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CN-121987585-A - Metronidazole particles, preparation containing same and preparation method

CN121987585ACN 121987585 ACN121987585 ACN 121987585ACN-121987585-A

Abstract

The invention discloses metronidazole particles, a preparation containing the metronidazole particles and a preparation method. The metronidazole particles comprise a drug core and a coating layer, wherein the coating layer is coated on the outer surface of the drug core, the drug core comprises metronidazole, the coating layer comprises a film-forming material, and the film-forming material comprises gastric-soluble acrylic resin and ethylcellulose. The low dissolution rate of the metronidazole particles in the invention in water and a medium with higher pH (such as pH 6.8), especially 15 minutes dissolution rate is less than or equal to 10 percent, and the dissolution rate at low pH (such as pH 1.2-4.5) is kept consistent with that of the commercially available tablets, so that the metronidazole particles are quickly dissolved.

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
20260508
Application Date
20241108

Claims (10)

  1. 1. The metronidazole particles are characterized by comprising 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, wherein the film forming material comprises gastric-soluble acrylic resin and ethyl cellulose.
  2. 2. The metronidazole granule as claimed in claim 1, characterized in that the drug core comprises the following components in mass percentage in the drug core: 50-90% of metronidazole; 10-30% of a diluent; 0-5% of glidant; 1-15% of adhesive.
  3. 3. The metronidazole granule as claimed in claim 2, wherein the drug core satisfies one or more of the following conditions: The content of the metronidazole is 60-80%, such as 70-80%, 70.4% or 80%, and the percentage is mass percentage in the drug core; The diluent comprises microcrystalline cellulose and/or lactose; The diluent is present in an amount of 10-25%, for example 13.0%, 22.5% or 24%, by mass in the drug core; the glidant is selected from the group consisting of silicon dioxide, such as colloidal silicon dioxide; the glidant is present in an amount of 0.5-1.0%, such as 0.8% or 1.0%, by mass in the drug core; The binder comprises one or more of hypromellose, hydroxypropyl cellulose, and polyvinylpyrrolidone solution, the binder may be selected from hypromellose, the viscosity of the hypromellose may be 5-50mPa.S, such as 5-30mPa.S, and also such as 15mPa.S, and The binder is present in an amount of 5-15%, for example 5.0%, 6.0% or 6.2%, by mass in the drug core.
  4. 4. The metronidazole granule as claimed in claim 2, wherein the drug core comprises the following components: 60-80% of metronidazole; 10-25% of a diluent selected from microcrystalline cellulose or microcrystalline cellulose and lactose; 0-5% of glidant; 5-15% of a binder selected from hypromellose; 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% Hydroxypropyl methylcellulose 5% Microcrystalline cellulose 16% Lactose 8% 1% Of colloidal silica; Preferably, the drug core comprises the following components: Metronidazole 70% Hydroxypropyl methylcellulose 5% Microcrystalline cellulose 12.5% 12.5% Of lactose; Preferably, the drug core comprises the following components: Metronidazole 70% Hydroxypropyl methylcellulose 5% Microcrystalline cellulose 16% Lactose 8% 1% Of colloidal silica; Preferably, the drug core comprises the following components: Metronidazole 80% Hydroxypropyl methylcellulose 6% Microcrystalline cellulose 13% 1% Of colloidal silica.
  5. 5. The metronidazole granule as claimed in any one of claims 1 to 4, characterized in that the metronidazole granule fulfils 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, e.g. 0.28 g/mL or 0.41 g/mL; ⑩ The gastric-soluble acrylic resin is selected from a copolymer of butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate, wherein the molar ratio of the butyl methacrylate to the dimethylaminoethyl methacrylate to the methyl methacrylate can be 1:2:1, and the gastric-soluble acrylic resin can be one or more of Eudragit E100, eudragit EPO and Eudragit L100, and is preferably Eudragit E100; The ethylcellulose has a labeled viscosity of 4-100 mPa s, for example 4mPa s, 7 mPa s, 10 mPa s, 20 mPa s, 45 mPa s or 100 mPa s; The mass ratio of the gastric-soluble acrylic resin to the ethylcellulose is 1 (1-3), such as 1:1, 1:3 or 2:3; The mass ratio of film-forming material to the drug core in the coating layer is ≡0.20:1, which may be (0.20-0.50): 1, for example (0.20-0.40): 1, for example (0.25-0.40): 1, for example 0.25:1, 0.30:1, 0.35:1, 0.40:1; the coating layer also comprises a surfactant and/or an anti-adhesion agent.
  6. 6. The metronidazole particles as claimed in claim 5, characterized in that they fulfil one or more of the following conditions: The content of the anti-adhesion agent is 1-25%, such as 1.38%, 1.59%, 8.9%, 11.5%, 13.0%, 9.1%, 18.8% or 20.6%, and the percentage refers to the mass percentage in the metronidazole particles; The anti-sticking agent is one or more of glyceryl monostearate, PLASACRYL T, magnesium stearate, talcum powder and micro powder silica gel, such as one or more of glyceryl monostearate, PLASACRYL T and talcum powder, wherein the anti-sticking agent can be selected from glyceryl monostearate or PLASACRYL T; The surfactant is Tween-80; The content of the surfactant is 0.1-1%, such as 0.39% or 0.72%, and the percentage refers to the mass percentage in the metronidazole particles.
  7. 7. The metronidazole particles as claimed 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%, such as 1.38% or 1.59%, wherein the percentage refers to the mass percentage in the metronidazole particles; Or the anti-adhesion agent is PLASACRYL T, the content of the anti-adhesion agent is 1-25%, such as 8.9%, 11.5%, 13.0%, 9.1%, 18.8% or 20.6%, and the percentage refers to the mass percentage in the metronidazole particles; Preferably, the metronidazole particles comprise: (1) Drug core: The medicine core comprises metronidazole powder, a diluent, a glidant and an adhesive; The content of the metronidazole powder in the obtained medicine core can be more than or equal to 70%, for example 80%; (2) The coating layer is coated on the surface of the medicine core; The coating layer comprises gastric-soluble acrylic resin and ethyl cellulose; the mass ratio of the gastric-soluble acrylic resin to the ethyl cellulose is 1 (1-3); preferably, the coating layer further comprises an anti-adhesion agent and/or a surfactant Tween 80.
  8. 8. A process for the preparation of the metronidazole particles as claimed in any one of claims 1 to 7, characterized in that it comprises the following steps: (1) Mixing the raw materials in the coating layer with a solvent to obtain a coating solution; (2) Coating the coating solution on the outer surface of the medicine core, and drying to obtain the metronidazole particles; Preferably, the preparation method of the metronidazole particles comprises the following steps: (1) Mixing the metronidazole, the diluent, the adhesive and the glidant to obtain a material, and granulating the material to obtain the medicine core; (2) Mixing the raw materials in the coating layer with a solvent to obtain a coating solution; (3) And coating the coating solution on the outer surface of the medicine core, and drying to obtain the metronidazole particles.
  9. 9. Metronidazole preparation, characterized in that it comprises metronidazole particles as claimed in any of claims 1 to 7.
  10. 10. The metronidazole preparation as claimed in claim 9, characterized in that the mass content of the metronidazole particles in the metronidazole dry suspension is 40-50%, such as 45.0%; and/or the metronidazole preparation further comprises an excipient, wherein the excipient comprises one or more of a flavoring agent, a suspending agent, a diluent, a disintegrating agent, a binder, a glidant, a surfactant and a colorant; In the metronidazole dry suspension, the flavoring agent can be one or more selected from sucralose, sodium cyclamate, aspartame, xylitol, sorbitol and orange flavor essence; in the metronidazole dry suspension, the mass content of the flavoring agent can be 0% -5%, for example 0.05% -0.5%, and also for example 0.06%; In the metronidazole dry suspension, the suspending agent can be selected from one or more of microcrystalline cellulose, xanthan gum, sodium carboxymethyl cellulose and microcrystalline cellulose sodium carboxymethyl cellulose; in the metronidazole dry suspension, the mass content of the suspension adjuvant can be 1% -10%, for example 1.27%; In the metronidazole dry suspension, the diluent can be selected from sucrose and/or microcrystalline cellulose; In the metronidazole dry suspension, the mass content of the diluent can be 50% -80%, such as 50.63%; In the metronidazole dry suspension, the disintegrating agent can be selected from crosslinked sodium carboxymethyl cellulose and/or crosslinked povidone; the mass content of the disintegrating agent in the metronidazole dry suspension can be 0.5% -6%, such as 1.27%; In the metronidazole dry suspension, the binder can be selected from hypromellose; The mass content of the binder in the metronidazole dry suspension can be 0.5% -5%, for example 0.51%; In the metronidazole dry suspension, the glidant can be one or more selected from silicon dioxide, polyethylene glycol 6000 and magnesium stearate, such as colloidal silicon dioxide; 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 can be selected from tween-80; in the metronidazole dry suspension, the colorant can be selected from lemon yellow and/or beta-carotene; the mass content of the colorant in the metronidazole dry suspension can be 0.05% -0.5%, for example 0.06%; preferably, the metronidazole dry suspension comprises the following components: 355 parts of metronidazole particles Sucrose 300 parts Hydroxypropyl methylcellulose 4 parts Microcrystalline cellulose 100 parts 10 Parts of xanthan gum 10 Parts of croscarmellose sodium 10 Parts of colloidal silica Orange flavor essence 0.5 part Lemon yellow 0.5 parts.

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. The metronidazole has extremely bitter taste, the tablet and capsule dosage forms on the market at present have bad taste, heavy bitter taste, nausea, regurgitation and other bad feelings after taking, are not easy to accept by patients, have poor compliance, influence continuous medication and clinical curative effect, and are not suitable for children under 6 years old, so development of a dosage form with good taste masking effect suitable for oral administration of children is needed, and the problem of compliance of oral administration of 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 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 the effect of improving the taste is limited. 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, cases of using gastric soluble materials to prepare taste masking formulations have been disclosed in the prior art patents. For example, CN1273133C, CN103169669a et al, CN1273133C discloses coating berberine hydrochloride particles with an ethanol solution of the gastric soluble acrylic resin Eudragit EPO or E100, and the active ingredient targeted in CN103169669a is agomelatine, which can be dispersed in the mouth and is not suitable for metronidazole. Therefore, how to select a proper taste masking coating layer according to the dissolution property of metronidazole, so that the metronidazole has a good taste masking effect and is suitable for children to take medicine 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. In the research and development process, the invention tries to use the metronidazole crystal particles for taste masking coating, and although a better taste masking effect can be obtained, the granularity and granularity distribution of the metronidazole crystal particles need to be controlled. Because the preparation of large-batch metronidazole crystal particles meeting the requirement of particle size distribution is difficult and is limited by accessibility of raw materials, and the industrialized and amplified production of the process route is difficult to realize, the invention provides the metronidazole particles, a preparation containing the metronidazole particles and a preparation method thereof. The metronidazole drug core can be subjected to taste masking coating by using a mature fluidized bed wuster coating process route, the taste masking coating layer is prepared by coating the drug core by using an organic solvent system of gastric-soluble acrylic resin and ethyl cellulose as coating liquid, and the prepared particles have good taste masking effect and are suitable for children to take medicines, and meanwhile, the quick dissolution of the medicines in gastric juice is not influenced. The invention provides metronidazole particles, which comprise 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, wherein the film forming material comprises gastric-soluble acrylic resin and ethyl cellulose. In the invention, the metronidazole has