CN116270514A - Micropill tablet and preparation method thereof - Google Patents
Micropill tablet and preparation method thereof Download PDFInfo
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- CN116270514A CN116270514A CN202310284542.5A CN202310284542A CN116270514A CN 116270514 A CN116270514 A CN 116270514A CN 202310284542 A CN202310284542 A CN 202310284542A CN 116270514 A CN116270514 A CN 116270514A
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- tablet
- pellets
- micropellet
- spraying
- pellet
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- 238000002360 preparation method Methods 0.000 title claims abstract description 70
- 239000008188 pellet Substances 0.000 claims abstract description 203
- 238000005507 spraying Methods 0.000 claims abstract description 130
- 239000003814 drug Substances 0.000 claims abstract description 102
- 238000000576 coating method Methods 0.000 claims abstract description 63
- 239000011248 coating agent Substances 0.000 claims abstract description 60
- 229940079593 drug Drugs 0.000 claims abstract description 60
- 239000000463 material Substances 0.000 claims abstract description 56
- 238000000034 method Methods 0.000 claims abstract description 52
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 238000003825 pressing Methods 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 49
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 49
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 49
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 49
- 238000013268 sustained release Methods 0.000 claims description 40
- RGHAZVBIOOEVQX-UHFFFAOYSA-N Metoprolol succinate Chemical compound OC(=O)CCC(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 RGHAZVBIOOEVQX-UHFFFAOYSA-N 0.000 claims description 35
- 229960000939 metoprolol succinate Drugs 0.000 claims description 34
- 238000013270 controlled release Methods 0.000 claims description 26
- 230000002459 sustained effect Effects 0.000 claims description 26
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims description 20
- 239000011259 mixed solution Substances 0.000 claims description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- 229960003174 lansoprazole Drugs 0.000 claims description 15
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000011230 binding agent Substances 0.000 claims description 14
- 239000012730 sustained-release form Substances 0.000 claims description 14
- 239000002245 particle Substances 0.000 claims description 12
- 239000000945 filler Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 229960000197 esomeprazole magnesium Drugs 0.000 claims description 6
- KWORUUGOSLYAGD-WLHYKHABSA-N magnesium;5-methoxy-2-[(r)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [Mg+2].C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-WLHYKHABSA-N 0.000 claims description 6
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 6
- 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 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 239000004353 Polyethylene glycol 8000 Substances 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 229940057838 polyethylene glycol 4000 Drugs 0.000 claims description 2
- 229940085678 polyethylene glycol 8000 Drugs 0.000 claims description 2
- 235000019446 polyethylene glycol 8000 Nutrition 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 91
- 239000010410 layer Substances 0.000 description 78
- 239000000243 solution Substances 0.000 description 67
- 230000004584 weight gain Effects 0.000 description 36
- 235000019786 weight gain Nutrition 0.000 description 36
- 239000008213 purified water Substances 0.000 description 30
- 238000003756 stirring Methods 0.000 description 30
- 239000011241 protective layer Substances 0.000 description 28
- 239000006187 pill Substances 0.000 description 26
- 238000000889 atomisation Methods 0.000 description 22
- 238000009826 distribution Methods 0.000 description 22
- 230000002572 peristaltic effect Effects 0.000 description 22
- 238000004090 dissolution Methods 0.000 description 21
- 238000005070 sampling Methods 0.000 description 20
- 239000007788 liquid Substances 0.000 description 18
- 238000007873 sieving Methods 0.000 description 18
- 238000005303 weighing Methods 0.000 description 14
- 238000007599 discharging Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 239000012055 enteric layer Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- 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 6
- 239000000454 talc Substances 0.000 description 6
- 229910052623 talc Inorganic materials 0.000 description 6
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 239000012738 dissolution medium Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000001856 Ethyl cellulose Substances 0.000 description 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
- 229920001249 ethyl cellulose Polymers 0.000 description 4
- 235000019325 ethyl cellulose Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000009384 kangtai Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012898 sample dilution Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 239000003643 water by type Substances 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a pellet tablet and a preparation method thereof. The preparation method of the micropill tablet comprises the following steps: dispersing the medicinal auxiliary materials in a solvent, spraying the medicinal auxiliary materials on the surfaces of the micropills to form a coating on the surfaces of the micropills, and finally pressing the micropills containing the coating into tablets; wherein the absolute humidity of the air in the spraying process is 2-30 kg/cm 3 . The preparation method is simple to operate, and the obtained micropill tablet releases the medicinal yeast before and after tablettingThe linear similarity factor f2 can reach more than 64, layering is not easy to occur in the process of tabletting the pellets, the tablet weight and the uniformity of the drug content are good, and the preparation method of the pellet tablet disclosed by the invention can be suitable for the common pellet tabletting in the market, is a universal preparation method, and has a good application prospect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a pellet tablet and a preparation method thereof.
Background
The oral sustained-release drug delivery system is an important field of pharmaceutical research and can be mainly divided into two main categories: single unit preparations, such as tablets, capsules, and the like, and multi-unit preparations, such as pellets, microcapsules, granules, or microparticles. Multiple unit formulations offer many advantages over single unit formulations, while pellets are the most studied and most widely used dosage forms in multiple unit formulations. From the pharmacodynamics, the micropill has a plurality of advantages, such as uniform distribution in gastrointestinal tracts, improving the bioavailability of the medicine, reducing the dosage of the medicine and alleviating adverse reactions; the defects in the preparation of individual pellets do not affect the overall therapeutic effect, are less affected by gastric emptying, reduce individual differences caused by food, and the like. In addition, the pellets have the advantages of good fluidity, uniform size and easy treatment (such as coating, dosage division, etc.).
At present, the preparation products based on the micropill are mainly used as capsules, such as pseudoephedrine/chlorpheniramine capsules (kangtai), ibuprofen capsules (fenpride) and the like. The pellet pressed tablet has a small number of products because of the great difficulty of the preparation process. Pellet tableting presents mainly the following 3 challenges: (1) the coating film of the pellets is easy to be damaged in the tabletting process, so that the drug release curves before and after tabletting are inconsistent; (2) layering easily occurs in the tabletting process, and tablet weight and medicine content uniformity are poor; (3) the pellets are mutually collided and fused in tabletting, and can not be rapidly disintegrated into single pellets in the gastrointestinal tract after being taken. Although having greater challenges, pellet tableting also has its own unique advantages, such as smaller volume after pellet tableting, and convenience for patient to swallow compared to capsules; the tablet can be scored and used in divided doses, has higher dose flexibility, and has important significance for medicines with smaller therapeutic indexes and doses to be adjusted at any time, such as metoprolol succinate, carbamazepine, topiramate and the like; or high-end preparations such as orally disintegrating tablets (orally disintegratingtablets, ODT) pressed by pellets, which have the characteristics of rapid oral disintegration and the like while ensuring the original drug release characteristics, are convenient for patients with dysphagia to take.
Disclosure of Invention
The technical problems solved by the invention are as follows: in the prior art, the number of products of the pellets for pressing tablets is small, and the coating film of the pellets is easy to be damaged in the process of tabletting, so that the drug release curves before and after tabletting are inconsistent; the pellets are easy to be layered in the tabletting process, and the tablet weight and the uniformity of the drug content are poor, so that the wide application of the pellet tabletting technology is limited.
In view of the above problems, it is an object of the present invention to provide a pellet tablet and a method for producing the same.
Specifically, the invention provides the following technical scheme:
in a first aspect, the present invention provides a method of preparing a pellet tablet comprising the steps of: dispersing the medicinal auxiliary materials in a solvent, spraying the medicinal auxiliary materials on the surfaces of the micropills to form a coating on the surfaces of the micropills, and finally pressing the micropills containing the coating into tablets; wherein the absolute humidity of the air in the spraying process is 2-30 kg/cm 3 。
In some embodiments, the weight ratio of the pharmaceutical excipients to the pellets is 1 (2-6).
In some embodiments, the pharmaceutical excipients include a binder and a filler material.
In some embodiments, the weight ratio of binder to filler material is (3-6): (4-7).
In some embodiments, the binder is selected from one or more of polyethylene glycol, polyvinyl alcohol, and polyethylene oxide.
In some embodiments, the filler material is selected from microcrystalline cellulose and/or lactose.
In some embodiments, the pharmaceutical excipients include polyethylene glycol and microcrystalline cellulose.
In some embodiments, the polyethylene glycol is selected from polyethylene glycol 4000, polyethylene glycol 6000 and/or polyethylene glycol 8000.
In some embodiments, the polyethylene glycol is polyethylene glycol 6000.
In some embodiments, the microcrystalline cellulose has a particle size of 10 to 200 microns.
In some embodiments, the microcrystalline cellulose has a particle size of 10 to 130 microns.
In some embodiments, the microcrystalline cellulose has a particle size of 10 to 100 microns.
In some embodiments, the conditions of the spraying are: the spraying speed is 2-30 mg/min.
In some embodiments, the conditions of the spraying are: the temperature of the materials is controlled to be 20-80 ℃.
In some embodiments, the conditions of the spraying are: the temperature of the materials is controlled to be 20-50 ℃.
In some embodiments, the conditions of the spraying are: intake air volume: 30-70 m 3 /h。
In some embodiments, the conditions of the spraying are: intake air volume: 40-60 m 3 /h。
In some embodiments, the solvent is selected from water, ethanol, or a mixed solution of the two.
In some embodiments, the weight percent of ethanol in the mixed solution is 10% to 90%.
In some embodiments, the weight ratio of solvent to binder is 1 (0.1 to 1).
In some embodiments, the pellets are tiny units with independent release capabilities.
In some embodiments, the pellets are drug-containing sustained-release pellets or drug-containing enteric pellets.
In some embodiments, the micropellet tablet has a similarity factor f2 value between the drug release profile of the micropellet of greater than 50.
In some embodiments, the micropellet tablet has a similarity factor f2 value between the drug release profile of the micropellet above 64.
In some embodiments, the micropellet tablet has a similarity factor f2 value between the drug release profile of the micropellet of 64-80.
In some embodiments, the drug content uniformity of the micropellet tablet is AV <15.
In some embodiments, the pellet tablet has a core hardness of less than 200N.
In some embodiments, the pellet tablet has a core hardness of 80 to 150N.
In some embodiments, the friability of the pellet tablet is 0.01% to 0.2%.
In a second aspect, the present invention provides a micropellet tablet prepared by the method of preparing a micropellet tablet.
In some embodiments, the pellets in the pellet tablet are any one of metoprolol succinate sustained and controlled release pellets, esomeprazole magnesium enteric pellets, and lansoprazole enteric pellets.
In a third aspect, the invention provides a protective pharmaceutical adjuvant composition for pellet tabletting, which is characterized by comprising a binder and a filler.
In some embodiments, the binder is polyethylene glycol and the filler material is microcrystalline cellulose and/or lactose.
In some embodiments, the microcrystalline cellulose has a particle size of 10 to 200 microns.
In some embodiments, the microcrystalline cellulose has a particle size of 10 to 130 microns.
In some embodiments, the microcrystalline cellulose has a particle size of 10 to 100 microns.
In some embodiments, the polyethylene glycol is polyethylene glycol 6000.
The beneficial effects of the invention are that
(1) The micropill tablet obtained by the preparation method disclosed by the invention is consistent with the drug release curve of the micropill before tabletting, the dissolution rate similarity factor F2 can reach more than 64, and F2 is more than 50 and is judged to be qualified.
(2) The micropill tablet prepared by the method has no layering phenomenon, and has better uniformity of medicine content and uniformity av <15.
(3) In the preparation method of the pellet tablet, the novel mixture is formed by adding the binder and the filling auxiliary materials in a polymerization mode, so that collision fusion among pellets can be effectively blocked.
(4) The hardness of the pellet tablet prepared by the preparation method can reach 80-150N, and the friability is less than 1%.
(5) The method for preparing the micropill tablet can be suitable for the micropill commonly used in the market, and is a universal preparation method.
Detailed Description
As described above, the present invention aims to provide a pellet tablet and a method for preparing the same. The micropill tablet obtained by the preparation method of the micropill tablet solves the following technical problems: 1) The coating film of the pellets is easy to be damaged in the tabletting process, so that the drug release curves before and after tabletting are inconsistent; 2) Layering easily occurs in the tabletting process, and tablet weight and medicine content uniformity are poor.
The micropill used in the preparation of the micropill tablet in the invention is a common micropill in the market, such as metoprolol succinate sustained and controlled release micropill, esomeprazole magnesium enteric micropill or lansoprazole enteric micropill.
In the prior art, microcrystalline cellulose is usually used as an additional auxiliary material to be mixed with the pellets to play a role of filling, but the applicant has the sharp idea that the microcrystalline cellulose is uniformly mixed with polyethylene glycol and dispersed in a solvent by regulating and controlling the granularity of the microcrystalline cellulose, and a protective layer is formed on the surface of the pellets by adopting a spraying mode, so that the protective strength of the pellets in the tabletting process can be remarkably improved, the drug release curves of the pellets before and after tabletting are kept consistent, the content uniformity of the drug is better, and collision fusion among the pellets is effectively blocked. In addition, the invention enhances the bridging mode between microcrystalline cellulose and polyethylene glycol by controlling the air humidity in the spraying process, so that the protective layer has better film forming property.
The various reagents/instruments used in the examples and comparative examples of the present invention, unless otherwise specified, are conventional commercially available products, and the experimental materials and instrument information used in the present invention are shown in the following table:
table 1 experimental materials/instruments and manufacturers
In order to better understand the technical scheme of the present invention, the following describes the technical scheme of the present invention in detail with reference to specific embodiments.
Example 1
1.1 preparation of metoprolol succinate sustained and controlled release pellets:
1.1.1 preparation of drug-containing layer pellets
Weighing each component of the medicine-containing layer, preparing medicine-containing layer solution, spraying and coating the bottom of the medicine-containing layer, and drying.
The components of the coating liquid containing the medicine layer and the preparation are as follows:
table 2 prescription of coating liquid for medicated layer
Preparing a medicine-containing layer solution:
(1) heating the purified water to 60 ℃;
(2) dissolving metoprolol succinate in 60% of purified water, stirring, dissolving and clarifying;
(3) dispersing hydroxypropyl methylcellulose with 25% of purified water, stirring, dissolving and clarifying;
(4) adding the step (3) into the step (2), stirring uniformly, and sieving with a 40-mesh sieve;
(5) rinsing the device with the remaining purified water and passing all through a 40 mesh screen;
and (3) the operation and parameter setting range of the bottom spraying coating of the medicine-containing layer:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; the drug-containing pellets are sieved by a 25-mesh sieve and a 60-mesh sieve, and the pellets in the middle of the two sieves are target pellets. And (5) sampling, analyzing and detecting, and measuring the content and the moisture.
TABLE 3 coating parameters setting ranges for drug-containing layers
Remarks: and after the operation is finished, the gradient sampling theory is 0.63mg/mg, and the content detection is carried out.
1.1.2 preparation of sustained-release pellets
Weighing each component of the slow release layer, preparing slow release layer solution, spraying and coating the slow release layer bottom, and drying.
TABLE 4 prescription information for sustained release layer
Preparing a slow release layer coating liquid:
(1) dissolving ethyl cellulose in ethanol solution, and uniformly stirring;
(2) dispersing talc in (1);
(3) dissolving acetyl triethyl citrate in purified water, and uniformly stirring;
(4) sieving the solution (3) with a 40-mesh sieve;
the operation of slow-release layer bottom-spraying coating and the parameter setting range:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; sieving the drug-containing pellets with 25-mesh and 60-mesh sieves, wherein the pellets in the middle of the two sieves are target pellets; and (5) sampling, analyzing and detecting, and measuring the content, the moisture and the dissolution.
TABLE 5 parameter settings for sustained release coatings
| Setting content | Parameters (parameters) |
| Fluidized bed middle barrel | Wurster column |
| Bottom height of guide cylinder | 15mm |
| Air flow distribution plate | Fixing |
| Nozzle diameter | 1.0mm |
| Nozzle/air nozzle position | Flush |
| Air inlet temperature | 50～60℃ |
| Material temperature | 30～40℃ |
| Peristaltic pump speed | 5～20rpm |
| Atomization pressure | 1.2bar |
| Intake air volume | 40～60m 3 /h |
| Humidity of the water | 15cm 3 /kg |
1.2 preparation of metoprolol succinate sustained and controlled release pellet tablets
Uniformly dispersing 60g of microcrystalline cellulose and 40g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 10 microns; then spraying 500g pill core with the mixed solution by bottom spraying, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 15mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 20%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 80-150N, and the friability is 0.01%. The similarity factor f2 between the drug release profile of the pellet tablets and pellets prepared in example 1 was 70.
Wherein, the friability test of the micropill tablet of the invention refers to 0923 tablet friability inspection method in the 2020 edition of Chinese pharmacopoeia. The hardness of the pellet tablets of the invention were tested as follows: taking 20 tablets, respectively placing the tablets with a tablet hardness tester (model: YD-35, manufacturing company: tianjin Tiantian Fa technology Co., ltd.) to measure the tablet hardness, and reading the value. The calculation of the similarity factor f2 is measured by referring to the general oral solid preparation dissolution curve measurement and comparison guiding principle, and the calculation formula is as follows:
wherein Rt is the average leaching amount of a reference sample at t time; tt is the average leaching amount of the tested sample at time t; n is the number of sampling time points.
Example 2
2.1 preparation of metoprolol succinate sustained and controlled release pellets:
2.1.1 preparation of drug-containing layer pellets:
weighing each component of the medicine-containing layer, preparing medicine-containing layer solution, spraying and coating the bottom of the medicine-containing layer, and drying.
The components of the coating liquid containing the medicine layer and the preparation are as follows:
table 6 prescription of coating solution for drug-containing layer
Preparing a medicine-containing layer solution:
(1) heating the purified water to 60 ℃;
(2) dissolving metoprolol succinate in 60% of purified water, stirring, dissolving and clarifying;
(3) taking 25% of purified water to disperse hydroxypropyl methylcellulose, stirring, dissolving and clarifying;
(4) Adding the step (3) into the step (2), stirring uniformly, and sieving with a 40-mesh sieve;
(5) rinsing the device with the remaining purified water and passing all through a 40 mesh screen;
and (3) the operation and parameter setting range of the bottom spraying coating of the medicine-containing layer:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; the drug-containing pellets are sieved by a 25-mesh sieve and a 60-mesh sieve, and the pellets in the middle of the two sieves are target pellets. And (5) sampling, analyzing and detecting, and measuring the content and the moisture.
TABLE 7 coating parameters settings for drug-containing layers
| Setting content | Parameters (parameters) |
| Fluidized bed middle barrel | Wurster column |
| Bottom height of guide cylinder | 15mm |
| Air flow distribution plate | Fixing |
| Nozzle diameter | 1.0mm |
| Nozzle/air nozzle position | Flush |
| Air inlet temperature | 50～60℃ |
| Material temperature | 30～40℃ |
| Peristaltic pump speed | 5～20rpm |
| Atomization pressure | 1.2bar |
| Intake air volume | 40～60m 3 /h |
Remarks: gradient sampling theory was 0.63mg/mg after completion of the procedure. And (5) detecting the content.
2.1.2 preparation of sustained-release pellets
Weighing each component of the slow release layer, preparing slow release layer solution, spraying and coating the slow release layer bottom, and drying.
Table 8 prescription information for sustained release layer
Preparing a slow release layer coating liquid:
(1) dissolving ethyl cellulose in ethanol solution, and uniformly stirring;
(2) dispersing talc in (1);
(3) Dissolving acetyl triethyl citrate in purified water, and uniformly stirring;
(4) sieving the solution (3) with a 40-mesh sieve;
the operation of slow-release layer bottom-spraying coating and the parameter setting range:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; sieving the drug-containing pellets with 25-mesh and 60-mesh sieves, wherein the pellets in the middle of the two sieves are target pellets; and (5) sampling, analyzing and detecting, and measuring the content, the moisture and the dissolution.
TABLE 9 parameter settings for sustained release coating
| Setting content | Parameters (parameters) |
| Fluidized bed middle barrel | Wurster column |
| Bottom height of guide cylinder | 15mm |
| Air flow distribution plate | Fixing |
| Nozzle diameter | 1.0mm |
| Nozzle/air nozzle position | Flush |
| Air inlet temperature | 50～60℃ |
| Material temperature | 30～40℃ |
| Peristaltic pump speed | 5～20rpm |
| Atomization pressure | 1.2bar |
| Intake air volume | 40～60m 3 /h |
| Humidity of the water | 15cm 3 /kg |
2.2 preparation of metoprolol succinate sustained and controlled release pellet tablets
Uniformly dispersing 60g of microcrystalline cellulose and 40g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 10 microns; thenSpraying 400g of pill core with the mixed solution by bottom spraying, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 16mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 25%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 85N, and the friability is 0.1%. The micropellet tablet prepared in example 2 has a similarity factor f2 value of 68 with the drug release profile of the micropellet.
Example 3
3.1 preparation of metoprolol succinate sustained and controlled release pellets:
3.1.1 preparation of drug-containing layer pellets
Weighing each component of the medicine-containing layer, preparing medicine-containing layer solution, spraying and coating the bottom of the medicine-containing layer, and drying.
And (3) weighing and preparing the coating liquid of the medicine-containing layer:
table 10 prescription of coating liquid for drug-containing layer
Preparing a medicine applying layer solution:
(1) heating the purified water to 60 ℃;
(2) dissolving metoprolol succinate in 60% of purified water, stirring, dissolving and clarifying;
(3) taking 25% of purified water to disperse hydroxypropyl methylcellulose, stirring, dissolving and clarifying;
(4) adding the step (3) into the step (2), stirring uniformly, and sieving with a 40-mesh sieve;
(5) rinsing the device with the remaining purified water and passing all through a 40 mesh screen;
And (3) the operation and parameter setting range of the bottom spraying coating of the medicine-containing layer:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; the drug-containing pellets are sieved by a 25-mesh sieve and a 60-mesh sieve, and the pellets in the middle of the two sieves are target pellets. And (5) sampling, analyzing and detecting, and measuring the content and the moisture.
Table 11 coating parameters setting ranges for drug-containing layers
Remarks: gradient sampling theory was 0.63mg/mg after completion of the procedure. And (5) detecting the content.
3.1.2 preparation of sustained-release pellets
Weighing each component of the slow release layer, preparing slow release layer solution, spraying and coating the slow release layer bottom, and drying.
Table 12 prescription information for sustained release layer
Preparing a slow release layer coating liquid:
(1) dissolving ethyl cellulose in ethanol solution, and uniformly stirring;
(2) dispersing talc in (1);
(3) dissolving acetyl triethyl citrate in purified water, and uniformly stirring;
(4) sieving the solution (3) with a 40-mesh sieve;
the operation of slow-release layer bottom-spraying coating and the parameter setting range:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; sieving the drug-containing pellets with 25-mesh and 60-mesh sieves, wherein the pellets in the middle of the two sieves are target pellets; and (5) sampling, analyzing and detecting, and measuring the content, the moisture and the dissolution.
TABLE 13 parameter settings for sustained release coatings
3.2 preparation of metoprolol succinate sustained and controlled release pellet tablets
Uniformly dispersing 60g of microcrystalline cellulose and 40g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 10 microns; then spraying 285g of the pill core with the mixed solution in a bottom spraying mode, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 13mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 35%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 90N, and the friability is 0.1%. The micropellet tablet prepared in example 3 has a similarity factor f2 value of 68 with the drug release profile of the micropellet.
Example 4: preparation of metoprolol succinate sustained and controlled release pellet tablets
4.1 preparation of metoprolol succinate sustained and controlled release pellets
4.1.1 preparation of drug-containing layer pellets
Weighing each component of the medicine-containing layer, preparing medicine-containing layer solution, spraying and coating the bottom of the medicine-containing layer, and drying.
The components of the coating liquid containing the medicine layer and the preparation are as follows:
table 14 prescription of coating liquid for medicated layer
Preparing a medicine applying layer solution:
(1) heating the purified water to 60 ℃;
(2) dissolving metoprolol succinate in 60% of purified water, stirring, dissolving and clarifying;
(3) taking 25% of purified water to disperse hydroxypropyl methylcellulose, stirring, dissolving and clarifying;
(4) adding the step (3) into the step (2), stirring uniformly, and sieving with a 40-mesh sieve;
(5) rinsing the device with the remaining purified water and passing all through a 40 mesh screen;
and (3) the operation and parameter setting range of the bottom spraying coating of the medicine-containing layer:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; the drug-containing pellets are sieved by a 25-mesh sieve and a 60-mesh sieve, and the pellets in the middle of the two sieves are target pellets. And (5) sampling, analyzing and detecting, and measuring the content and the moisture.
TABLE 15 coating parameters settings for drug-containing layers
| Setting content | Parameters (parameters) |
| Fluidized bed middle barrel | Wurster column |
| Bottom height of guide cylinder | 15mm |
| Air flow distribution plate | Fixing |
| Nozzle diameter | 1.0mm |
| Nozzle/air nozzle position | Flush |
| Air inlet temperature | 50～60℃ |
| Material temperature | 30～40℃ |
| Peristaltic pump speed | 5～20rpm |
| Atomization pressure | 1.2bar |
| Intake air volume | 40～60m 3 /h |
Remarks: gradient sampling theory was 0.63mg/mg after completion of the procedure. And (5) detecting the content.
4.1.2 preparation of sustained-release pellets
Weighing each component of the slow release layer, preparing slow release layer solution, spraying and coating the slow release layer bottom, and drying.
TABLE 16 prescription information for sustained release layer
Preparing a slow release layer coating liquid:
(1) dissolving ethyl cellulose in ethanol solution, and uniformly stirring;
(2) dispersing talc in (1);
(3) dissolving acetyl triethyl citrate in purified water, and uniformly stirring;
(4) sieving the solution (3) with a 40-mesh sieve;
the operation of slow-release layer bottom-spraying coating and the parameter setting range:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; sieving the drug-containing pellets with 25-mesh and 60-mesh sieves, wherein the pellets in the middle of the two sieves are target pellets; and (5) sampling, analyzing and detecting, and measuring the content, the moisture and the dissolution.
Table 17 ranges for parameters of the slow release coating
| Setting content | Parameters (parameters) |
| Fluidized bed middle barrel | Wurster column |
| Bottom height of guide cylinder | 15mm |
| Air flow distribution plate | Fixing |
| Nozzle diameter | 1.0mm |
| Nozzle/air nozzle position | Flush |
| Air inlet temperature | 50～60℃ |
| Material temperature | 30～40℃ |
| Peristaltic pump speed | 5～20rpm |
| Atomization pressure | 1.2bar |
| Intake air volume | 40～60m 3 /h |
| Humidity of the water | 15cm 3 /kg |
4.2 preparation of metoprolol succinate sustained and controlled release micropill tablet
Uniformly dispersing 60g of microcrystalline cellulose and 40g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 10 microns; then spraying 217g of the pill core with the mixed solution in a bottom spraying mode, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 17mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 45%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 100N, and the friability is 0.1%. The micropellet tablet prepared in example 4 has a similarity factor f2 value of 70 with the drug release profile of the micropellet.
Example 5
5.1 preparation of Esomeprazole magnesium enteric pellets
5.1.1 preparation of drug-containing layer pellets
Weighing each component of the medicine-containing layer, preparing medicine-containing layer solution, spraying and coating the bottom of the medicine-containing layer, and drying.
The components of the coating liquid containing the medicine layer and the preparation are as follows:
prescription of coating liquid for drug-containing layer of table 18
Preparing a medicine-containing layer solution:
(1) heating the purified water to 60 ℃;
(2) dissolving esomeprazole magnesium intestine in 60% purified water, stirring, dissolving and clarifying;
(3) taking 25% of purified water to disperse hydroxypropyl methylcellulose, stirring, dissolving and clarifying;
(4) adding the step (3) into the step (2), stirring uniformly, and sieving with a 40-mesh sieve;
(5) rinsing the device with the remaining purified water and passing all through a 40 mesh screen;
and (3) the operation and parameter setting range of the bottom spraying coating of the medicine-containing layer:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; the drug-containing pellets are sieved by a 25-mesh sieve and a 60-mesh sieve, and the pellets in the middle of the two sieves are target pellets. And (5) sampling, analyzing and detecting, and measuring the content and the moisture.
Table 19 coating parameters settings for drug-containing layer
| Setting content | Parameters (parameters) |
| Fluidized bed middle barrel | Wurster column |
| Bottom height of guide cylinder | 15mm |
| Air flow distribution plate | Fixing |
| Nozzle diameter | 1.0mm |
| Nozzle/air nozzle position | Flush |
| Air inlet temperature | 50～60℃ |
| Material temperature | 30～40℃ |
| Peristaltic pump speed | 5～20rpm |
| Atomization pressure | 1.2bar |
| Intake air volume | 40～60m 3 /h |
Remarks: gradient sampling theory was 0.63mg/mg after completion of the procedure. And (5) detecting the content.
5.1.2 preparation of enteric micropellets
Weighing each component of the enteric layer, preparing an enteric layer solution, spraying and coating the bottom of the enteric layer, and drying.
Table 20 enteric layer prescription information
Preparing enteric pellet coating liquid:
(1) dissolving methacrylic acid-ethyl acrylate copolymer water dispersion L30D55 in water, and uniformly stirring;
(2) dispersing talc in (1);
(3) dissolving acetyl triethyl citrate in purified water, and uniformly stirring;
(4) sieving the solution (3) with a 40-mesh sieve;
enteric pellet bottom spray coating operation and parameter setting range:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; sieving the drug-containing pellets with 25-mesh and 60-mesh sieves, wherein the pellets in the middle of the two sieves are target pellets; and (5) sampling, analyzing and detecting, and measuring the content, the moisture and the dissolution.
Table 21 enteric pellet coating parameters settings
| Setting content | Parameters (parameters) |
| Fluidized bed middle barrel | Wurster column |
| Bottom height of guide cylinder | 15mm |
| Air flow distribution plate | Fixing |
| Nozzle diameter | 1.0mm |
| Nozzle/air nozzle position | Flush |
| Air inlet temperature | 50～60℃ |
| Material temperature | 30～40℃ |
| Peristaltic pump speed | 5～20rpm |
| Atomization pressure | 1.2bar |
| Intake air volume | 40～60m 3 /h |
| Humidity of the water | 15cm 3 /kg |
5.2 preparation of Esomeprazole magnesium enteric-coated pellet tablets
Uniformly dispersing 60g of microcrystalline cellulose and 40g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 10 microns; then spraying 217g of the pill core with the mixed solution in a bottom spraying mode, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 14mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 45%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 120N, and the friability is 0.1%. The pellets prepared in example 5 were both less than 10% release in medium with ph=1.0 and were acceptable. Wherein, the measurement of the release rate is measured by a second method of "0931 dissolution rate and release rate measurement" according to the fourth edition of the Chinese pharmacopoeia 2020. The micropellet tablet prepared in example 5 has a factor f2 of 76 similar to the drug release profile of the micropellet.
Example 6
6.1 preparation of Lansoprazole enteric-coated pellets
6.1.1 preparation of drug-containing layer pellets
Weighing each component of the medicine-containing layer, preparing medicine-containing layer solution, spraying and coating the bottom of the medicine-containing layer, and drying.
And (3) weighing and preparing the coating liquid of the medicine-containing layer:
prescription of coating liquid for medicine-containing layer of table 22
Preparing a medicine applying layer solution:
(1) heating the purified water to 60 ℃;
(2) dissolving lansoprazole in 60% of purified water, stirring, dissolving and clarifying;
(3) taking 25% of purified water to disperse hydroxypropyl methylcellulose, stirring, dissolving and clarifying;
(4) adding the step (3) into the step (2), stirring uniformly, and sieving with a 40-mesh sieve;
(5) rinsing the device with the remaining purified water and passing all through a 40 mesh screen;
and (3) the operation and parameter setting range of the bottom spraying coating of the medicine-containing layer:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; the drug-containing pellets are sieved by a 25-mesh sieve and a 60-mesh sieve, and the pellets in the middle of the two sieves are target pellets. And (5) sampling, analyzing and detecting, and measuring the content and the moisture.
Table 23 coating parameters settings for drug-containing layer
| Setting content | Parameters (parameters) |
| Fluidized bed middle barrel | Wurster column |
| Bottom height of guide cylinder | 15mm |
| Air flow distribution plate | Fixing |
| Nozzle diameter | 1.0mm |
| Nozzle/air nozzle position | Flush |
| Air inlet temperature | 50～60℃ |
| Material temperature | 30～40℃ |
| Peristaltic pump speed | 5～20rpm |
| Atomization pressure | 1.2bar |
| Intake air volume | 40～60m 3 /h |
Remarks: gradient sampling theory was 0.63mg/mg after completion of the procedure. And (5) detecting the content.
6.1.2 preparation of enteric micropellets
Weighing each component of the enteric layer, preparing an enteric layer solution, spraying and coating the bottom of the enteric layer, and drying.
Table 24 enteric layer prescription information
Preparing enteric pellet coating liquid:
(1) dissolving methacrylic acid-ethyl acrylate copolymer water dispersion L30D55 in water, and uniformly stirring;
(2) dispersing talc in (1);
(3) dissolving acetyl triethyl citrate in purified water, and uniformly stirring;
(4) sieving the solution (3) with a 40-mesh sieve;
enteric pellet bottom spray coating operation and parameter setting range:
firstly taking out the solution according to the dosage of 100%, spraying the solution into a fluidized bed, discharging the material, observing whether the theoretical weight gain is achieved, if the theoretical weight gain is not achieved, calculating the dosage of the solution to be added until the theoretical weight gain is achieved; sieving the drug-containing pellets with 25-mesh and 60-mesh sieves, wherein the pellets in the middle of the two sieves are target pellets; and (5) sampling, analyzing and detecting, and measuring the content, the moisture and the dissolution.
Table 25 coating parameters set ranges for enteric pellets
| Setting content | Parameters (parameters) |
| Fluidized bed middle barrel | Wurster column |
| Bottom height of guide cylinder | 15mm |
| Air flow distribution plate | Fixing |
| Nozzle diameter | 1.0mm |
| Nozzle/air nozzle position | Flush |
| Air inlet temperature | 50～60℃ |
| Material temperature | 30～40℃ |
| Peristaltic pump speed | 5～20rpm |
| Atomization pressure | 1.2bar |
| Intake air volume | 40～60m 3 /h |
| Humidity of the water | 15cm 3 /kg |
6.2 preparation of lansoprazole enteric-coated pellet tablets
Uniformly dispersing 60g of microcrystalline cellulose and 40g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 10 microns; then spraying 217g of the pill core with the mixed solution in a bottom spraying mode, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 12mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 45%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 110N, and the friability is 0.1%. The pellets prepared in example 6 were acceptable with a release of less than 10% in the medium at ph=1.0. The micropellet tablet prepared in example 6 has a similarity factor f2 value of 80 with the drug release profile of the micropellet.
Example 7
7.1 preparation of Lansoprazole enteric-coated pellets
Lansoprazole enteric coated pellets were prepared as in example 6.
7.2 preparation of lansoprazole enteric-coated pellet tablets
Uniformly dispersing 60g of microcrystalline cellulose and 40g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 150 microns; then spraying 217g of the pill core with the mixed solution in a bottom spraying mode, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 13mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 45%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 110N, and the friability is 0.1%. Both the pellet tablets prepared in example 7 and the pellets were acceptable with a release of less than 10% in a medium with ph=1.0. The micropellet tablet prepared in example 7 has a factor f2 of 64 similar to the drug release profile of the micropellet.
Example 8
8.1 preparation of metoprolol succinate sustained and controlled release pellets
The preparation of metoprolol succinate sustained and controlled release pellets is the same as in example 1.
8.2 preparation of metoprolol succinate sustained and controlled release pellet tablets
Uniformly dispersing 60g of microcrystalline cellulose and 40g of polyethylene glycol 6000 in 200g of water, wherein the particle size of the microcrystalline cellulose is 125 microns; then spraying 217g of the pill core with the mixed solution in a bottom spraying mode, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 18mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 45%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 100N, and the friability is 0.13%. The micropellet tablet prepared in example 8 has a similarity factor f2 value of 74 with the drug release profile of the micropellet.
Example 9
9.1 preparation of metoprolol succinate sustained and controlled release pellets
The preparation of metoprolol succinate sustained and controlled release pellets is the same as in example 1.
9.2 preparation of metoprolol succinate sustained and controlled release pellet tablets
Uniformly dispersing 60g of microcrystalline cellulose and 40g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 10 microns; then spraying 217g of the pill core with the mixed solution in a bottom spraying mode, wherein the humidity of air in the spraying process is 2kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 16mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 2cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 45%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 100N, and the friability is 0.12%. The micropellet tablet prepared in example 9 has a factor f2 of 76 similar to the drug release profile of the micropellet.
Example 10
10.1 preparation of Lansoprazole enteric-coated pellets
Lansoprazole enteric coated pellets were prepared as in example 6.
10.2 preparation of lansoprazole enteric-coated pellet tablets
Uniformly dispersing 40g of microcrystalline cellulose and 60g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 10 microns; then spraying 217g of the pill core with the mixed solution in a bottom spraying mode, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 16mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5 to20rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 45%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 110N, and the friability is 0.1%. Both the pellet tablets prepared in example 10 and the pellets were acceptable with a release of less than 10% in a medium with ph=1.0. The micropellet tablet prepared in example 10 has a similarity factor f2 value of 82 with the drug release profile of the micropellet.
Example 11
11.1 preparation of metoprolol succinate sustained and controlled release pellets
The preparation of metoprolol succinate sustained and controlled release pellets is the same as in example 1.
11.2 preparation of metoprolol succinate sustained and controlled release pellet tablets
Uniformly dispersing 70g of microcrystalline cellulose and 30g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 10 microns; then spraying 217g of the pill core with the mixed solution in a bottom spraying mode, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 17mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 45%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 100N, and the friability is 0.14%. The micropellet tablet prepared in example 11 has a factor f2 of 65 similar to the drug release profile of the micropellet.
Comparative example 1
1.1 preparation of Metroprolol succinate micropills
Metoprolol succinate pellets were prepared as in example 1.
1.2 preparation of metoprolol succinate pellet tablets
Uniformly dispersing 60g of microcrystalline cellulose and 40g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 250 microns; then spraying 217g of the pill core with the mixed solution in a bottom spraying mode, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 15mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 45%. During the spraying process, particles are too large to accumulate at the muzzle, so that the spray gun is blocked, and the operation process cannot be finished.
Comparative example 2
2.1 preparation of Lansoprazole enteric-coated pellets
Lansoprazole enteric coated pellets were prepared as in example 6.
2.2 preparation of lansoprazole enteric-coated pellet tablets
Uniformly dispersing 90g of microcrystalline cellulose and 10g of polyethylene glycol 6000 in 200g of water, wherein the grain size of the microcrystalline cellulose is 10 microns; then spraying 217g of the pill core with the mixed solution in a bottom spraying mode, wherein the air humidity in the spraying process is 23kg/cm 3 . The parameters of spraying are as follows: fluidized bed middle barrel: wurster column; the bottom of the guide cylinder is high: 15mm; airflow distribution plate: fixing; nozzle diameter: 1.0mm; nozzle/air nozzle position: flush; spraying speed: 14mg/min; air inlet temperature: 40-45 ℃; material temperature: 30-40 ℃; peristaltic pump speed: 5-20 rpm; atomization pressure: 1.2bar; intake air volume: 40-60 m 3 /h; air inlet humidity: 23cm 3 /kg。
After spraying, a protective layer is formed on the surface of the pill core, and the weight of the protective layer is increased by about 45%. The sprayed pellets were dried and at 60 ℃ for 2 hours. Tabletting the dried pellets by using a GZP-16 tabletting machine, wherein the tabletting conditions are as follows: the main pressure is 20-35N, the rotating speed of the rotary table is 30-50 rpm, the hardness of the obtained pellet tablet is 110N, and the friability is 0.1%. The release degree of the micropill tablets prepared in comparative example 2 and the micropill in the medium with PH=1.0 is more than 10%, and the pellets are not qualified. The similarity factor f2 value between the micropill tablets prepared in comparative example 2 and the drug release curve of the micropill is <50.
The microcrystalline cellulose content of comparative example 2 was outside the range defined in the claims, resulting in a lower viscosity of the mixture and reduced adhesion, losing the protective effect, and the resulting tablet was unacceptable. When the microcrystalline cellulose content is lower than the range defined by the claims, the viscosity of the mixture is increased due to the too large dosage of polyethylene glycol 6000 as the proportion of the binder is too large, and the pellets are too much adhered in the coating process, so that the process requirements cannot be met.
Application example 1: performance testing
1.1 dissolution test
The dissolution rate of the metoprolol succinate sustained and controlled release pellet tablets prepared in examples 1 to 4 was tested. The dissolution rate measurement of the present invention refers to the second method of "0931 dissolution rate and release rate measurement" by the fourth edition of the Chinese pharmacopoeia 2015. Dissolution conditions: 500mL of phosphate buffer (ph=6.8) is used as a dissolution medium, the rotation speed is 50 revolutions per minute, the dissolution medium is taken out after 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20 and 24 hours according to the law, and the dissolution medium with the same temperature and the same volume is immediately replenished. The test solution (solution containing metoprolol succinate sustained and controlled release pellets) is prepared by respectively taking the dissolution liquid of 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20 and 24 hours, filtering, and taking the subsequent filtrate. The dissolution rate was measured, and the results are shown in table 2. The dissolution rate of each tablet in 1 hour, 4 hours, 8 hours and 20 hours is respectively 25% of the marked amount, 20% -40%, 40% -60% and more than 80% of the marked amount. The calculation formulas of the dissolution rate and the accumulated dissolution rate refer to the inlet registration standard: JX20170108.
The dissolution rate was calculated as follows:
wherein: cs: concentration of control, mg/mL; as: main peak area in the control solution; au: main peak area in the sample solution; vu: sample dilution factor, 1; l: a labeled amount, 95mg or 47.5mg;500: volume of dissolution medium.
The calculation formula of the cumulative dissolution is as follows:
wherein: v (V) 1 : sampling volume, mL; v (V) 2 : dissolution medium volume, mL; an: the relative percent dissolution was actually measured n times.
The dissolution test results of the metoprolol succinate sustained and controlled release pellet tablets and pellets obtained in examples 1 to 4 are shown in table 26.
Table 26 dissolution test results of metoprolol succinate sustained and controlled release pellet tablets and pellets obtained in examples 1 to 4
From the above table, it can be seen that the release curves of the pellet tablets prepared in examples 1 to 4 are substantially consistent with those of the pellets, and the pellet tablets still reach 100% release end point, which indicates that the protection effect on the pellets can be remarkably enhanced by adopting polyethylene glycol and microcrystalline cellulose auxiliary materials in combination with a specific preparation process.
1.2 uniformity test
10 micropill tablets were prepared using the preparation procedure of example 1, and content uniformity was tested using liquid chromatography. The test method of the content of the active ingredient metoprolol succinate refers to JX 20170108-import registration standard, and specific test conditions are as follows: chromatographic column Waters symmetry C (4.6X250 mm,5 μm), acetonitrile-phosphate buffer (pH=3.0) (24:76) as mobile phase, wavelength 280nm, flow rate 1.2mL/min, test sample concentration approximately 0.05mg of micropellet tablet per 1 mL. The results of the test are shown in table 27 below.
Table 27 test results of content uniformity of micropellet tablets prepared in example 1
As can be seen from Table 3, the metoprolol succinate sustained and controlled release pellet tablets prepared in example 1 all meet the quality standard.
The applicant states that the present invention is illustrated by the above examples as well as the method of preparing the pellet tablets of the present invention, but the present invention is not limited to the above examples, i.e. it is not meant that the present invention must be practiced in dependence upon the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of selected raw materials, addition of auxiliary components, selection of specific modes, etc. fall within the scope of the present invention and the scope of disclosure.
Claims (13)
1. A method of preparing a pellet tablet comprising the steps of:
dispersing the medicinal auxiliary materials in a solvent, spraying the medicinal auxiliary materials on the surfaces of the micropills to form a coating on the surfaces of the micropills, and finally pressing the micropills containing the coating into tablets;
wherein the absolute humidity of the air in the spraying process is 2-30 kg/cm 3 。
2. The method for preparing a pellet tablet as claimed in claim 1, wherein the weight ratio of the pharmaceutical excipients to the pellets is 1 (2-6).
3. The method of preparing a pellet tablet according to claim 1 or 2, wherein the pharmaceutical excipients comprise a binder and a filler material;
preferably, the weight ratio of the binder to the filler is (3-6): (4-7).
4. The method for producing a pellet tablet as claimed in claim 3, wherein the binder is one or more selected from polyethylene glycol, polyvinyl alcohol and polyethylene oxide;
and/or the filler material is selected from microcrystalline cellulose and/or lactose.
5. The method of preparing a pellet tablet as claimed in any one of claims 1-4, wherein the pharmaceutical excipients comprise polyethylene glycol and microcrystalline cellulose;
preferably, the polyethylene glycol is selected from polyethylene glycol 4000, polyethylene glycol 6000 and/or polyethylene glycol 8000;
more preferably, the polyethylene glycol is polyethylene glycol 6000.
6. The method for producing a micropellet tablet according to claim 4 or 5, wherein the microcrystalline cellulose has a particle size of 10 to 200 μm;
preferably, the microcrystalline cellulose has a particle size of 10 to 100 microns.
7. The method of preparing a pellet tablet as claimed in any one of claims 1-6, wherein the spray coating conditions are: the spraying speed is 2-30 mg/min;
And/or controlling the temperature of the materials to be 20-80 ℃; preferably, the material control temperature is 20-50 ℃;
and/or, the intake: 30-70 m 3 /h。
8. The method of preparing a pellet tablet as claimed in any one of claims 1 to 7, wherein the solvent is selected from water, ethanol, or a mixed solution of both;
preferably, the weight ratio of the solvent to the binder is 1 (0.1-1).
9. The method of preparing a pellet tablet according to any one of claims 1-8, wherein the pellets are microcells having independent release capability;
preferably, the micropill is a drug-containing sustained-release micropill or a drug-containing enteric micropill.
10. The method of preparing a micropellet tablet according to any one of claims 1-9, wherein the micropellet tablet has a similarity factor f2 value between the drug release profile of the micropellet of 50 or more;
preferably, the similarity factor f2 value between the micropellet tablet and the drug release profile of the micropellet is above 64;
preferably, the drug content uniformity of the pellet tablet is AV <15;
preferably, the pellet tablet has a core hardness of less than 200N.
11. A micropellet tablet, characterized in that it is prepared by the process for the preparation of a micropellet tablet as claimed in any one of claims 1 to 10.
12. The micropellet tablet according to claim 11, wherein the micropellet in the micropellet tablet is any one of a metoprolol succinate sustained and controlled release micropellet, an esomeprazole magnesium enteric micropellet and a lansoprazole enteric micropellet.
13. A protective pharmaceutical adjuvant composition for pellet tabletting, which is characterized by comprising a binder and a filler;
preferably, the binder is polyethylene glycol, and the filling material is microcrystalline cellulose and/or lactose;
more preferably, the microcrystalline cellulose has a particle size of 10 to 200 microns; further preferably, the microcrystalline cellulose has a particle size of 10 to 100 μm;
more preferably, the polyethylene glycol is polyethylene glycol 6000.
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| CN109646417A (en) * | 2018-06-14 | 2019-04-19 | 深圳翰宇药业股份有限公司 | A kind of Trimetazidine sustained release tablets and preparation method thereof |
| CN109875971A (en) * | 2019-03-19 | 2019-06-14 | 中山大学 | A kind of Berberine hydrochloride sustained release tablets and preparation method thereof |
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| EP1837016A2 (en) * | 2006-03-08 | 2007-09-26 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical multiple-unit composition |
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