to obtain the particle size distribution of metronidazole crystals as D90: 346μm; D50: 113μm; D10: 16μm.

[0275] (2) Prepare metronidazole isolation-coated granules. The isolation coating formula is shown in Table 3 below.

[0276] Table 3

[0277]

[0278] According to the formulation shown in Table 3, the preparation process for the isolation coating is as follows:

[0279] Add purified water to ethanol (ethanol concentration approximately 74%) and stir until homogeneous. Divide the ethanol-water mixture into two equal portions. Add talc to one portion and disperse under high shear to obtain solution A.

[0280] Add polyethylene glycol 6000 to another part of ethanol-water, stir to dissolve, then add hydroxypropyl methylcellulose and stir until completely dissolved to obtain solution B.

[0281] Solution A is added to solution B and mixed to obtain the coating solution.

[0282] Coating: Metronidazole crystals are added to a fluidized bed, and airflow is introduced to fluidize the particles. The above coating solution is used to isolate and coat the metronidazole crystal particles. During the coating process, the airflow rate is 25-50 m³ / h, the airflow temperature is 45-70℃, the atomization pressure is 1.5-2 bar, and the material temperature is controlled at 35-45℃. After the coating is completed, the material is taken out after fluidized drying for 10-20 minutes. The adhering particles are removed by passing the material through a 40-mesh sieve, and the metronidazole isolated and coated particles are collected.

[0283] The second step is to prepare metronidazole-masked granules.

[0284] Take an appropriate amount of the metronidazole isolation coating granules from the first step, such as 1000 bags or 1500 bags, and coat them with the formula shown in Table 4 below to mask the odor.

[0285] Table 4

[0286]

[0287] The process for preparing the flavor-masking granule coating is as follows:

[0288] ① Preparation of coating solution:

[0289] In Example 1, Eudragit E100 is added to a 60% ethanol solution and stirred until completely dissolved.

[0290] In Example 2, an appropriate amount of ethanol solution is first used to wet the talc powder, and then the talc powder is evenly dispersed using a high-shear homogenizer before being added to the prepared Eudragit E100 ethanol solution.

[0291] In Example 3, PlasACRYL T20 is added to the prepared Eudragit E100 ethanol solution.

[0292] ② Coating process: The metronidazole isolation coating granules are coated by bottom spraying in a fluidized bed using the above coating solution. The air volume during the coating process is 25-50 m³ / h, the air temperature is 35-40℃, the atomization pressure is 2 bar, and the material temperature is controlled at 25-30℃ during the coating process. After the coating is completed, continue drying for about 15-30 minutes to control the moisture content to be below 2.0%. The material is then removed to obtain metronidazole taste-masked coated granules.

[0293] The third step is to prepare metronidazole dry suspension.

[0294] Table 5

[0295]

[0296] Preparation of suspending granules: Approximately 1000g of suspending granule components, including sucrose, sucralose, xanthan gum, colloidal microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, and colloidal silica, are passed through a 30-mesh sieve and added to a wet granulator. The stirring speed is 200-400 rpm, the shearing speed is 400-800 rpm, and the mixture is stirred for 5-10 minutes. Granulation is then carried out with an appropriate amount of purified water at a stirring speed of 300-600 rpm and a shearing speed of 1000-2000 rpm for 1-3 minutes. The wet granules are then transferred to a fluidized bed for drying. A suitable airflow is introduced to keep the granules fluidized at an inlet air temperature of 50-65℃. The granules are dried until the moisture content is below 2.0%. The granules are then sized using a 1.2mm sieve and passed through a 30-mesh sieve. The granules that pass through the 30-mesh sieve are collected.

[0297] The metronidazole odor-masking granules and suspension-aiding granules obtained in Examples 1-3 were packaged in two-component bags according to the proportions in Table 5 to obtain metronidazole odor-masking dry suspension.

[0298] Example 3

[0299] The first step is to prepare metronidazole isolation-coated particles:

[0300] (1) API sieving: Metronidazole raw material was sieved to obtain the particle size distribution of metronidazole crystals as D90: 346μm; D50: 113μm; D10: 16μm.

[0301] (2) Prepare metronidazole isolation-coated granules. The isolation coating formula is shown in Table 6 below.

[0302] Table 6

[0303]

[0304] ① Add polyethylene glycol 6000 and hydroxypropyl methylcellulose to ethanol and stir until completely dissolved to obtain solution B.

[0305] ② Heat purified water to 70-80℃, add Tween-80 and glyceryl monostearate to the hot water, and homogenize for 30 minutes using a high-speed shear disperser to obtain solution C.

[0306] Add solution B to solution C and mix.

[0307] Isolation coating: Metronidazole crystals are added to a fluidized bed, and airflow is introduced to keep the particles in a fluidized state. The airflow rate is controlled at 25-50 m³ / h, the airflow temperature at 45-70℃, and the atomization pressure at 1.5-2 bar. During the coating process, the material temperature is controlled at 35-45℃. The above coating solution is used to isolate and coat the metronidazole crystal particles. After the coating is completed, the fluidized drying continues for 10-30 minutes. The material is then removed, passed through a 40-mesh sieve, and the isolated and coated metronidazole particles are collected.

[0308] The second step is to prepare metronidazole taste-masked coated granules:

[0309] Take 200g of the metronidazole isolation-coated granules from the first step and add them to a fluidized bed. Introduce an airflow to fluidize the granules. Perform odor-masking coating according to the odor-masking coating solution formula shown in Table 7. During the coating process, the airflow rate is 25-50 m³ / h, the airflow temperature is 35-40℃, and the atomization pressure is 2 bar. Control the material temperature during the coating process at 25-30℃. After coating, continue drying for approximately 10-30 minutes until the moisture content drops below 2.0%. Remove the material to obtain the metronidazole odor-masked coated granules.

[0310] Table 7

[0311]

[0312] The odor-masking coating solution is prepared as follows:

[0313] ① Take an appropriate amount of water, heat it to 70~80℃, add Tween-80 and glyceryl monostearate to the hot water, and homogenize it for 30 minutes using a high-speed shear disperser.

[0314] ② Mix the ethanol and the remaining water, then add Eudragit E100 and stir until dissolved;

[0315] ③ Add the homogenized glyceryl monostearate solution to the Eudragit E100 solution while stirring, and mix well to obtain the flavor-masking coating solution.

[0316] The third step is to prepare metronidazole-masked dry suspension.

[0317] Metronidazole flavor-masked coated granules were mixed evenly with sucrose, xanthan gum, sodium carboxymethyl cellulose, microcrystalline cellulose, and colloidal silica, and then packaged into bags to obtain a metronidazole dry suspension formulation.

[0318] The third step is to prepare metronidazole-masked dry suspension.

[0319] The formulations of the dry suspension are shown in Table 8 below.

[0320] Table 8

[0321]

[0322] Preparation of suspension granules: The suspension granule components, including sucrose, sucralose, xanthan gum, microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, and colloidal silica, are passed through a 30-mesh sieve and added to a wet granulator. The stirring speed is 200-400 rpm and the shearing speed is 400-800 rpm. The mixture is stirred for 5-10 minutes. Granulation is carried out with an appropriate amount of purified water. The stirring speed is 300-600 rpm and the shearing speed is 1000-2000 rpm. The granulation is carried out for 1-3 minutes. The wet granules are transferred to a fluidized bed for drying. A suitable airflow is introduced to keep the granules fluidized. The inlet air temperature is 50-65℃. The granules are dried until the moisture content is below 2.0%. The granules are then sized using a 1.2 mm sieve. After sizing, the granules are passed through a 30-mesh sieve. The granules that pass through the 30-mesh sieve are collected.

[0323] The metronidazole odor-masking granules and suspension-aiding granules obtained in Example 3 were packaged in two-component bags according to the proportions in Table 8 to obtain the metronidazole odor-masking dry suspension.

[0324] Effect Example

[0325] 1. Evaluation of dissolution effect

[0326] Take 6 bags each of metronidazole-masked granules from Example 1 and Comparative Example 1, and 6 bags each of masked dry suspensions from Examples 1-3 and Example 3 in Example 2. Determine the dissolution and release rate according to the method of determination of dissolution and release rate (Chinese Pharmacopoeia (2020 edition, General Chapter 0931, Method II), using 900 ml of purified water as the dissolution medium and a rotation speed of 50 rpm. Take appropriate samples at 5, 10, 15, 30, 45, and 60 minutes, filter them through a 0.8 μm mixed fiber filter membrane, and use them as the test solution.

[0327] Reference solution: Accurately weigh 2 mg of metronidazole reference standard, place it in a 20 ml volumetric flask, add an appropriate amount of diluent (dissolution medium), sonicate to dissolve, and dilute to the mark with diluent. Shake well to obtain the metronidazole reference solution (0.1 mg / ml).

[0328] Chromatographic conditions: Agilent InfinityLab Poroshell 120 EC-C18, 4.6×100mm 2.7μm, methanol-water (15:85) as mobile phase, flow rate 1.0ml / min, injection volume 5µl, detection wavelength 230nm.

[0329] Assay: Accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, record the chromatograms, and calculate the dissolution amount per bag.

[0330] The same procedure was followed, using 0.1N hydrochloric acid solution and pH 4.5 acetate buffer as the dissolution medium, respectively.

[0331] The dissolution rate of commercially available metronidazole tablets (200mg, batch number: 240141, manufacturer: Grand Pharmaceutical (China) Co., Ltd.) was determined using the same method as above.

[0332] The dissolution results of Comparative Example 1, each example, and the control drug, commercially available metronidazole tablets, in purified water are shown in Table 9 below.

[0333] Table 9. Results of Dissolution Test in Purified Water

[0334]

[0335] Table 10 Dissolution test results in pH 4.5 acetate buffer medium

[0336]

[0337] Table 11 Dissolution test results in 0.1NHCl medium

[0338]

[0339] As shown in Tables 9-11, compared with commercially available metronidazole tablets, the granules coated with ethyl cellulose in Comparative Example 1 had a solubility of less than 10% in water after 10 minutes. Although this achieved a masking effect, the solubility in 0.1N HCl failed to reach more than 85% after 60 minutes, affecting in vivo absorption. In contrast, the metronidazole masking granules or metronidazole masking dry suspensions prepared in the other examples all had a solubility of less than 10% in pure water after 10 minutes, especially in Example 2, where the solubility was less than 10% after 60 minutes, demonstrating excellent masking effects. The solubility in pH 4.5 and 0.1N HCl was consistent with that of commercially available tablets; therefore, the masking coating did not alter drug absorption in vivo.

[0340] The above dissolution results also indicate that different types of anti-adhesion agents, such as talc, water-based anti-adhesion agents and plasticizer mixtures like PlasACRYL T20, and glyceryl monostearate, can achieve the masking effect in the taste-masking coating formulation. However, the use of talc results in slightly lower dissolution in pH 4.5 medium. Nevertheless, metronidazole taste-masked dry suspensions with different types of anti-adhesion agents all dissolve rapidly in 0.1N hydrochloric acid medium. That is, metronidazole preparations using the taste-masking technology of this invention still dissolve rapidly in gastric juice after administration, without altering their in vivo absorption or affecting bioavailability.

[0341] 2. Settlement volume ratio

[0342] 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.

[0343] Table 12

[0344]

[0345] 3. Oral test

[0346] 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.

[0347] Table 13

[0348]

[0349] The above experiments show that metronidazole masking dry suspension has a good taste, completely masking the characteristic bitterness of metronidazole, with no obvious gritty feeling or unpleasant odor, making it more easily accepted by pediatric patients.

Claims

1. A metronidazole granule A, characterized in that, It includes an active ingredient core and a first coating layer covering the outer surface of the active ingredient core; The core of the active ingredient comprises metronidazole particles; the D90 particle size of the metronidazole particles ranges from 50μm to 500μm. The first coating layer includes a first film-forming material, which includes a gastrosoluble acrylic resin.

2. The metronidazole granules A as described in claim 1, characterized in that, The metronidazole granules A satisfy one or more of the following conditions: The D90 particle size range of the metronidazole particles is 150μm-350μm, for example 346μm; The mass ratio of the active ingredient core to the first film-forming material in the first coating layer is 1:(0.1-0.5), for example, 1:(0.2-0.3). The D50 particle size of the metronidazole particles ranges from 10μm to 300μm, for example, 10μm-200μm, or 10μm-150μm, or even 113μm. The D10 particle size of the metronidazole particles ranges from 1 μm to 50 μm, for example, 1 μm to 20 μm, and also for example, 16 μm; The gastrointestinal soluble acrylic resin is selected from a copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate or a copolymer of methyl methacrylate-diethylaminoethyl methacrylate, wherein the molar ratio of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate may be 1:2:1, and the molar ratio of methyl methacrylate to diethylaminoethyl methacrylate may be 7:3; or, the gastrointestinal soluble acrylic resin is selected from one or more of Eudragit E100, Eudragit EPO, and Kollicoat Smartseal 100P; and The first coating layer also includes surfactants and / or anti-sticking agents; Preferably, the metronidazole granules A comprise: Metronidazole granules: 200mg First coating layer: Eudragit E100: 40mg-80mg, anti-adhesive: 0-8mg, surfactant: 0-0.1mg.

3. The metronidazole granules A as described in claim 2, characterized in that, The surfactant is Tween-80; And / or, the content of the surfactant is 1-10%, for example 2.6%; the percentage refers to the mass percentage in the first coating layer; And / or, the anti-adhesive is one or more of the following: glyceryl monostearate, water-based anti-adhesive and plasticizer mixed emulsion PlasACRYL T20, magnesium stearate, talc, and micronized silica gel, such as one or more of glyceryl monostearate, water-based anti-adhesive and plasticizer mixed emulsion PlasACRYL T20, and talc. And / or, the content of the anti-adhesive is 1-40%, for example 6.3%, 8.7% or 33.3%; the percentage refers to the mass percentage in the first coating layer.

4. A metronidazole granule B, characterized in that, It includes an active ingredient core, a second coating layer covering the outer surface of the active ingredient core, and a first coating layer covering the outer surface of the second coating layer; The active ingredient core includes metronidazole granules; the metronidazole granules have a D... 90 Particle size range: 50μm-500μm; The first coating layer includes a first film-forming material, which includes a gastrosoluble acrylic resin; The second coating layer includes a second film-forming material.

5. The metronidazole granules B as described in claim 4, characterized in that, The metronidazole granules B meet one or more of the following conditions: The mass ratio of the active ingredient core to the first film-forming material in the first coating layer is 1:(0.1-0.5), for example, 1:(0.2-0.53). The gastrosoluble acrylic resin is the gastrosoluble acrylic resin as described in claim 2; The first coating layer further includes a surfactant and / or an anti-adhesion agent; the surfactant may be the surfactant as described in claim 3, and the anti-adhesion agent may be the anti-adhesion agent as described in claim 3; The second film-forming material includes hydroxypropyl methylcellulose and polyethylene glycol; the viscosity of the hydroxypropyl methylcellulose may be less than 15 mPa·s, for example less than 10 mPa·s; the degree of polymerization of the polyethylene glycol may be 4000-8000, for example 6000; the mass ratio of the hydroxypropyl methylcellulose to the polyethylene glycol may be (1-10):1, for example 5:1; The mass ratio of the active ingredient core coating the second coating layer to the first film-forming material in the first coating layer is 1:(0.1-0.5), for example, 1:(0.2-0.3). The mass ratio of the active ingredient core to the second film-forming material in the second coating layer is 1:(0.01-0.05). The D90 particle size range of the metronidazole particles is 150μm-350μm, for example 346μm; The D50 particle size of the metronidazole particles ranges from 10μm to 300μm, for example, 10μm-200μm, or 10μm-150μm, or even 113μm. The D10 particle size of the metronidazole particles ranges from 1 μm to 50 μm, for example, 1 μm to 20 μm, and also, for example, 16 μm; and The second coating layer also includes surfactants and / or anti-sticking agents.

6. The metronidazole granules B as described in claim 5, characterized in that, The surfactant is Tween-80; And / or, the content of the surfactant is 1-10%, for example 3%; the percentage refers to the mass percentage in the second coating layer; And / or, the anti-adhesive is one or more of the following: glyceryl monostearate, water-based anti-adhesive and plasticizer mixed emulsion PlasACRYL T20, magnesium stearate, talc, and micronized silica gel, such as one or more of glyceryl monostearate, water-based anti-adhesive and plasticizer mixed emulsion PlasACRYL T20, and talc. And / or, the content of the anti-adhesive is 1-50%, for example 7.4% or 40%; the percentage refers to the mass percentage in the second coating layer; Preferably, the second coating layer comprises hydroxypropyl methylcellulose, polyethylene glycol and talc, or hydroxypropyl methylcellulose, polyethylene glycol, glyceryl monostearate and Tween-80; Preferably, the metronidazole granules B comprise: (1) Metronidazole particles with a D90 particle size range of 150μm-350μm; (2) A second coating layer covering the outer surface of the metronidazole particles, the second coating layer comprising hydroxypropyl methylcellulose, polyethylene glycol 6000, and talc; (3) A first coating layer covering the outer surface of the second coating layer, wherein the first coating layer comprises Eudragit E100, a gastrosoluble butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate copolymer; Preferably, the metronidazole granules B comprise: (1) Metronidazole granules coated with the second coating layer: 200-210mg First coating layer: Eudragit E100: 40-63mg, anti-adhesive: 0-31.5mg, surfactant: 0-1.4mg; (2) The metronidazole particles coated with the second coating layer include: Metronidazole granules: 200mg Second coating layer: hydroxypropyl methylcellulose: 5mg, polyethylene glycol 6000: 1mg, talc: 4mg; Preferably, the metronidazole granules B comprise: (1) Metronidazole granules coated with the second coating layer: 200-210mg First coating layer: Eudragit E100: 40-63mg, anti-adhesive: 0-31.5mg, surfactant: 0-1.4mg; (2) The metronidazole particles coated with the second coating layer include: Metronidazole granules: 200mg The second coating layer consists of: hydroxypropyl methylcellulose: 5 mg, polyethylene glycol 6000: 1 mg, glyceryl monostearate: 0.5 mg, and Tween-80: 0.2 mg.

7. A method for preparing metronidazole granules A as described in any one of claims 1-3, characterized in that, It includes the following steps: (1) The raw material in the first coating layer and the first solvent are mixed to obtain the first coating solution; (2) The first coating solution is coated onto the core of the active ingredient and dried to obtain the metronidazole granules A.

8. A method for preparing metronidazole granules B as described in any one of claims 4-6, characterized in that, It includes the following steps: S1: Mix the raw material and the second solvent in the second coating layer to obtain the second coating solution; S2: The second coating solution is coated onto the active ingredient core, and then dried to obtain active ingredient core A; S3: Mix the raw material in the first coating layer with the first solvent to obtain the first coating solution; S4: Coat the active ingredient core A with the first coating solution and dry to obtain the metronidazole granules B.

9. A metronidazole preparation, characterized in that, It comprises metronidazole granules A as described in any one of claims 1-3 or metronidazole granules B as described in any one of claims 4-6.

10. The metronidazole preparation according to claim 9, characterized in that, The metronidazole formulation further includes excipients; the excipients include one or more of the following: flavoring agents, suspending agents, fillers, disintegrants, flow aids, and binders; The flavoring agent may be selected from one or more of sucralose, cyclamate, aspartame, xylitol, and sorbitol; The content of the flavoring agent can be 0%-1%, and the percentage refers to the mass percentage in the metronidazole dry suspension. The suspending agent may be selected from xanthan gum and / or colloidal microcrystalline cellulose; The content of the suspending agent can be 1%-15%, where the percentage refers to the mass percentage in the metronidazole dry suspension. The filler may be selected from sucrose and / or microcrystalline cellulose; The content of the filler can be 50-70%, and the percentage refers to the mass percentage in the metronidazole dry suspension. The disintegrant may be selected from one or more of croscarmellose sodium, carboxymethyl starch sodium, and croscarmellose, for example, croscarmellose sodium; The content of the disintegrant can be 0.9-4%, and the percentage refers to the mass percentage in the metronidazole dry suspension. The adhesive may be selected from one or more of hydroxypropyl methylcellulose, povidone and hydroxypropyl cellulose, such as hydroxypropyl methylcellulose; The content of the adhesive can be 0.1-2%, and the percentage refers to the mass percentage in the metronidazole dry suspension; The flow aid may be selected from silica and / or magnesium stearate; The content of the glidant can be 0.9%-4%, and the percentage refers to the mass percentage in the metronidazole dry suspension.

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