CN113116838A - Olmesartan medoxomil dispersible tablet and preparation method thereof - Google Patents
Olmesartan medoxomil dispersible tablet and preparation method thereof Download PDFInfo
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- CN113116838A CN113116838A CN202110334470.1A CN202110334470A CN113116838A CN 113116838 A CN113116838 A CN 113116838A CN 202110334470 A CN202110334470 A CN 202110334470A CN 113116838 A CN113116838 A CN 113116838A
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- olmesartan medoxomil
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- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 title claims abstract description 89
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 title claims abstract description 88
- 229960001199 olmesartan medoxomil Drugs 0.000 title claims abstract description 88
- 239000007919 dispersible tablet Substances 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000008188 pellet Substances 0.000 claims abstract description 33
- 238000013268 sustained release Methods 0.000 claims abstract description 32
- 239000012730 sustained-release form Substances 0.000 claims abstract description 32
- 239000011248 coating agent Substances 0.000 claims abstract description 25
- 238000000576 coating method Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 20
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 15
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 15
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 15
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 14
- 239000000314 lubricant Substances 0.000 claims abstract description 14
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000661 sodium alginate Substances 0.000 claims abstract description 13
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 13
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 13
- 239000000853 adhesive Substances 0.000 claims abstract description 12
- 230000001070 adhesive effect Effects 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 239000000796 flavoring agent Substances 0.000 claims abstract description 12
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 239000003085 diluting agent Substances 0.000 claims abstract description 8
- 238000005469 granulation Methods 0.000 claims abstract description 7
- 230000003179 granulation Effects 0.000 claims abstract description 7
- 238000001125 extrusion Methods 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims description 7
- 239000007884 disintegrant Substances 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 238000005563 spheronization Methods 0.000 claims description 5
- 238000005550 wet granulation Methods 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 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 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- YGCFIWIQZPHFLU-UHFFFAOYSA-N acesulfame Chemical compound CC1=CC(=O)NS(=O)(=O)O1 YGCFIWIQZPHFLU-UHFFFAOYSA-N 0.000 claims description 2
- 229960005164 acesulfame Drugs 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical group OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 239000008119 colloidal silica Substances 0.000 claims description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 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 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
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- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
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- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 2
- 238000005096 rolling process Methods 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 18
- 239000005480 Olmesartan Substances 0.000 description 9
- 229960005117 olmesartan Drugs 0.000 description 9
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 5
- 102000005862 Angiotensin II Human genes 0.000 description 3
- 101800000733 Angiotensin-2 Proteins 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 108010062481 Type 1 Angiotensin Receptor Proteins 0.000 description 3
- 102000010913 Type 1 Angiotensin Receptor Human genes 0.000 description 3
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- 239000005541 ACE inhibitor Substances 0.000 description 2
- 101800004538 Bradykinin Proteins 0.000 description 2
- 102400000967 Bradykinin Human genes 0.000 description 2
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 2
- 102100028255 Renin Human genes 0.000 description 2
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- 230000000903 blocking effect Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
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- 230000001603 reducing effect Effects 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- IQMYIPVRCAGESV-UHFFFAOYSA-N 2,3-dihydroxybut-2-enyl 5-(2-hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound CCCC1=NC(C(C)(C)O)=C(C(=O)OCC(O)=C(C)O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 IQMYIPVRCAGESV-UHFFFAOYSA-N 0.000 description 1
- 101150059573 AGTR1 gene Proteins 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
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- 108010017384 Blood Proteins Proteins 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
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- 229940055053 benicar Drugs 0.000 description 1
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- 229960000932 candesartan Drugs 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
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- KJNFMGMNZKFGIE-UHFFFAOYSA-N n-(4-hydroxyphenyl)acetamide;5-(2-methylpropyl)-5-prop-2-enyl-1,3-diazinane-2,4,6-trione;1,3,7-trimethylpurine-2,6-dione Chemical compound CC(=O)NC1=CC=C(O)C=C1.CN1C(=O)N(C)C(=O)C2=C1N=CN2C.CC(C)CC1(CC=C)C(=O)NC(=O)NC1=O KJNFMGMNZKFGIE-UHFFFAOYSA-N 0.000 description 1
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- 230000003639 vasoconstrictive effect Effects 0.000 description 1
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- 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
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
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- 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
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- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Abstract
The invention discloses an olmesartan medoxomil sustained-release dispersible tablet and a preparation method thereof, wherein the preparation method comprises the following steps: 50 percent of olmesartan medoxomil coated pellets (slow release part) obtained by olmesartan medoxomil with effective treatment dose, residual olmesartan medoxomil bulk drug physically mixed with the pellets (quick release part) and other pharmaceutically acceptable auxiliary materials. The pellet is obtained by taking a mixture of microcrystalline cellulose and sodium alginate with equal mass as a base material, preparing a pellet core with olmesartan medoxomil by a centrifugal granulation method or an extrusion rolling method, and coating an HPMC sustained release coating film on a fluidized bed. The pharmaceutically acceptable auxiliary materials comprise a diluent, an adhesive, a disintegrating agent, a flavoring agent, a lubricant and a glidant. The olmesartan medoxomil sustained-release dispersible tablet prepared by the invention is rapidly disintegrated and completely disintegrated within 2min, and has good stability.
Description
Technical Field
The invention relates to the field of medicinal preparations, in particular to a dispersible tablet of olmesartan medoxomil for treating hypertension and a preparation method thereof.
Background
Olmesartan medoxomil (Candesartan celexetl), chemical name: 2, 3-dihydroxy-2-butenyl-4- (1-hydroxy-1-methylethyl) -2-propyl-1- [ p- (o-1H-tetrazol-5-ylphenyl) benzyl]Imidazole-5-carboxylate, cyclic 2, 3-carbonate. The molecular formula is as follows: c29H30N6O6The structural formula is as follows:
olmesartan is a selective angiotensin II type 1 receptor (AT1) antagonist that blocks the vasoconstrictive action of angiotensin II by selectively blocking its binding to vascular smooth muscle AT1 receptors, and therefore its action is independent of the AT II synthetic pathway. Olmesartan has an affinity for AT1 that is 12500 times greater than its affinity for AT 2. Blockade of the renin-angiotensin system (RAS) by ACE inhibitors is a mechanism of many drugs for hypertension, but ACE inhibitors also inhibit the degradation of bradykinin, while olmesartan medoxomil does not inhibit ACE and therefore does not affect bradykinin, and it is unclear whether there is clinical relevance for this distinction. Blocking angiotensin II receptor inhibits the negative feedback regulation mechanism of angiotensin II on renin secretion. However, the resulting increase in plasma renin activity and increase in circulating angiotensin II concentration does not affect the hypotensive effect of olmesartan.
The olmesartan medoxomil is a precursor drug of olmesartan medoxomil, is absorbed by gastrointestinal tract after being taken orally, is rapidly and completely de-esterified and hydrolyzed into olmesartan medoxomil, and has the absolute bioavailability of about 26 percent. The peak blood concentration can be reached after oral administration for 1-2 hours. Eating does not affect the bioavailability of olmesartan. The plasma protein binding rate of olmesartan is as high as 99%, the olmesartan does not penetrate red blood cells, and the steady-state distribution volume is about 17L. In rat experiments, olmesartan does not readily pass through the blood-brain barrier, but can pass through the placental barrier and be distributed into fetal rats, or can be distributed in small amounts in rat milk. After olmesartan medoxomil is rapidly and completely converted into olmesartan, no further metabolism is performed. Olmesartan is eliminated in a biphasic manner with a final elimination half-life of about 13 hours, a total plasma elimination of 1.3L/hour and a renal clearance of 0.6L/hour. About 35% to 50% of the absorbed drug is excreted in urine, and the rest is excreted in feces via bile.
The patent application document with the application number of CN202010893361.9 discloses an olmesartan medoxomil tablet and a preparation method thereof, wherein the olmesartan medoxomil tablet comprises an olmesartan medoxomil tablet core and a film coat, the olmesartan medoxomil tablet core comprises olmesartan medoxomil, a diluent, a disintegrant, a glidant and a lubricant, and the film coat is in a gastric-soluble type, preferably an Opadry gastric-soluble type coating premix. The olmesartan medoxomil tablet is prepared by adopting a powder direct compression preparation process, under the condition that three auxiliary materials are used as filling agents and the formula proportion is similar, the in vitro dissolution curves of the olmesartan medoxomil tablet with the specification of 20mg and the olmesartan medoxomil tablet with the specification of 40mg in various pH media are similar, and the in vitro dissolution curves of the olmesartan medoxomil tablet with the specification of 40mg and a reference preparation (trade name: BENICAR, with the specification of 40mg) in various pH media are similar.
Patent application document CN202011389236.0 discloses an olmesartan medoxomil tablet and a preparation method thereof. The olmesartan medoxomil tablet consists of the following components in percentage by weight: 5-20% of olmesartan medoxomil, and a filler 1: 40% -60%, filler 2: 10-25% of disintegrating agent: 5% -25%, adhesive: 0.5% -2.5%, lubricant: 0.1-3 percent of the weight of the coating agent is increased by 3.5-5 percent. The invention obviously improves the dissolution rate of olmesartan medoxomil tablets to 85-95%, the in vitro standard is consistent with the standard of the original medicine, the in vivo bioequivalence is consistent with the standard of the original medicine, and the preparation method comprises pretreatment, premixing, granulation, drying, granule finishing, total mixing, tabletting and coating. Simple operation, suitability for large-scale production and great application value. The patent application document with the application number of CN201811651051.5 relates to a preparation method of olmesartan medoxomil tablets, the method adopts a dry granulation process to prepare the olmesartan medoxomil tablets, and the method is simple to operate, less in influencing factors and strong in controllability.
Olmesartan medoxomil tablets have a hypotensive effect within their recommended therapeutic dose range. Has definite curative effect and convenient use in clinical treatment, thereby being widely used for treating hypertension. The currently marketed dosage form is an immediate release tablet.
The dispersible tablet solves the problems of slow effect and inconvenient administration of the tablet. Is convenient for patients to use, especially for the elderly or dysphagia patients. Therefore, the problem to be solved is to prepare the olmesartan medoxomil sustained-release dispersible tablet which has rapid disintegration, good taste and continuous blood pressure reduction. At present, no report related to olmesartan medoxomil sustained-release dispersible tablets exists.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides an olmesartan medoxomil sustained-release dispersible tablet and a preparation method thereof, and the obtained olmesartan medoxomil sustained-release dispersible tablet has smooth and bright surface morphology, no cracking, rapid disintegration and good dispersion uniformity, can be completely disintegrated within 2min and passes through a 40-mesh sieve. The dissolution rate in the phosphate buffer solution within 30min can reach more than 90%. The preparation method is simple in process and suitable for industrial production.
In order to solve the problems in the prior art, the technical solution adopted by the invention is as follows:
an olmesartan medoxomil sustained-release dispersible tablet, comprising: coated olmesartan medoxomil pellets, residual olmesartan medoxomil bulk drug and other pharmaceutically acceptable auxiliary materials accounting for a part of the amount of the effective treatment amount;
the coated olmesartan medoxomil pellet is obtained by taking a mixture of microcrystalline cellulose and sodium alginate as a base material, preparing a pellet core with olmesartan medoxomil by a centrifugal granulation method or an extrusion and spheronization method, and then coating a slow release coating film.
The amount of the component accounting for the effective treatment amount is 50-60% by mass.
Preferably, the mass ratio of the microcrystalline cellulose to the sodium alginate is 10:3-5: 5. In the mixture of the microcrystalline cellulose and the sodium alginate, the microcrystalline cellulose and the sodium alginate are mixed in equal mass.
The slow release coating film is formed by coating an HPMC slow release layer on the surface of a pellet core by adopting a fluidized bed.
The pharmaceutically acceptable auxiliary materials comprise a diluent, an adhesive, a disintegrating agent, a flavoring agent, a lubricant and a glidant. Specifically, in every 100g of dispersible tablets, the mass of each raw material and each auxiliary material is as follows:
5 to 35g of olmesartan medoxomil, 10 to 85g of filler, 20 to 70g of adhesive, 1 to 50g of disintegrant, 0.02 to 10g of flavoring agent, 0.1 to 12g of lubricant and 0.1 to 10g of glidant.
In each 100g of dispersible tablets, the mass of each raw material and each auxiliary material is as follows: 8 to 30g of olmesartan medoxomil, 25 to 60g of diluent, 30 to 60g of adhesive, 5 to 45g of disintegrant, 0.5 to 3g of flavoring agent, 0.5 to 3g of lubricant and 0.5 to 3g of glidant.
The pharmaceutically acceptable auxiliary material and the diluent are selected from one or a mixture of more than two of lactose, mannitol, pregelatinized starch and microcrystalline cellulose; the disintegrant is selected from one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, and crospovidone; the adhesive is selected from one or a mixture of two of hydroxypropyl cellulose or hydroxypropyl methylcellulose; the flavoring agent is selected from aspartame or acesulfame; the lubricant is magnesium stearate or talcum powder; the glidant is selected from colloidal silica or colloidal silicon dioxide.
The preparation method of the olmesartan medoxomil sustained-release dispersible tablet comprises the following steps:
(1) mixing microcrystalline cellulose, sodium alginate and the like, mixing with a part of olmesartan medoxomil in a therapeutically effective amount and an adhesive, and preparing olmesartan medoxomil pellets by using water as a solvent through a centrifugal granulation method or an extrusion spheronization method;
(2) coating the surface of the pellet by a fluidized bed method, wherein the adopted coating solution is an HPMC coating film; coating to obtain coated olmesartan medoxomil pellets;
(3) and (3) carrying out wet granulation and drying on the coated olmesartan medoxomil pellets and the binder solution in the rest olmesartan medoxomil bulk drug and auxiliary materials, adding a lubricant, a disintegrating agent, a flavoring agent and a glidant into the dried pellets, granulating and tabletting.
Has the advantages that:
1. according to the olmesartan medoxomil sustained-release dispersible tablet disclosed by the invention, part of olmesartan medoxomil is coated in the pellet and is slowly released under the action of the HPMC coating layer, the blood pressure reducing effect is continuously exerted, and part of olmesartan medoxomil is positioned outside the coated pellet, is mixed with other auxiliary materials and the pellet, and is prepared into the dispersible tablet after wet granulation and tabletting, so that the dispersible tablet is quickly disintegrated, and the drug effect can be exerted more quickly than that of the traditional tablet. Olmesartan medoxomil is uniformly distributed in the pellets and the outer layer of the auxiliary material, while the coated pellets are uniformly dispersed in the dispersible tablet. The whole disintegration is rapid, the dispersion uniformity is good, and the dissolution rate in 30min can reach more than 90%.
2. The olmesartan medoxomil sustained-release dispersible tablet prepared by the invention is prepared by wet granulation, has simple process and is suitable for industrial mass production.
3. The olmesartan medoxomil sustained-release dispersible tablet prepared by the invention has small stimulation to the alimentary canal mucous membrane, the main drugs uniformly distributed in the tablet uniformly enter the stomach after being rapidly disintegrated, and the main drugs in the pellet are released and absorbed in the intestinal tract under the protection of HPMC, thereby reducing the amount of the main drugs in the stomach, but having better bioavailability.
Drawings
Fig. 1 is a dissolution curve of olmesartan medoxomil sustained-release dispersible tablets prepared in example 1 of the present invention in a phosphate buffer.
Detailed Description
The present invention will be described in further detail with reference to the following drawings and examples.
The mass of each 100g of dispersible tablet raw materials prepared in examples 1-5 is shown in table 1:
TABLE 1
Example 1-5 method for preparing olmesartan medoxomil sustained release dispersible tablets, the steps are as follows:
(1) mixing microcrystalline cellulose, sodium alginate and the like, mixing with a part of olmesartan medoxomil in a therapeutically effective amount and an adhesive, and preparing olmesartan medoxomil pellets by using water as a solvent through a centrifugal granulation method or an extrusion spheronization method;
(2) coating the surface of the pellet by a fluidized bed method, wherein the adopted coating solution is an HPMC coating film; coating to obtain coated olmesartan medoxomil pellets;
(3) and (3) carrying out wet granulation and drying on the coated olmesartan medoxomil pellets and the binder solution in the rest olmesartan medoxomil bulk drug and auxiliary materials, adding a lubricant, a disintegrating agent, a flavoring agent and a glidant into the dried pellets, granulating and tabletting.
Performance assessment
Appearance: the olmesartan medoxomil sustained-release dispersible tablets prepared in examples 1 to 5 are white or off-white, have smooth and bright surface morphology and no split.
Dispersion uniformity: and (3) putting 2 prepared olmesartan medoxomil sustained-release dispersible tablets into 100ml of pure water, shaking, completely disintegrating in 2min at 20 +/-1 ℃, and passing through a No. 2 sieve.
Dissolution rate: taking 6 olmesartan medoxomil sustained-release dispersible tablets prepared in example 2, taking phosphate buffer solution with pH6.8 as a dissolution medium, and observing the dissolution rate for 30min, as shown in figure 1. (second appendix XC of the second part of the Chinese pharmacopoeia 2010 edition).
Example 5 the olmesartan medoxomil sustained-release dispersible tablets prepared in example 2 were subjected to stability examination, and specific test conditions, examination time and examination items are shown in table 2, and test results are shown in table 3:
TABLE 2
TABLE 3
As can be seen from table 3, the olmesartan medoxomil sustained-release dispersible tablets obtained by the present invention have good stability.
Claims (10)
1. An olmesartan medoxomil sustained-release dispersible tablet, which is characterized by comprising: coated olmesartan medoxomil pellets, residual olmesartan medoxomil bulk drug and other pharmaceutically acceptable auxiliary materials accounting for a part of the amount of the effective treatment amount;
the coated olmesartan medoxomil pellet is obtained by taking a mixture of microcrystalline cellulose and sodium alginate as a base material, preparing a pellet core with olmesartan medoxomil by a centrifugal granulation method or an extrusion and spheronization method, and then coating a slow release coating film.
2. The olmesartan medoxomil sustained-release dispersible tablet according to claim 1, wherein the therapeutically effective amount of the olmesartan medoxomil sustained-release dispersible tablet is 50 to 60% by mass.
3. The olmesartan medoxomil sustained-release dispersible tablet according to claim 1, wherein the mass ratio of the microcrystalline cellulose to the sodium alginate in the mixture of the microcrystalline cellulose and the sodium alginate is 10:3-5: 5.
4. The olmesartan medoxomil sustained-release dispersible tablet according to claim 3, wherein in the mixture of the microcrystalline cellulose and the sodium alginate, the microcrystalline cellulose and the sodium alginate are mixed by the same mass.
5. The olmesartan medoxomil sustained-release dispersible tablet according to claim 1, wherein the sustained-release coating film is formed by coating an HPMC sustained-release layer on the surface of the pellet core by adopting a fluidized bed.
6. The olmesartan medoxomil sustained-release dispersible tablet according to claim 1, wherein the pharmaceutically acceptable auxiliary materials comprise diluents, binders, disintegrants, flavoring agents, lubricants and glidants.
7. The olmesartan medoxomil sustained-release dispersible tablet according to claim 6, wherein the mass of each raw material and each auxiliary material in each 100g of the dispersible tablet is as follows:
5-35 g of olmesartan medoxomil
The filler accounts for 10-85 g
The adhesive accounts for 20-70 g
The disintegrating agent accounts for 1-50 g
0.02 g-10 g of flavoring agent
0.1-12 g of lubricant
The glidant accounts for 0.1-10 g.
8. The olmesartan medoxomil sustained-release dispersible tablet according to claim 6, wherein the mass of each raw material and each auxiliary material in each 100g of the dispersible tablet is as follows:
8-30 g of olmesartan medoxomil
The diluent accounts for 25-60 g
The adhesive accounts for 30-60 g
The disintegrating agent accounts for 5-45 g
0.5-3 g of flavoring agent
0.5-3 g of lubricant
The flow aid accounts for 0.5-3 g.
9. Olmesartan medoxomil sustained release dispersible tablets according to any of claims 6 to 8,
the diluent is selected from one or more of lactose, mannitol, pregelatinized starch, and microcrystalline cellulose;
the disintegrant is selected from one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, and crospovidone;
the adhesive is selected from one or a mixture of two of hydroxypropyl cellulose or hydroxypropyl methylcellulose;
the flavoring agent is selected from aspartame or acesulfame;
the lubricant is magnesium stearate or talcum powder;
the glidant is selected from colloidal silica or colloidal silicon dioxide.
10. The preparation method of olmesartan medoxomil sustained-release dispersible tablets according to claim 1, which is characterized by comprising the following steps:
(1) mixing microcrystalline cellulose, sodium alginate and the like, mixing with a part of olmesartan medoxomil in a therapeutically effective amount and an adhesive, and preparing olmesartan medoxomil pellets by using water as a solvent through a centrifugal granulation method or an extrusion spheronization method;
(2) coating the surface of the pellet by a fluidized bed method, wherein the adopted coating liquid is HPMC coating liquid; coating to obtain coated olmesartan medoxomil pellets;
(3) and (3) carrying out wet granulation and drying on the coated olmesartan medoxomil pellets and the binder solution in the rest olmesartan medoxomil bulk drug and auxiliary materials, adding a lubricant, a disintegrating agent, a flavoring agent and a glidant into the dried pellets, granulating and tabletting.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102716100A (en) * | 2012-07-12 | 2012-10-10 | 南京正大天晴制药有限公司 | Tablets comprising olmesartan medoxomil and method for preparing same |
| CN112294769A (en) * | 2020-10-27 | 2021-02-02 | 浙江诺得药业有限公司 | Candesartan cilexetil orally disintegrating tablet and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102716100A (en) * | 2012-07-12 | 2012-10-10 | 南京正大天晴制药有限公司 | Tablets comprising olmesartan medoxomil and method for preparing same |
| CN112294769A (en) * | 2020-10-27 | 2021-02-02 | 浙江诺得药业有限公司 | Candesartan cilexetil orally disintegrating tablet and preparation method thereof |
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Application publication date: 20210716 |