CN115444823B - Rebamipide-containing particles and preparation method and application thereof - Google Patents
Rebamipide-containing particles and preparation method and application thereof Download PDFInfo
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- CN115444823B CN115444823B CN202211246032.0A CN202211246032A CN115444823B CN 115444823 B CN115444823 B CN 115444823B CN 202211246032 A CN202211246032 A CN 202211246032A CN 115444823 B CN115444823 B CN 115444823B
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- rebamipide
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- attapulgite
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- ALLWOAVDORUJLA-UHFFFAOYSA-N Rebamipida Chemical compound C=1C(=O)NC2=CC=CC=C2C=1CC(C(=O)O)NC(=O)C1=CC=C(Cl)C=C1 ALLWOAVDORUJLA-UHFFFAOYSA-N 0.000 title claims abstract description 102
- 229950004535 rebamipide Drugs 0.000 title claims abstract description 102
- 239000002245 particle Substances 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 229960000892 attapulgite Drugs 0.000 claims abstract description 29
- 229910052625 palygorskite Inorganic materials 0.000 claims abstract description 29
- 229960000540 polacrilin potassium Drugs 0.000 claims abstract description 27
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 claims abstract description 27
- 239000000945 filler Substances 0.000 claims abstract description 11
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 239000007884 disintegrant Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims description 47
- 239000000463 material Substances 0.000 claims description 34
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 17
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 17
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 17
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 17
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 17
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 17
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 17
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 16
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 16
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 16
- 239000008187 granular material Substances 0.000 claims description 16
- 239000000741 silica gel Substances 0.000 claims description 13
- 229910002027 silica gel Inorganic materials 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 10
- 238000003825 pressing Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 229960003943 hypromellose Drugs 0.000 claims description 8
- 238000007908 dry granulation Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 239000000853 adhesive Substances 0.000 claims description 3
- 230000001070 adhesive effect Effects 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 235000020985 whole grains Nutrition 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 1
- 238000010298 pulverizing process Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract description 2
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 238000009826 distribution Methods 0.000 abstract description 2
- 230000035515 penetration Effects 0.000 abstract description 2
- 230000002195 synergetic effect Effects 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 20
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 9
- 239000011248 coating agent Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 239000000872 buffer Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000007882 Gastritis Diseases 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 206010061164 Gastric mucosal lesion Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 208000027744 congestion Diseases 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- -1 oxygen free radical Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229960005455 polacrilin Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910021487 silica fume Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the field of medicine preparation, in particular to rebamipide-containing particles, and a preparation method and application thereof. The invention provides rebamipide-containing particles, which comprise the following raw material components in percentage by mass: 18-22% of rebamipide, 7-10% of polacrilin potassium, 15-17% of attapulgite, 3-6% of binder, 46-47% of filler, 2-5% of disintegrant and 1-4% of glidant; wherein the mass ratio of the attapulgite to the polacrilin potassium is (1.5-2.5): 1. according to the invention, attapulgite and polacrilin potassium are added into the rebamipide particles, and the mass ratio of the attapulgite and the polacrilin potassium is controlled, so that the water distribution of microenvironment in the particles can be improved by the synergistic effect of the attapulgite and the polrvinyl chloride, the water absorption is bidirectionally controlled, the trace water penetration is reduced, the stability of the rebamipide-containing particles can be effectively improved, and the generation of impurities in the rebamipide-containing particles is reduced.
Description
Technical Field
The invention relates to the field of medicine preparation, in particular to rebamipide-containing particles, and a preparation method and application thereof.
Background
Rebamipide as a novel antiulcer agent can increase prostaglandin synthesis, promote epidermal growth factor and its receptor expression, inhibit neutrophil activation, scavenge oxygen free radical, etc. The present research shows that it is effective for various experimental gastric ulcers, can promote prostaglandin production, protect gastric mucosa from being damaged by various ulcer-causing factors, and has higher clinical application value.
The rebamipide granules on the market are developed and produced by the Japanese Katsukamurella pharmaceutical Co., ltd, and can be used for improving and treating gastric ulcer, acute gastritis, acute heavy-phase gastric mucosal lesion (erosion, hemorrhage, congestion and edema) of chronic gastritis. However, because of the wettability and unstable illumination of rebamipide, rebamipide particles are generally prepared into coated particles in the prior art, but the coated particles have complicated procedures and high cost, and related substances still have obvious increase and poor stability under the acceleration condition.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defects that the existing rebamipide particles are poor in stability, such as complex process, high cost and limited stability improvement effect when being treated by adopting a coating technology, so that the rebamipide-containing particles, and the preparation method and application thereof are provided.
The invention provides rebamipide-containing particles, which comprise the following raw material components in percentage by mass: 18-22% of rebamipide, 7-10% of polacrilin potassium, 15-17% of attapulgite, 3-6% of binder, 46-47% of filler, 2-5% of disintegrant and 1-4% of glidant; wherein the mass ratio of the attapulgite to the polacrilin potassium is (1.5-2.5): 1.
preferably, the binder is selected from one or more of hypromellose, povidone, and hydroxyethyl cellulose;
the filler is selected from one or more of microcrystalline cellulose, lactose and corn starch;
the disintegrating agent is one or more selected from carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl cellulose, crosslinked povidone, carboxymethyl cellulose and carboxymethyl cellulose calcium;
the glidant comprises micro powder silica gel.
The invention also provides a preparation method of the rebamipide-containing particles, which comprises the following steps:
1) Mixing rebamipide, polacrilin potassium, attapulgite, an adhesive, a filler, a disintegrating agent and a glidant to obtain a mixed material;
2) And (3) carrying out dry granulation on the mixed material to obtain the rebamipide-containing particles.
Preferably, the mixing step comprises mixing rebamipide and polacrilin potassium at a speed of 10-15rpm for 2-10min, adding attapulgite and mixing at a speed of 10-15rpm for 2-10min, and finally adding binder, filler, disintegrant and glidant and mixing at a speed of 10-15rpm for 2-10min to obtain a mixed material.
Preferably, the dry granulation step comprises pushing the mixture at a rotation speed of 35-100rpm, pressing the mixture at a pressure of 30-50bar, crushing the mixture at a rotation speed of 90-150rpm, and granulating the crushed mixture at a rotation speed of 150-200rpm to obtain the rebamipide-containing granules; the number of the whole grain meshes used in the finishing step is 10-30 meshes.
Preferably, the particles with the particle diameter below 80 meshes in the rebamipide-containing particles do not exceed 15wt%.
The invention also provides a solid preparation, which comprises the rebamipide-containing particles or the rebamipide-containing particles prepared by the preparation method.
Preferably, the solid preparation is a tablet, a capsule or a granule.
The technical scheme of the invention has the following advantages:
1. the invention provides rebamipide-containing particles, which comprise the following raw material components in percentage by mass: 18-22% of rebamipide, 7-10% of polacrilin potassium, 15-17% of attapulgite, 3-6% of binder, 46-47% of filler, 2-5% of disintegrant and 1-4% of glidant; wherein the mass ratio of the attapulgite to the polacrilin potassium is (1.5-2.5): 1.
according to the invention, attapulgite and polacrilin potassium are added into the rebamipide particles, and the mass ratio of the attapulgite and the polacrilin potassium is controlled, so that the water distribution of microenvironment in the particles can be improved by the synergistic effect of the attapulgite and the polrvinyl chloride, the water absorption is bidirectionally controlled, the trace water penetration is reduced, the stability of the rebamipide-containing particles can be effectively improved, and the generation of impurities in the rebamipide-containing particles is reduced; meanwhile, the rebamipide-containing particles provided by the invention have high dissolution speed and can realize the quick release effect.
2. Furthermore, the preparation method of the rebamipide-containing granules provided by the invention adopts dry granulation, does not need granule coating, has simple process, simple and convenient operation and good process reproducibility, and is suitable for industrial production.
Detailed Description
The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments described herein, but are not intended to limit the scope of the invention, any product which is the same or similar to the present invention, whether in light of the present teachings or in combination with other prior art features, falls within the scope of the present invention.
The specific experimental procedures or conditions are not noted in the examples and may be followed by the operations or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
Rebamipide used in examples and comparative examples was purchased from ataxia pharmaceutical company, ltd;
potassium polacrilin is available from Luo-auxiliary medicine development technology Co., ltd., model KYRON T-314.
Example 1
The present embodiment provides a rebamipide-containing granule comprising: 20wt% of rebamipide, 10wt% of polacrilin potassium, 15wt% of attapulgite, 46wt% of microcrystalline cellulose, 5wt% of hypromellose, 3wt% of croscarmellose sodium and 1wt% of micro powder silica gel.
The preparation method of the rebamipide-containing particles comprises the following steps:
1) Mixing 100g of rebamipide and 50g of polacrilin potassium in a mixing barrel at a rotating speed of 12rpm for 3min, adding 75g of attapulgite in the mixing barrel and mixing at the rotating speed of 12rpm for 3min, adding 230g of microcrystalline cellulose, 25g of hydroxypropyl methylcellulose, 15g of croscarmellose sodium and 5g of micropowder silica gel in the mixing barrel and mixing at the rotating speed of 12rpm for 5min to obtain a mixed material;
2) Pushing the mixed material obtained in the step 1) at a rotating speed of 40rpm, pressing at a pressure of 45bar, crushing in a crusher at a rotating speed of 120rpm, transferring the crushed material into a granulator, and granulating (the number of the granulating sieve is 10 meshes) at a rotating speed of 180rpm in the granulator to obtain the rebamipide-containing particles (the particle size of the rebamipide-containing particles is less than 80 meshes and is 12 wt%).
Example 2
The present embodiment provides a rebamipide-containing granule comprising: 20wt% of rebamipide, 8wt% of polacrilin potassium, 16wt% of attapulgite, 47wt% of microcrystalline cellulose, 5wt% of hypromellose, 3wt% of croscarmellose sodium and 1wt% of micro powder silica gel.
The preparation method of the rebamipide-containing particles comprises the following steps:
1) Mixing 100g of rebamipide and 40g of polacrilin potassium in a mixing barrel at a rotating speed of 12rpm for 3min, adding 80g of attapulgite in the mixing barrel and mixing at the rotating speed of 12rpm for 3min, adding 235g of microcrystalline cellulose, 25g of hydroxypropyl methylcellulose, 15g of croscarmellose sodium and 5g of micropowder silica gel in the mixing barrel and mixing at the rotating speed of 12rpm for 5min to obtain a mixed material;
2) Pushing the mixed material obtained in the step 1) at a rotating speed of 40rpm, pressing at a pressure of 45bar, crushing in a crusher at a rotating speed of 120rpm, transferring the crushed material into a granulator, and granulating (the number of the granulating sieve is 10 meshes) at a rotating speed of 180rpm in the granulator to obtain the rebamipide-containing particles (the particle size of the rebamipide-containing particles is less than 80 meshes and is 12 wt%).
Example 3
The present embodiment provides a rebamipide-containing granule comprising: 20wt% of rebamipide, 7wt% of polacrilin potassium, 17.4wt% of attapulgite, 46.6wt% of microcrystalline cellulose, 5wt% of hydroxypropyl methylcellulose, 3wt% of croscarmellose sodium and 1wt% of micro powder silica gel.
The preparation method of the rebamipide-containing particles comprises the following steps:
1) Mixing 100g of rebamipide and 35g of polacrilin potassium in a mixing barrel at a rotating speed of 12rpm for 3min, adding 87g of attapulgite in the mixing barrel and mixing at the rotating speed of 12rpm for 3min, adding 233g of microcrystalline cellulose, 25g of hydroxypropyl methylcellulose, 15g of croscarmellose sodium and 5g of micropowder silica gel in the mixing barrel and mixing at the rotating speed of 12rpm for 5min to obtain a mixed material;
2) Pushing the mixed material obtained in the step 1) at a rotating speed of 40rpm, pressing at a pressure of 45bar, crushing in a crusher at a rotating speed of 120rpm, transferring the crushed material into a granulator, and granulating (the number of the granulating sieve is 10 meshes) at a rotating speed of 180rpm in the granulator to obtain the rebamipide-containing particles (the particle size of the rebamipide-containing particles is less than 80 meshes and is 12 wt%).
Comparative example 1
This comparative example provides a rebamipide-containing granule comprising: 20wt% of rebamipide, 15wt% of attapulgite, 56wt% of microcrystalline cellulose, 5wt% of hypromellose, 3wt% of croscarmellose sodium and 1wt% of micro silica gel.
The preparation method of the rebamipide-containing particles provided in this comparative example comprises the following steps:
1) Mixing 100g of rebamipide and 75g of attapulgite in a mixing barrel at a rotating speed of 12rpm for 3min, adding 280g of microcrystalline cellulose, 25g of hydroxypropyl methylcellulose, 15g of croscarmellose sodium and 5g of superfine silica powder into the mixing barrel, and mixing at a rotating speed of 12rpm for 5min to obtain a mixed material;
2) Pushing the mixed material obtained in the step 1) at a rotating speed of 40rpm, pressing at a pressure of 45bar, crushing in a crusher at a rotating speed of 120rpm, transferring the crushed material into a granulator, and granulating (the number of the granulating sieve is 10 meshes) at a rotating speed of 180rpm in the granulator to obtain the rebamipide-containing particles (the particle size of the rebamipide-containing particles is less than 80 meshes and is 12 wt%).
Comparative example 2
This comparative example provides a rebamipide-containing granule comprising: 20% by weight of rebamipide, 10% by weight of polacrilin potassium, 61% by weight of microcrystalline cellulose, 5% by weight of hypromellose, 3% by weight of croscarmellose sodium and 1% by weight of colloidal silica.
The preparation method of the rebamipide-containing particles provided in this comparative example comprises the following steps:
1) Mixing 100g of rebamipide and 50g of polacrilin potassium in a mixing barrel at a rotating speed of 12rpm for 3min, adding 305g of microcrystalline cellulose, 25g of hydroxypropyl methylcellulose, 15g of croscarmellose sodium and 5g of superfine silica gel powder in the mixing barrel, and mixing at a rotating speed of 12rpm for 5min to obtain a mixed material;
2) Pushing the mixed material obtained in the step 1) at a rotating speed of 40rpm, pressing at a pressure of 45bar, crushing in a crusher at a rotating speed of 120rpm, transferring the crushed material into a granulator, and granulating (the number of the granulating sieve is 10 meshes) at a rotating speed of 180rpm in the granulator to obtain the rebamipide-containing particles (the particle size of the rebamipide-containing particles is less than 80 meshes and is 12 wt%).
Comparative example 3
This comparative example provides a rebamipide-containing granule comprising: 20% by weight of rebamipide, 12% by weight of polacrilin potassium, 13% by weight of attapulgite, 46% by weight of microcrystalline cellulose, 5% by weight of hypromellose, 3% by weight of croscarmellose sodium and 1% by weight of colloidal silica.
The preparation method of the rebamipide-containing particles comprises the following steps:
1) Mixing 100g of rebamipide and 60g of polacrilin potassium in a mixing barrel at a rotating speed of 12rpm for 3min, adding 65g of attapulgite in the mixing barrel and mixing at the rotating speed of 12rpm for 3min, adding 230g of microcrystalline cellulose, 25g of hydroxypropyl methylcellulose, 15g of croscarmellose sodium and 5g of micropowder silica gel in the mixing barrel and mixing at the rotating speed of 12rpm for 5min to obtain a mixed material;
2) Pushing the mixed material obtained in the step 1) at a rotating speed of 40rpm, pressing at a pressure of 45bar, crushing in a crusher at a rotating speed of 120rpm, transferring the crushed material into a granulator, and granulating (the number of the granulating sieve is 10 meshes) at a rotating speed of 180rpm in the granulator to obtain the rebamipide-containing particles (the particle size of the rebamipide-containing particles is less than 80 meshes and is 12 wt%).
Comparative example 4
This comparative example provides a rebamipide-containing granule comprising: 20% by weight of rebamipide, 71% by weight of microcrystalline cellulose, 5% by weight of hypromellose, 3% by weight of croscarmellose sodium and 1% by weight of gum acacia.
The preparation method of the rebamipide-containing particles provided in this comparative example comprises the following steps:
1) Mixing 100g of rebamipide, 355g of microcrystalline cellulose, 25g of hydroxypropyl methylcellulose, 15g of croscarmellose sodium and 5g of superfine silica gel powder in a mixing barrel at a rotating speed of 12rpm for 5min to obtain a mixed material;
2) Pushing the mixed material obtained in the step 1) at a rotating speed of 40rpm, pressing at a pressure of 45bar, crushing in a crusher at a rotating speed of 120rpm, transferring the crushed material into a granulator, and granulating (the number of the granulating sieve is 10 meshes) at a rotating speed of 180rpm in the granulator to obtain the rebamipide-containing particles (the particle size of the rebamipide-containing particles is less than 80 meshes and is 12 wt%).
Comparative example 5
The comparative example provides a preparation method of rebamipide-containing particles, comprising the following steps:
1) Mixing 100g of rebamipide, 330g of microcrystalline cellulose, 25g of hydroxypropyl methylcellulose, 15g of croscarmellose sodium and 5g of superfine silica gel powder in a mixing barrel at a rotating speed of 12rpm for 5min to obtain a mixed material;
2) Pushing the mixed material obtained in the step 1) at a rotating speed of 40rpm, pressing at a pressure of 45bar, crushing in a crusher at a rotating speed of 120rpm, transferring the crushed material into a granulator, and granulating (the number of the granulating sieve is 10 meshes) at a rotating speed of 180rpm in the granulator to obtain the rebamipide-containing particles (the particle size of the rebamipide-containing particles is less than 80 meshes and is 12 wt%).
3) Transferring the rebamipide-containing particles obtained in the step 2) into a fluidized bed for coating to obtain rebamipide-containing coated particles, wherein the coating material is the moisture-proof coating powder of the opadry abm, and the coating material is 25g.
Test case
1. Dissolution rate
The dissolution of the particles containing rebamipide in the examples and comparative examples was tested by the slurry method in the four-rule of the chinese pharmacopoeia 2020 edition, and the specific method comprises: the dissolution rate of the particles containing rebamipide in examples and comparative examples was measured by an ultraviolet spectrophotometer after stirring at 37℃for 60 minutes at a stirring rate of 50r/min in 900ml of a buffer (the buffer is phosphate buffer, the pH of the buffer is 6.0), and the measurement results are shown in Table 1.
TABLE 1
| Examples | 1 | 2 | 4 | Comparative example | 1 | 2 | 3 | 4 | 5 |
| Dissolution in wt% | 101％ | 95％ | 99％ | Dissolution in wt% | 96％ | 70％ | 85％ | 103％ | 100％ |
2. Impurity and moisture testing
The stability of the rebamipide-containing particles (rebamipide-containing coated particles of comparative example 5) obtained finally in examples and comparative examples was tested by: the rebamipide-containing particles obtained in the examples and comparative examples were subjected to accelerated stability test in an environment of 40℃and 75% RH, and the differences were determined by high performance liquid chromatographyThe contents of the related substances and moisture after the standing time are shown in Table 2. Wherein the impurity 1 in the related substances is an O-isomer, and the impurity 2 is debenzoyl impurity 。
TABLE 2
Note that: other single impurities below 0.05% were not reported, "/" represents undetected.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (7)
1. The rebamipide-containing granule is characterized by comprising the following raw materials in percentage by mass: 18-22% of rebamipide, 7-10% of polacrilin potassium, 15-17% of attapulgite, 3-6% of binder, 46-47% of filler, 2-5% of disintegrant and 1-4% of glidant; wherein the mass ratio of the attapulgite to the polacrilin potassium is (1.5-2.5): 1, a step of;
the binder is selected from hypromellose;
the filler is selected from microcrystalline cellulose;
the disintegrating agent is selected from croscarmellose sodium;
the glidant comprises micro powder silica gel;
the preparation method of the rebamipide-containing particles is characterized by comprising the following steps of:
1) Mixing rebamipide, polacrilin potassium, attapulgite, an adhesive, a filler, a disintegrating agent and a glidant to obtain a mixed material;
2) And (3) carrying out dry granulation on the mixed material to obtain the rebamipide particles.
2. A process for the preparation of the rebamipide-containing particles according to claim 1, comprising the steps of:
1) Mixing rebamipide, polacrilin potassium, attapulgite, an adhesive, a filler, a disintegrating agent and a glidant to obtain a mixed material;
2) And (3) carrying out dry granulation on the mixed material to obtain the rebamipide particles.
3. The method of claim 2, wherein the mixing step comprises mixing rebamipide and polacrilin potassium at a speed of 10-15rpm for 2-10min, adding attapulgite and mixing at a speed of 10-15rpm for 2-10min, and finally adding binder, filler, disintegrant and glidant and mixing at a speed of 10-15rpm for 2-10min to obtain a mixed material.
4. A process for the preparation of rebamipide-containing granules according to claim 2 or 3, wherein the dry granulation step comprises pushing the mixture at a speed of 35-100rpm, pressing at a pressure of 30-50bar, pulverizing at a speed of 90-150rpm, and granulating at a speed of 150-200rpm to obtain the rebamipide-containing granules; the number of the whole grain meshes used in the finishing step is 10-30 meshes.
5. The method for producing rebamipide-containing particles according to claim 2, wherein the amount of particles having a particle diameter of 80 mesh or less in the rebamipide-containing particles is not more than 15% by weight.
6. A solid formulation comprising the rebamipide-containing particles of claim 1 or the rebamipide-containing particles produced by the process for producing rebamipide-containing particles of any one of claims 2-5.
7. The solid preparation according to claim 6, wherein the solid preparation is a tablet, a capsule or a granule.
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| CN112603899A (en) * | 2020-12-23 | 2021-04-06 | 南京友杰医药科技有限公司 | Rebamipide enteric-coated tablet and preparation method thereof |
| WO2021091188A1 (en) * | 2019-11-05 | 2021-05-14 | 아주대학교산학협력단 | Sustained-release pharmaceutical composition for oral administration, containing rebamipide or pharmaceutically acceptable salt thereof |
| CN114053242A (en) * | 2021-11-19 | 2022-02-18 | 苏州天马医药集团天吉生物制药有限公司 | Rebamipide tablet and preparation method thereof |
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| WO2021091188A1 (en) * | 2019-11-05 | 2021-05-14 | 아주대학교산학협력단 | Sustained-release pharmaceutical composition for oral administration, containing rebamipide or pharmaceutically acceptable salt thereof |
| CN112603899A (en) * | 2020-12-23 | 2021-04-06 | 南京友杰医药科技有限公司 | Rebamipide enteric-coated tablet and preparation method thereof |
| CN114053242A (en) * | 2021-11-19 | 2022-02-18 | 苏州天马医药集团天吉生物制药有限公司 | Rebamipide tablet and preparation method thereof |
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| 陈强等.《水生动物药物学》.中国农业出版社,2005,第32页. * |
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