CN-122005485-A - Metronidazole particles, preparation containing same and preparation method

CN122005485ACN 122005485 ACN122005485 ACN 122005485ACN-122005485-A

Abstract

The invention discloses metronidazole particles, a preparation containing the metronidazole particles and a preparation method. The metronidazole particles A comprise an active ingredient inner core and a first coating layer coated on the outer surface of the active ingredient inner core, wherein the active ingredient inner core comprises metronidazole particles, the D90 particle size range of the metronidazole particles is 50-500 mu m, the first coating layer comprises a first film forming material, and the film forming material comprises gastric-soluble acrylic resin. The metronidazole particles and the preparation containing the same provided by the invention can enable the metronidazole to be dissolved slowly or even not in water or saliva, and can be dissolved in gastric juice rapidly, so that the taste masking effect is achieved, and meanwhile, the metronidazole particles and the preparation containing the metronidazole particles are dissolved and absorbed in the stomach rapidly after oral administration. In addition, the settling volume ratio of the metronidazole dry suspension is not less than 0.90, the stability is good, the taste is good, the peculiar bitter taste of the metronidazole is completely covered, no obvious sand grain feel and bad smell are generated, and the metronidazole dry suspension is more easily accepted by children patients.

Inventors

Li lane
TAN ZOUNIAN
ZHAO XIAODONG
WANG HAO

Assignees

上海惠永制药有限公司
上海惠永药物研究有限公司

Dates

Publication Date: 20260512
Application Date: 20241108

Claims (10)

1. Metronidazole particles A are characterized by comprising an active ingredient inner core and a first coating layer coated on the outer surface of the active ingredient inner core; The active ingredient inner core comprises metronidazole particles, wherein the particle size of the metronidazole particles D90 ranges from 50 mu m to 500 mu m; The first coating layer comprises a first film forming material comprising a gastric soluble acrylic resin.
2. The metronidazole particles a as claimed in claim 1, characterized in that the metronidazole particles a fulfil one or more of the following conditions: The D90 particle size of the metronidazole particles ranges from 150 μm to 350 μm, for example 346 μm; 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 is in the range of 10 μm to 300. Mu.m, for example 10 μm to 200. Mu.m, further for example 10 μm to 150. Mu.m, further for example 113. Mu.m; the D10 particle size of the metronidazole particles is in the range of 1 μm to 50. Mu.m, for example 1 μm to 20. Mu.m, and also for example 16. Mu.m; the gastric-soluble acrylic resin is selected from a copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate or a copolymer of methyl methacrylate-diethylaminoethyl methacrylate, the molar ratio of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate can be 1:2:1, the molar ratio of methyl methacrylate and diethylaminoethyl methacrylate can be 7:3, or the gastric-soluble acrylic resin is selected from one or more of Eudragit E100, eudragit EPO, kollicoat Smartseal P, and The first coating layer also comprises a surfactant and/or an anti-adhesion agent; Preferably, the metronidazole particles a comprise: Metronidazole particles 200mg The first coating layer comprises 40mg-80mg of Eudragit E100, 0mg-8 mg of anti-adhesion agent and 0 mg-0.1 mg of surfactant.
3. The metronidazole particles a as claimed in claim 2, characterized in that the surfactant is tween-80; And/or the surfactant is present in an amount of 1-10%, for example 2.6%, by mass in the first coating layer; And/or the anti-sticking agent is one or more of glyceryl monostearate, water-based anti-sticking agent and plasticizer mixed emulsion PLASACRYL T, magnesium stearate, talcum powder and micro-powder silica gel, such as one or more of glyceryl monostearate, water-based anti-sticking agent and plasticizer mixed emulsion PLASACRYL T and talcum powder; And/or the content of the anti-sticking agent is 1-40%, such as 6.3%, 8.7% or 33.3%, the percentages referring to the mass percentage in the first coating layer.
4. The metronidazole particles B are characterized by comprising an active ingredient inner core, a second coating layer coated on the outer surface of the active ingredient inner core and a first coating layer coated on the outer surface of the second coating layer; the active ingredient inner core comprises metronidazole particles, wherein the D 90 particle diameter of the metronidazole particles ranges from 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; the second coating layer includes a second film forming material.
5. The metronidazole particles B as claimed in claim 4, characterized in that the metronidazole particles B fulfil 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 gastric-soluble acrylic resin as described in claim 2; The first coating layer further comprises a surfactant and/or an anti-adhesion agent, wherein the surfactant can be the surfactant as claimed in claim 3, and the anti-adhesion agent can be the anti-adhesion agent as claimed in claim 3; The second film forming material comprises hypromellose and polyethylene glycol, wherein the viscosity of the hypromellose can be less than 15 mPa.s, such as less than 10 mPa.s, the polymerization degree of the polyethylene glycol can be 4000-8000, such as 6000, and the mass ratio of the hypromellose to the polyethylene glycol can be (1-10): 1, such as 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), such as 1 (0.2-0.3); the mass ratio of the active ingredient inner core to the second film forming material in the second coating layer is 1 (0.01-0.05); The D90 particle size of the metronidazole particles ranges from 150 μm to 350 μm, for example 346 μm; the D50 particle size of the metronidazole particles is in the range of 10 μm to 300. Mu.m, for example 10 μm to 200. Mu.m, further for example 10 μm to 150. Mu.m, further for example 113. Mu.m; the D10 particle diameter of the metronidazole particles ranges from 1 μm to 50. Mu.m, for example from 1 μm to 20. Mu.m, further for example 16. Mu.m, and The second coating layer also comprises a surfactant and/or an anti-adhesion agent.
6. The metronidazole particles B as claimed in claim 5, wherein the surfactant is tween-80; And/or the surfactant is present in an amount of 1-10%, for example 3%, by mass in the second coating layer; And/or the anti-sticking agent is one or more of glyceryl monostearate, water-based anti-sticking agent and plasticizer mixed emulsion PLASACRYL T, magnesium stearate, talcum powder and micro-powder silica gel, such as one or more of glyceryl monostearate, water-based anti-sticking agent and plasticizer mixed emulsion PLASACRYL T and talcum powder; And/or the content of the anti-sticking agent is 1-50%, such as 7.4% or 40%, the percentages referring to the mass percentage in the second coating layer; Preferably, the second coating layer comprises hypromellose, polyethylene glycol and talcum powder, or hypromellose, polyethylene glycol, glyceryl monostearate and tween-80; preferably, the metronidazole particles B comprise: (1) Metronidazole particles with the D90 particle size ranging from 150 mu m to 350 mu m; (2) The second coating layer is coated on the outer surface of the metronidazole particles and comprises hypromellose, polyethylene glycol 6000 and talcum powder; (3) The first coating layer is coated on the outer surface of the second coating layer and comprises gastric-soluble butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate copolymer Eudragit E100; preferably, the metronidazole particles B comprise: (1) The metronidazole particles coated with the second coating layer are 200-210mg 40-63Mg of Eudragit E100, 0-31.5mg of anti-adhesion agent and 0-1.4mg of surfactant; (2) The metronidazole particles coated with the second coating layer include: Metronidazole particles 200mg The second coating layer comprises 5mg of hydroxypropyl methylcellulose, 6000 mg of polyethylene glycol, and 4mg of talcum powder; preferably, the metronidazole particles B comprise: (1) The metronidazole particles coated with the second coating layer are 200-210mg 40-63Mg of Eudragit E100, 0-31.5mg of anti-adhesion agent and 0-1.4mg of surfactant; (2) The metronidazole particles coated with the second coating layer include: Metronidazole particles 200mg The second coating layer comprises 5mg of hydroxypropyl methylcellulose, 6000 g of polyethylene glycol, 0.5mg of glyceryl monostearate and 0.2mg of tween-80.
7. A process for the preparation of metronidazole particles a as claimed in any one of claims 1 to 3, characterised in that it comprises the steps of: (1) Mixing the raw materials in the first coating layer with a first solvent to obtain a first coating solution; (2) And coating the first coating solution on the active ingredient inner core, and drying to obtain the metronidazole particles A.
8. A process for the preparation of metronidazole particles B as claimed in any one of claims 4 to 6, characterised in that it comprises the following steps: S1, mixing the raw materials in the second coating layer with a second solvent to obtain a second coating solution; s2, coating the second coating solution on the active ingredient core, and drying to obtain an active ingredient core A; S3, mixing the raw materials in the first coating layer with a first solvent to obtain a first coating solution; And S4, coating the first coating solution on the active ingredient kernel A, and drying to obtain the metronidazole particles B.
9. Metronidazole preparation, characterized in that it comprises metronidazole particles A according to any of claims 1 to 3 or metronidazole particles B according to any of claims 4 to 6.
10. The metronidazole formulation of claim 9, further comprising excipients, wherein the excipients include one or more of flavoring agents, suspending agents, fillers, disintegrants, glidants, binders; the flavoring agent can be one or more selected from sucralose, sodium cyclamate, aspartame, xylitol and sorbitol; The content of the flavoring agent can be 0% -1%, and the percentage refers to the mass percentage of 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%, and the percentage refers to the mass percentage of 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 of the metronidazole dry suspension; the disintegrant may be selected from one or more of croscarmellose sodium, sodium carboxymethyl starch and crospovidone, for example croscarmellose sodium; the content of the disintegrating agent can be 0.9-4%, and the percentage refers to the mass percentage of the metronidazole dry suspension; The binder may be selected from one or more of hypromellose, povidone, and hypromellose, for example hypromellose; the content of the binder can be 0.1-2%, and the percentage refers to the mass percentage of the metronidazole dry suspension; The glidant may be selected from silicon dioxide and/or magnesium stearate; The content of the glidant can be 0.9-4%, and the percentage refers to the mass percentage of the metronidazole dry suspension.

Description

Metronidazole particles, preparation containing same and preparation method Technical Field The invention relates to metronidazole particles, a preparation containing the metronidazole particles and a preparation method. Background Metronidazole is used for treating and preventing infections caused by anaerobic bacteria, and has inhibitory activity against a variety of pathogenic microorganisms, particularly Bacteroides, fusobacterium, clostridium, eubacteria, pediococcus, anaerobic coccus and Gardnerella vaginalis. Metronidazole also has therapeutic effects on trichomonas, entamoeba histolytica, giardia, ciliate colonosocomiae, and Maidenafil nematodes, and at present, metronidazole has clear indications and dosage in pediatric populations. Metronidazole has extremely bitter taste, and the tablets and capsules on the market at present have bad taste, heavy bitter taste, and bad feelings such as nausea, regurgitation and the like after taking, are not easy to accept by patients, have poor compliance, and influence the continuous medication and clinical curative effect. Tablet and capsule dosage forms which are marketed in China have bitter taste and dysphagia when being taken by children, and do not meet clinical requirements. Therefore, development of a dosage form with good taste masking effect suitable for oral administration by children is needed, and the problem of compliance of oral administration by children is solved. Metronidazole oral suspension (trade name: LIKMEZ) is marketed in the United states in 2023, and the bad taste is relieved by disturbing the taste buds by adding a large amount of auxiliary materials such as sucrose, sucralose flavoring agent and the like, and the method is simple but has limited effect. In addition, the oral suspension LIKMEZ is a liquid preparation, a preservative is required to be used, and the application of auxiliary materials is unsafe. The materials used for taste masking coating at present are mainly gastric-soluble acrylic resin which is dissolved in acidic gastric juice with pH less than 5 and is insoluble in neutral saliva and water, and the materials can be used for masking the medicine, so that the medicine can be dissolved in water or saliva slowly or even not, can be dissolved in gastric juice quickly, has taste masking effect, and can be dissolved and absorbed in stomach quickly after oral administration. According to the current report, the use of gastric soluble materials for the preparation of taste masking formulations such as CN1273133C (berberine hydrochloride), CN103169669a (agomelatine) and the like has been disclosed in the prior art. However, CN103169669a discloses that a prescribed amount of agomelatine is coated on a blank pellet core to prepare a pill core, and then the pill core is covered with a taste masking layer to prepare coated pellets with taste masking effect. Therefore, the medicine is applied to a blank pill core, and because the content of the metronidazole in the metronidazole preparation is high, and the metronidazole is slightly soluble in water and ethanol, the metronidazole cannot be directly replaced by the metronidazole. Chinese patent C1273133C discloses a preparation process of berberine hydrochloride taste masking preparation, wherein berberine hydrochloride is subjected to fluidized bed top-spraying granulation drying by using a taste masking coating material, and then is subjected to rotary fluidized bed taste masking coating, the granules obtained by top-spraying granulation are loose, drug-containing granules are easy to fall off during taste masking coating, and meanwhile, the taste masking coating liquid is used for granulating and coating, the dosage of the taste masking coating material is large, the children's medicine of the metronidazole preparation does not meet clinical requirements, the dosage of the children's medicine is 50mg at the minimum, the metronidazole dry suspension for children is prepared according to the technology of the patent, the dosage of auxiliary materials is large, and the safety of children's medicine is at risk. Therefore, how to provide a metronidazole preparation with good taste masking effect and high safety based on the properties of metronidazole is a technical problem to be solved in the field. Disclosure of Invention The invention aims to overcome the defects that the metronidazole preparation in the prior art has poor taste masking effect and is not suitable for children to use, and provides the metronidazole particles, the preparation containing the metronidazole particles and a preparation method. The invention provides metronidazole particles A, which comprise an active ingredient inner core and a first coating layer coated on the outer surface of the active ingredient inner core; The active ingredient inner core comprises metronidazole particles, wherein the D90 particle size of the metronidazole particles ranges from 50 mu m to 500 mu m; The first coating layer comprise