CN115245496B - Preparation method of stable epalrestat tablets - Google Patents
Preparation method of stable epalrestat tablets Download PDFInfo
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- CN115245496B CN115245496B CN202211151232.8A CN202211151232A CN115245496B CN 115245496 B CN115245496 B CN 115245496B CN 202211151232 A CN202211151232 A CN 202211151232A CN 115245496 B CN115245496 B CN 115245496B
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- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 title claims abstract description 61
- 229950010170 epalrestat Drugs 0.000 title claims abstract description 60
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000002156 mixing Methods 0.000 claims abstract description 43
- 239000002245 particle Substances 0.000 claims abstract description 32
- 239000011248 coating agent Substances 0.000 claims abstract description 26
- 238000000576 coating method Methods 0.000 claims abstract description 26
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 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 28
- 229930195725 Mannitol Natural products 0.000 claims description 28
- 239000000594 mannitol Substances 0.000 claims description 28
- 235000010355 mannitol Nutrition 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 26
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 239000008187 granular material Substances 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
- 239000000463 material Substances 0.000 claims description 20
- 238000005520 cutting process Methods 0.000 claims description 16
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 15
- 239000011575 calcium Substances 0.000 claims description 15
- 229910052791 calcium Inorganic materials 0.000 claims description 15
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 14
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 14
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 14
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 14
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 9
- 238000005469 granulation Methods 0.000 claims description 8
- 230000003179 granulation Effects 0.000 claims description 8
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 7
- 238000010008 shearing Methods 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 238000000889 atomisation Methods 0.000 claims description 5
- 238000007599 discharging Methods 0.000 claims description 5
- 235000020985 whole grains Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 239000001923 methylcellulose Substances 0.000 claims 1
- 235000010981 methylcellulose Nutrition 0.000 claims 1
- 238000007873 sieving Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 28
- 239000003814 drug Substances 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 10
- 238000000338 in vitro Methods 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 2
- 235000001465 calcium Nutrition 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000009475 tablet pressing Methods 0.000 description 3
- 208000004044 Hypesthesia Diseases 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 208000034783 hypoesthesia Diseases 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000016912 Aldehyde Reductase Human genes 0.000 description 1
- 108010053754 Aldehyde reductase Proteins 0.000 description 1
- 206010061666 Autonomic neuropathy Diseases 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 206010063547 Diabetic macroangiopathy Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 230000009251 neurologic dysfunction Effects 0.000 description 1
- 208000015015 neurological dysfunction Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 231100000862 numbness Toxicity 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- 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
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2072—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
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention relates to the technical field of medicine production and preparation, in particular to a preparation method of a stable epalrestat tablet. The epalrestat tablet is prepared by crushing epalrestat to the particle size D90 of less than or equal to 15 mu m, designing multiple particles inside and outside, and finally carrying out technologies such as final total mixing, tabletting, coating and the like. The epalrestat tablet prepared by the invention has better in-vitro dissolution curve, dissolution stability and drug stability.
Description
Technical Field
The invention relates to the technical field of medicine production and preparation, in particular to a preparation method of a stable epalrestat tablet.
Background
Diabetic peripheral neuropathy is a common complication of diabetes, and the main pathological changes are distal neuropathy, staged demyelination and nerve fiber loss, and the clinical manifestations are pain, numbness and hypoesthesia. If the treatment is not conducted, it is easy to cause muscular atrophy or even amputation, which is one of the main causes of diabetes.
Epalrestat is a reversible, non-competitive inhibitor of aldose reductase and acts on the polyol pathway involved in the pathogenesis of diabetic complications. A plurality of clinical studies at home and abroad show that epalrestat not only effectively improves the subjective symptoms and the neurological dysfunction of patients with diabetic peripheral neuropathy, but also has effect on autonomic neuropathy, and has certain treatment effect on diabetic macroangiopathy, diabetic nephropathy and the like. Epalrestat has low adverse reaction incidence rate, and is an effective and safe medicament for treating chronic complications of diabetes, particularly diabetic neuropathy.
Chemical name of epalrestat (epalrestat): 5- [ (1Z, 2E) -2-methyl-3-phenyl-2-propenylidene ] -4-oxo-2-thioxo-3-thiazolidineacetic acid. Epalrestat belongs to BCS II medicines, tmax is about 1.05 hours, absorption is rapid, and the dissolution process of the medicines is the rate-limiting step of in vivo absorption. In addition, according to the national requirements for the consistency evaluation of the imitation drugs, the imitation drugs need to have the same pharmaceutical properties and curative effect properties as the original medicines, and have the same or even better quality. Of the consistent pharmaceutical properties, the most important are the dissolution characteristics and the content of the relevant substances.
Chinese patent document CN1692903A discloses an epalrestat tablet, which comprises the following raw and auxiliary materials by weight: 15% -65% of epalrestat, 10% -80% of lactose, 10% -80% of microcrystalline cellulose, 1% -10% of low-substituted hydroxypropyl cellulose, 1% -10% of carboxymethyl starch sodium and 0.1% -3% of magnesium stearate. However, the epalrestat tablets have low average dissolution rate and large inter-tablet difference of dissolution rate. Chinese patent document CN114762683A discloses a pharmaceutical composition for treating diabetic neuropathy and a preparation method thereof, and discloses an epalrestat pharmaceutical composition, wherein the content percentage of epalrestat is 40-50%, and the particle size D90 is less than or equal to 15 mu m. According to the application, the epalrestat is crushed to D90 not more than 15 mu m, preferably not more than 8.9 mu m, and more preferably not more than 7.0 mu m, so that the specific surface area of the raw material medicine is increased, the release and absorption of active ingredients are accelerated, and the average dissolution rate of the prepared epalrestat tablets is improved. However, the finely pulverized raw materials not only bring certain difficulties to the preparation and increase the production cost, but also may affect the stability of the raw materials.
Therefore, it is important to study a novel epalrestat tablet and a method for producing the same in order to increase the stability of the epalrestat tablet, to prepare an epalrestat tablet that meets the in vitro dissolution requirements, and to promote the in vivo absorption of the epalrestat tablet.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of epalrestat tablets, and the epalrestat tablets prepared by the method have excellent dissolution performance and obviously improved stability.
Specifically, through the intensive research on the preparation process, the invention provides a preparation process of epalrestat tablets, which is characterized in that epalrestat and specific auxiliary materials distributed according to a certain proportion are prepared into double granules, and proper epalrestat raw material grain size is selected in a matching manner, so that a tablet product which has a similar in vitro dissolution curve with a reference preparation (trade name: KINEDAK) published by the national drug administration and has better dissolution stability and quality stability is finally prepared.
Specifically, the epalrestat tablets of the present invention have the composition shown in table 1:
table 1:
wherein the coating is preferably Opadry YS-1-7003.
Specifically, the preparation method of the epalrestat tablet at least comprises the following steps:
s1, crushing epalrestat to obtain a particle size D90 of less than or equal to 15 microns;
s2, preparing inner particles: adding epalrestat, part of carboxymethyl cellulose calcium and part of mannitol into a wet granulator, uniformly mixing, granulating, drying and finishing to obtain inner granules containing epalrestat;
s3, preparing premixed particles: adding the inner granules, the residual mannitol, the residual calcium carboxymethylcellulose and the hydroxypropyl cellulose into a wet granulator, mixing, granulating, drying and grading to obtain premixed granules;
s4, total mixing: uniformly mixing the premixed granules with magnesium stearate;
s5, tabletting;
and S6, coating.
In S1, epalrestat is crushed to a particle size D90 of 15 μm or less.
As an improved technical scheme of the invention, in S1, mannitol and magnesium stearate are respectively sieved by a 60-mesh sieve.
As an improved technical solution of the present invention, in S2: part of the calcium carboxymethyl cellulose accounts for 40-60% of the total mass of the calcium carboxymethyl cellulose; part of mannitol accounts for 40-60% of the total mass of mannitol. And further preferably: part of the calcium carboxymethyl cellulose accounts for 45-55% of the total mass of the calcium carboxymethyl cellulose; part of mannitol accounts for 45-55% of the total mass of mannitol. Still more preferably: part of the calcium carboxymethyl cellulose accounts for 48-52% of the total mass of the calcium carboxymethyl cellulose; part of mannitol accounts for 48-52% of the total mass of mannitol. Most preferably, a portion of the calcium carboxymethylcellulose comprises 50% of the total mass of the calcium carboxymethylcellulose; part of mannitol accounts for 50% of the total mass of mannitol. Screening experiments show that the preparation has good dissolution effect and excellent stability only by adopting an internal and external double-particle process and adding mannitol in a certain proportion in the preparation of the internal particles.
In S3, the sum of the remaining mannitol and the part of mannitol in step S2 is 100%, and the sum of the remaining calcium carboxymethylcellulose and the part of calcium carboxymethylcellulose in step S2 is 100%.
As a modified technical scheme of the invention, in S2 and/or S3, the preparation of the inner particles and the premixing particles can be carried out by adopting basically the same steps, and the selection of specific conditions can be selected according to actual production conditions. Namely, the invention adopts the multi-particle preparation technology that epalrestat, a disintegrant and a diluent with a specific proportion (preferably 50%) are prepared into inner particles (no adhesive is added in the inner particles), and then the inner particles and partial auxiliary materials are further prepared into premixed particles.
Specifically, the mixing conditions can be selected from: the stirring rotating speed is 120-240 rpm, the cutting rotating speed is 800-1600 rpm, and the mixing time is 3-8 minutes; preferably, the stirring speed is 180 rpm, the cutting speed is 1200 rpm, and the mixing time is 5 min.
Specifically, the granulation conditions can be selected from: adding purified water for granulating, and stirring and shearing at the same time, wherein the stirring rotating speed is 120-240 rpm, and the cutting rotating speed is 800-1600 rpm. Preferably, the stirring speed is 180 rpm, the cutting speed is 1200 rpm, and the mixing time is 5 min. And preferably, the atomization liquid adding method is adopted for liquid adding, and the atomization pressure is set to be 0.2 Mpa.
Specifically, the drying conditions can be selected from: the drying temperature is 55-65 ℃, and the drying is stopped when the material is dried until the moisture is not more than 2.0%. Preferably, drying is carried out in a fluidized bed, the drying temperature is set to be 55-65 ℃, preferably 60 ℃, the proper air quantity is adjusted, and the material is discharged when the material is dried until the moisture is not more than 2.0%.
Specifically, the whole grain conditions can be selected from: the method is carried out in a granulator, the diameter of a screen is 0.5 mm-1.5 mm, preferably, the diameter of a round hole screen is 1.0 mm in the step S2, and the diameter of a round hole screen is 1.5mm in the step S2, and the rotating speed is 200-400 rpm, preferably 300 rpm.
As an improved technical scheme of the invention, in S4, the obtained premixed particles and magnesium stearate are placed in a hopper mixer to be mixed, the mixing rotating speed is set to be 5-15 rpm, and the mixing time is set to be 5-10 minutes. Preferably, the speed of mixing is 10 rpm and the mixing time is 8 minutes.
In S5, circular deep-concave punching with the diameter of 6 mm-7 mm, preferably 6.5mm is used for tabletting, and the hardness of the tablet is 50N-90N. Specifically, the tablet weight is required to be = (50 mg/average content) according to the reduction of the content result, the tablet weight difference is controlled to be not more than +/-7.5%, and the friability is controlled to be not more than 1%.
As an improved technical scheme of the invention, in S6, after coating, the mass of the tablet is increased by 8-12%, preferably 10%, and the coating liquid used for coating is Opadry YS-1-7003 with the mass percentage concentration of 10-15%, preferably 13%. The preparation method of the coating liquid can adopt the following steps: weighing a certain amount of purified water, starting mechanical stirring, slowly dispersing the film coating premix in the water, and continuously stirring until the dispersion is uniform, wherein the dispersion time is not less than 45 min, and preparing a coating solution. Specifically, the air inlet temperature of the coating machine is 55-65 ℃, the temperature of the slice bed is 35-45 ℃, and the atomization pressure is 0.15-0.25 MPa.
Compared with the prior art, the technical scheme provided by the embodiment of the invention has the following advantages:
the epalrestat tablet prepared by the invention has a similar in vitro dissolution curve with a reference preparation (trade name: KINEDAK) published by the national drug administration, and the stability of the epalrestat tablet is obviously superior to that of the reference preparation.
Detailed Description
In order that the above objects, features and advantages of the present invention may be more clearly understood, a solution of the present invention will be further described below. It should be noted that the embodiments of the present invention and features of the embodiments may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those described herein; it is to be understood that the embodiments described in this specification are only some embodiments of the invention, and not all embodiments.
Example 1
The composition of the epalrestat tablets of this example is shown in table 2:
table 2:
the preparation process of the epalrestat tablet in the embodiment is as follows:
1. pretreating raw materials and auxiliary materials:
the epalrestat raw material is crushed, and the particle size D90 is less than or equal to 15 mu m; the mannitol and magnesium stearate are respectively sieved by a 60-mesh sieve.
2. Preparing inner particles:
adding epalrestat, 50% of carboxymethyl cellulose calcium and 50% of mannitol into a wet granulator for mixing, setting the stirring speed to be 180 rpm, the cutting speed to be 1200 rpm, and setting the mixing time to be 5 min; after uniform mixing, starting stirring and shearing, setting the stirring rotation speed to be 180 rpm and the cutting rotation speed to be 1200 rpm, atomizing liquid adding in a wet mixing granulator, setting the atomizing pressure to be 0.2 Mpa, and adding purified water for granulation; transferring the prepared granular material into a fluidized bed for drying, setting the drying temperature to be 60 ℃, adjusting the proper air quantity, and discharging when the material is dried until the moisture is not more than 2.0%; placing the dried material in a crushing and granulating machine for granulating (selecting a 1.0 mm round hole screen, setting the rotating speed at 300 rpm), so as to obtain the epalrestat-containing inner particles;
3. preparation of premix particles:
sequentially adding the inner granules, the rest 50% of mannitol, 50% of carboxymethylcellulose calcium and hydroxypropyl cellulose into a wet granulator for mixing, wherein the stirring speed is set to be 180 rpm, the cutting speed is set to be 1200 rpm, and the mixing time is 5 min; after uniform mixing, starting stirring and shearing, setting the stirring rotation speed to be 180 rpm and the cutting rotation speed to be 1200 rpm, atomizing liquid adding in a wet mixing granulator, setting the atomizing pressure to be 0.2 Mpa, and adding purified water for granulation; transferring the prepared granular material into a fluidized bed for drying, setting the drying temperature to be 60 ℃, adjusting the proper air quantity, and discharging when the material is dried until the moisture is not more than 2.0%; placing the dried material in a crushing and granulating machine for granulating (selecting a 1.5mm round hole screen with the set rotating speed of 300 rpm) to obtain premixed particles;
4. total mixing:
the obtained premixed granules and magnesium stearate were mixed in a hopper mixer at a mixing speed of 10 rpm for 8 min.
5. Tabletting:
converting the content result into tablet pressing, and performing tablet pressing by using a phi 6.5mm circular deep concave punch according to the tablet pressing weight = (50 mg/average content), wherein the hardness of the tablet is controlled to be 50-90N, the difference of the tablet weight is not more than +/-7.5%, and the friability is not more than 1%.
6. Coating:
preparing coating liquid, namely weighing a certain amount of purified water, starting mechanical stirring, slowly dispersing a film coating premix (Opadry YS-1-7003) in the water, continuously stirring until the dispersion is uniform (not less than 45 min), and preparing the coating liquid with the concentration of 13% (w/w) for later use without stopping stirring before and during use; coating: and (3) adjusting parameters of a coating machine, setting the air inlet temperature of the coating machine to be 60 ℃, controlling the temperature of a tablet bed to be within 35-45 ℃, and controlling the atomization pressure to be 0.15-0.25 MPa, so that the coating is carried out, and the coating weight is increased by 10%.
Comparative example 1
Except that the epalrestat raw material is crushed and the grain diameter D90 is less than or equal to 30 mu m, the other steps are carried out by the preparation process of the invention.
Comparative example 2:
1. pretreating raw materials and auxiliary materials:
epalrestat raw material, mannitol and magnesium stearate are sieved by a 60-mesh sieve.
2. Premixing: sequentially adding epalrestat, carboxymethyl cellulose calcium, mannitol and hydroxypropyl cellulose into a wet granulator for mixing, wherein the stirring speed is set to be 180 rpm, the cutting speed is set to be 1200 rpm, and the mixing time is 5 min; after uniform mixing, starting stirring and shearing, setting the stirring rotation speed to be 180 rpm and the cutting rotation speed to be 1200 rpm, atomizing and adding liquid in a wet mixing granulator, setting the atomizing pressure to be 0.2 Mpa, and adding purified water for granulation; transferring the prepared granular material into a fluidized bed for drying, setting the drying temperature to be 60 ℃, adjusting the proper air quantity, and discharging when the material is dried until the moisture is not more than 2.0%; placing the dried material in a crushing and granulating machine for granulating (selecting a 1.0 mm round hole screen, setting the rotating speed to be about 300 rpm), and obtaining premixed particles;
the premix granules were prepared into tablets by the same method as in example 1 of the present invention, i.e., a single granule preparation process.
Comparative example 3
The inner granule was prepared without adding mannitol, and only mannitol was added in its entirety during the premix granule preparation in step 3, and the rest of the procedure was the same as in example 1.
Example 2: drug dissolution detection
The dissolution rate determination method comprises the following specific steps:
dissolution method and rotation speed: paddle method, 75 rpm;
dissolution medium and volume: pH4.5 acetate buffer +1.0% SDS,900 mL;
pH6.8 phosphate buffer, 900 mL;
sampling time points are as follows: sampling times were 5, 10, 15, 30, 45, 60, 90 and 120 minutes;
sampling volume: taking the dissolution liquid 5 mL, filtering by a 0.45 mu m filter membrane, calculating the cumulative dissolution rate of each sampling point, and drawing a dissolution curve.
The dissolution medium and the preparation of the invention refer to the 'determination of dissolution curve and comparative guiding principle of common oral solid preparation', and the dissolution medium and the preparation method thereof are finally selected as follows:
ph4.5 acetate buffer +1.0% sds medium: taking sodium acetate trihydrate 2.99 g and sodium dodecyl sulfate 10 g, adding water to dissolve and dilute to 1000 mL, and adjusting the pH to 4.5 by using acetic acid;
ph6.8 phosphate buffer medium: potassium dihydrogen phosphate 1.7 g and disodium hydrogen phosphate 1.775 g (calculated as anhydride) were taken and dissolved in water to 1000 mL.
This example examined the drug release stability by leaving the drug at 40 ℃ and 75% relative humidity for 3 months.
The information of the reference preparation selected by the invention is as follows:
epalrestat tablets, trade name: KINEDAK, specification 50 mg.
The results of the experiment are shown in tables 3 and 4:
table 3: dissolution of phosphate solution (900 mL, paddle 75 rev) at pH6.8
From the results in Table 3, it is understood that the dissolution of example 1 of the present invention is very close to that of the reference preparation (original research) under the condition of pH6.8, and meets the national requirement for chemical consistency evaluation, and the performance is excellent. While comparative example 2, which selects the larger particle size material, has a slightly lower dissolution rate than the reference formulation. Comparative examples 2 and 3 clearly dissolve faster than the reference formulation and are difficult to meet the approval requirements. Meanwhile, an accelerated experiment of standing for 3 months proves that the stability of the single-particle preparation process of the comparative example 2 is obviously lower than that of the single-particle preparation process of the application example 1, the standing is accelerated for 3 months, and the dissolution reduction within 1 hour reaches 4.15 percent; while comparative examples 2 and 3, although superior to the reference formulation, are clearly inferior to the dissolution stability of example 1.
Table 4: pH4.5 acetic acid solution +1.0% dissolution of SDS (900 mL, paddle method 75 revolutions)
As is clear from the results in Table 4, the elution of the epalrestat tablets was significantly slower than that at pH6.8 in the elution environment of pH4.5 acetic acid solution +1.0% SDS. Among them, the tablets prepared by the multiple granulation process of example 1 of the present application showed the closest dissolution performance to the reference formulation. While comparative example 2 showed significantly faster dissolution at the previous stage, much higher than example 1 and the reference formulation. Surprisingly, comparative example 3 exhibited a significantly slower dissolution.
Example 3: drug stability testing (impurity content)
In this embodiment, the stability of epalrestat tablets is further examined through an accelerated experiment, the control of the maximum single impurity and the total impurity is mainly examined, the accelerated experiment is performed by placing the tablets at 40 ℃ and 75% of relative humidity for 6 months, and the detection conditions of the impurity content are shown in table 5:
table 5: impurity content of accelerated test
Table 5 the results show that under accelerated conditions the stability of the tablets of example 1 of the present application is higher than that of the reference reagent; also significantly better than comparative examples 1-3.
The foregoing are merely exemplary embodiments of the present invention, which enable those skilled in the art to understand or practice the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (13)
1. A preparation method of epalrestat tablets comprises the following steps: 50 parts of epalrestat, 50.6 parts of mannitol, 6.6 parts of hydroxypropyl cellulose, 2.2 parts of carboxymethyl cellulose calcium and 0.6 part of magnesium stearate; the preparation method is characterized by at least comprising the following steps:
s1, crushing epalrestat to obtain a particle size D90 of less than or equal to 15 microns; respectively sieving mannitol and magnesium stearate with 60 mesh sieve;
s2, preparing inner particles: adding epalrestat, part of carboxymethyl cellulose calcium and part of mannitol into a wet granulator, uniformly mixing, granulating, drying and finishing to obtain inner granules containing epalrestat; the part of the calcium carboxymethyl cellulose accounts for 40-60% of the total mass of the calcium carboxymethyl cellulose; the mannitol accounts for 40% -60% of the total mass of the mannitol;
s3, preparing premixed particles: adding the inner granules, the rest mannitol, the rest calcium carboxymethylcellulose and the rest hydroxypropyl cellulose into a wet granulator, uniformly mixing, granulating, drying and finishing to obtain premixed granules;
s4, total mixing: uniformly mixing the premixed granules with magnesium stearate;
s5, tabletting;
and S6, coating.
2. The method according to claim 1, wherein in S2 and/or S3: the mixing conditions are as follows: the stirring rotating speed is 120-240 rpm, the cutting rotating speed is 800-1600 rpm, and the mixing time is 3-8 minutes; the granulation conditions were: adding purified water for granulating, and stirring and shearing at the same time, wherein the stirring rotating speed is 120-240 rpm, and the cutting rotating speed is 800-1600 rpm.
3. The method according to claim 2, wherein in S2 and/or S3:
the drying conditions are as follows: the drying temperature is 55-65 ℃, and the drying is stopped when the material is dried until the moisture is not more than 2.0%.
4. The method according to claim 3, wherein in S2 and/or S3: the whole grain is carried out in a granulator, the diameter of a screen is 0.5 mm-1.5 mm, and the rotating speed is 200-400 rpm.
5. The method according to claim 4, wherein the step S2 is: adding epalrestat, 50% of carboxymethyl cellulose calcium and 50% of mannitol into a wet granulator for mixing, setting the stirring speed to be 180 rpm, the cutting speed to be 1200 rpm, and the mixing time to be 5 min; after uniform mixing, starting stirring and shearing, setting the stirring rotation speed to be 180 rpm and the cutting rotation speed to be 1200 rpm, atomizing and adding liquid in a wet granulator, setting the atomizing pressure to be 0.2 Mpa, and adding purified water for granulation; transferring the prepared granular material into a fluidized bed for drying, setting the drying temperature at 60 ℃, adjusting the air quantity, and discharging when the material is dried until the moisture is not more than 2.0%; and placing the dried material in a granulator, selecting a 1.0 mm round hole screen, setting the rotating speed to 300 rpm, and granulating to obtain the epalrestat-containing inner particles.
6. The method according to claim 4, wherein the step S3 is: adding the inner granules, the rest Gan Suo calcium methyl cellulose and hydroxypropyl cellulose into a wet granulator, mixing, setting the stirring speed to be 180 rpm, the cutting speed to be 1200 rpm, and mixing for 5 min; after uniform mixing, starting stirring and shearing, setting the stirring rotation speed to be 180 rpm and the cutting rotation speed to be 1200 rpm, atomizing and adding liquid in a wet granulator, setting the atomizing pressure to be 0.2 Mpa, and adding purified water for granulation; transferring the prepared granular material into a fluidized bed for drying, setting the drying temperature at 60 ℃, adjusting the air quantity, and discharging when the material is dried until the moisture is not more than 2.0%; and (3) placing the dried material in a granulator, selecting a 1.5mm round hole screen, and setting the rotating speed to 300 rpm to granulate to obtain premixed particles.
7. The method according to claim 1, wherein in S4: and placing the obtained premixed particles and magnesium stearate into a hopper mixer for mixing, wherein the mixing rotating speed is set to be 5-15 rpm, and the mixing time is set to be 5-10 minutes.
8. The method according to claim 7, wherein in S4: the obtained premixed granules and magnesium stearate were mixed in a hopper mixer at a mixing speed of 10 rpm for 8 minutes.
9. The method according to claim 1, wherein in S5: the tablets were compressed using a circular deep-concave punch with a diameter of 6 mm-7 mm and a tablet hardness of 50N-90N.
10. The method according to claim 1, wherein, in S6: after the coating, the mass of the tablet is increased by 8-12%; the coating liquid used for coating is Opadry YS-1-7003 with the mass percentage concentration of 10% -15%.
11. The production method according to claim 10, wherein, in S6: after the coating, the mass of the tablet is increased by 10%; the coating liquid used for coating is Opadry YS-1-7003 with the mass percentage concentration of 13%.
12. The method according to claim 11, wherein in S6: the coating conditions are as follows: the air inlet temperature of the coating machine is 55-65 ℃, the temperature of the slice bed is 35-45 ℃, and the atomization pressure is 0.15-0.25 MPa.
13. The epalrestat tablet produced by the production method according to any one of claims 1 to 12.
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