CN113648304A - Pharmaceutical composition containing dapagliflozin and preparation method and application thereof - Google Patents
Pharmaceutical composition containing dapagliflozin and preparation method and application thereof Download PDFInfo
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- CN113648304A CN113648304A CN202111038307.7A CN202111038307A CN113648304A CN 113648304 A CN113648304 A CN 113648304A CN 202111038307 A CN202111038307 A CN 202111038307A CN 113648304 A CN113648304 A CN 113648304A
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- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 title claims abstract description 109
- 229960003834 dapagliflozin Drugs 0.000 title claims abstract description 108
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 52
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 70
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 56
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 35
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 21
- 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 abstract description 19
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 19
- 239000008101 lactose Substances 0.000 claims abstract description 19
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 19
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 19
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 19
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 17
- 239000002245 particle Substances 0.000 claims abstract description 15
- 229960001866 silicon dioxide Drugs 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 13
- 229960001375 lactose Drugs 0.000 claims abstract description 3
- 229940057948 magnesium stearate Drugs 0.000 claims abstract description 3
- 229940079832 sodium starch glycolate Drugs 0.000 claims abstract description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims abstract description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims description 29
- 229920002472 Starch Polymers 0.000 claims description 25
- 229910052708 sodium Inorganic materials 0.000 claims description 25
- 239000011734 sodium Substances 0.000 claims description 25
- 229940032147 starch Drugs 0.000 claims description 25
- 239000008107 starch Substances 0.000 claims description 25
- 235000019698 starch Nutrition 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- 239000011812 mixed powder Substances 0.000 claims description 22
- 239000008187 granular material Substances 0.000 claims description 21
- 238000007908 dry granulation Methods 0.000 claims description 6
- 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 claims description 5
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 239000007902 hard capsule Substances 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000007901 soft capsule Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims description 2
- 238000010298 pulverizing process Methods 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 16
- 238000000338 in vitro Methods 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 abstract description 8
- 239000000463 material Substances 0.000 abstract description 2
- 238000003825 pressing Methods 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 13
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 12
- 238000005469 granulation Methods 0.000 description 11
- 230000003179 granulation Effects 0.000 description 11
- 229940079593 drug Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- FLDSMVTWEZKONL-AWEZNQCLSA-N 5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,7,8-tetrahydrooxepino[4,5-c]pyrazole-3-carboxamide Chemical compound CC1(CC2=C(NN=C2C(=O)N[C@@H]2C(N(C3=C(OC2)C=CC=C3)C)=O)CCO1)C FLDSMVTWEZKONL-AWEZNQCLSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 102000003673 Symporters Human genes 0.000 description 1
- 108090000088 Symporters Proteins 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229940110266 farxiga Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005550 wet granulation 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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 provides a pharmaceutical composition containing dapagliflozin and a preparation method and application thereof. The preparation raw materials of the pharmaceutical composition containing dapagliflozin comprise: dapagliflozin with D90 of less than 30 μm, lactose, microcrystalline cellulose, silicon dioxide, sodium starch glycolate and magnesium stearate. The medicinal composition controls the particle size of D90 of the raw material medicament to be less than 30 mu m, thereby fully improving the in vitro dissolution capability; and by selecting the auxiliary materials, the dissolution rate and the speed of dapagliflozin can be effectively improved while the stability of dapagliflozin is ensured.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing dapagliflozin, and a preparation method and application thereof.
Background
Diabetes mellitus is a common endocrine-metabolic disease characterized by hyperglycemia accompanied by disturbances in the metabolism of sugar, fat and protein due to insufficient insulin secretion and/or defective action.
The dapagliflozin tablet is jointly developed by the companies of Baishiguibao and Aslicon, is a novel antidiabetic drug, is approved by European Committee to be on the market in 11 months of 2012, and has the trade name of Forxiga. Approved by the U.S. FDA for marketing in 1 month 2014 under the trade name Farxiga. The CFDA is approved in 3 months in 2017, and the SGLT2 inhibitor becomes the first marketed inhibitor for treating type 2 diabetes in China, is named Andangtang in Chinese trade name, and has the specification of 5mg and 10 mg.
Dapagliflozin is a highly selective human kidney sodium glucose co-transporter (SGLT2) inhibitor, and can promote the excretion of glucose through urine by inhibiting the reabsorption of glucose by kidney, thereby reducing blood sugar. As a diet-and exercise-assisted therapy, first-line therapy for type 2 diabetic patients who are not drug-treated, who are only under diet control and exercise but have poor blood sugar control, is used to improve blood sugar control.
At present, the existing dapagliflozin pharmaceutical composition has the following problems: 1) most of the new preparations have more complex preparation processes, lower possibility of mass production and higher difficulty, and the treatment effect needs to be further verified; 2) the physical and chemical quality of the medicine can be properly improved by changing the prescription, but certain potential safety hazards exist compared with the original prescription preparation which is used for a long time; 3) the safety and curative effect need further verification.
CN107648194A discloses a dapagliflozin composition, wherein a unit dose of the composition contains 5-10mg of dapagliflozin with D50 of 32-46 mu m, 26-35mg of lactose, 48-60mg of microcrystalline cellulose, 60005-8mg of polyethylene glycol, 9-12mg of sodium citrate, 303-8mg of povidone K, 3-8mg of crospovidone, 0.9-1.2mg of sodium dodecyl sulfate and 1-1.5mg of magnesium stearate. The preparation method solves the problem of stability of the content uniformity of dapagliflozin, but has poor in-vitro dissolution due to large particle size of the raw material medicine.
CN111374968A discloses a dapagliflozin-containing composition, a preparation method and application thereof. The invention provides a dapagliflozin-containing composition which comprises the following components in parts by mass: 15-25 parts of dapagliflozin, 20-70 parts of organic carrier, 30-70 parts of filler, 5-15 parts of disintegrant and 10-20 parts of lubricant. A high-energy granulation process is required because drying is required once the wet granulation process is completed, energy consumption can be slightly reduced by using spray drying granulation, and the problems of large particle size of the crude drug and poor in-vitro dissolution property also exist.
Therefore, if the physicochemical quality of the dapagliflozin tablet is to be improved practically and feasible and the qualified product can be smoothly produced in each production process, the optimization of the preparation process is feasible and necessary.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a pharmaceutical composition containing dapagliflozin and a preparation method and application thereof. The medicinal composition controls the particle size of the raw material medicaments and ensures in-vitro dissolution.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a pharmaceutical composition containing dapagliflozin, wherein the preparation raw materials of the pharmaceutical composition containing dapagliflozin comprise: dapagliflozin with D90 of less than 30 μm, lactose, microcrystalline cellulose, silicon dioxide, sodium starch glycolate and magnesium stearate.
The particle size of D90 of dapagliflozin is less than 30 μm, and may be 29 μm, 28 μm, 26 μm, 24 μm, 22 μm, 20 μm, 15 μm, 10 μm, 8 μm, 5 μm, 2 μm, 1 μm, and the like.
In the present invention, first, the pharmaceutical composition is controlled to control the particle size of D90 of the drug substance to be less than 30 μm, thereby sufficiently improving the in vitro dissolution ability. Secondly, the auxiliary materials are selected, so that the dissolution rate and the speed of dapagliflozin can be effectively improved while the stability of dapagliflozin is ensured.
Preferably, the preparation raw materials of the pharmaceutical composition containing dapagliflozin comprise, by weight: 5-10 parts of dapagliflozin with the D90 smaller than 30 mu m, 45-100 parts of lactose, 90-270 parts of microcrystalline cellulose, 5-15 parts of silicon dioxide, 4.5-45 parts of carboxymethyl starch sodium and 2-13.5 parts of magnesium stearate.
Wherein the dapagliflozin with D90 less than 30 μm content is 5-10 parts, such as 5 parts, 5.5 parts, 6 parts, 6.5 parts, 7 parts, 7.5 parts, 8 parts, 8.5 parts, 9 parts, 9.5 parts, 10 parts and the like.
The content of lactose is 45-100 parts, for example, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, 100 parts, etc.
The microcrystalline cellulose content is 90 to 270 parts, and may be, for example, 90 parts, 100 parts, 120 parts, 140 parts, 160 parts, 180 parts, 200 parts, 220 parts, 240 parts, 260 parts, 270 parts, or the like.
The silica content is 5 to 15 parts, and may be, for example, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, or the like.
Wherein, the content of the carboxymethyl starch sodium is 4.5 to 45 parts, such as 4.5 parts, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts and the like.
The magnesium stearate content is 2 to 13.5 parts, and may be, for example, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 13.5 parts, and the like.
Preferably, the dosage form of the pharmaceutical composition containing dapagliflozin comprises any one of tablets, hard capsules, soft capsules, pills, powder or paste or the combination of at least two of the tablets, the hard capsules, the soft capsules, the pills and the powder.
In a second aspect, the present invention provides a method for preparing a dapagliflozin-containing pharmaceutical composition, as described in the first aspect, comprising the following steps:
(1) mixing dapagliflozin with the D90 of less than 30 mu m, lactose, microcrystalline cellulose, part of sodium carboxymethyl starch, part of silicon dioxide and part of magnesium stearate to obtain mixed powder;
(2) performing dry granulation on the mixed powder obtained in the step (1) to obtain granules;
(3) and (3) mixing the granules obtained in the step (2) with the residual sodium carboxymethyl starch, the residual silicon dioxide and the residual magnesium stearate to obtain the pharmaceutical composition containing dapagliflozin.
In the invention, the preparation method of the pharmaceutical composition containing dapagliflozin can improve the physicochemical quality of the dapagliflozin tablet practically and feasible through the optimization of the preparation process, and ensure that qualified products can be produced smoothly in each production process. The process preparation process is simple and controllable, and the reproducibility is good; can effectively control the particle size of the raw material medicine and ensure the in vitro dissolution.
Preferably, in the step (1), the dapagliflozin with the D90 of less than 30 μm is prepared by a crushing method.
Preferably, in step (1), the rotation speed of the mixing is 5-30rpm, such as 5rpm, 6rpm, 7rpm, 8rpm, 9rpm, 10rpm, 12rpm, 14rpm, 16rpm, 18rpm, 20rpm, 22rpm, 24rpm, 26rpm, 28rpm, 30rpm, etc., and the mixing time is 3-15min, such as 3min, 4min, 5min, 6min, 7min, 8min, 9min, 10min, 11min, 12min, 13min, 14min, 15min, etc.
Preferably, the portion of the sodium carboxymethyl starch accounts for 0 to 100% by mass of the total mass of the sodium carboxymethyl starch, and may be, for example, 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, etc., i.e., the sodium carboxymethyl starch may be added all together, or a portion thereof.
Preferably, in step (1), the mass of the partial silica accounts for 0.5 to 10% of the total mass of the silica, and may be, for example, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or the like.
Preferably, in step (1), the part of magnesium stearate accounts for 0.5-10% of the total mass of magnesium stearate, and may be, for example, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc.
Preferably, in step (2), the dry granulation is performed in a dry granulator, and the equipment parameters are specifically: the pressure of the press roll is 20-70bar (for example, 20bar, 22bar, 24bar, 26bar, 28bar, 30bar, 40bar, 50bar, 60bar, 70bar, etc.), the feeding speed is 10-40rpm (for example, 10rpm, 12rpm, 14rpm, 16rpm, 18rpm, 20rpm, 25rpm, 30rpm, 35rpm, 40rpm, etc.), the press roll speed is 5-30rpm (for example, 5rpm, 6rpm, 7rpm, 8rpm, 9rpm, 10rpm, 15rpm, 20rpm, 25rpm, 30rpm, etc.), and the pulverizing speed is 50-150rpm (for example, 50rpm, 60rpm, 70rpm, 80rpm, 90rpm, 100rpm, 110rpm, 120rpm, 130rpm, 140rpm, 150rpm, etc.).
Preferably, in step (2), the dry granulation particles have a particle size of 20-80 mesh (e.g., 20 mesh, 30 mesh, 40 mesh, 50 mesh, 60 mesh, 70 mesh, 80 mesh, etc.) and account for 40-70% (e.g., 40%, 45%, 50%, 55%, 60%, 65%, 70%, etc.) of the total mass.
Preferably, in step (3), the rotation speed of the mixing is 5-30rpm, such as 5rpm, 10rpm, 15rpm, 20rpm, 25rpm, 30rpm, etc., and the mixing time is 3-15min, such as 3min, 5min, 7min, 9min, 11min, 13min, 15min, etc.
In a third aspect, the present invention provides a use of the pharmaceutical composition containing dapagliflozin according to the first aspect in preparation of a medicament for treating diabetes.
Compared with the prior art, the invention has the following beneficial effects:
(1) the pharmaceutical composition containing dapagliflozin disclosed by the invention controls the particle size of the raw material medicine, and fully ensures in-vitro dissolution, namely the cumulative dissolution rate of the pharmaceutical composition containing dapagliflozin can reach more than 90% in 30 min;
(2) the pharmaceutical composition containing dapagliflozin has the advantages of simple and controllable process and preparation process and good reproducibility.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
The sources of the components of the following examples are as follows:
example 1
The embodiment provides a pharmaceutical composition containing dapagliflozin, which is prepared from the following raw materials (1000 preparation units):
the preparation method of the pharmaceutical composition containing dapagliflozin comprises the following steps:
(1) adding 10g of dapagliflozin with the D90 of 15 mu m, 140g of lactose, 140g of microcrystalline cellulose, 27g of sodium carboxymethyl starch, 5g of colloidal silicon dioxide and 4g of magnesium stearate into a mixer, and uniformly mixing to obtain mixed powder;
(2) adding the mixed powder obtained in the step (1) into a dry-method granulator for granulation, wherein the equipment parameters are as follows: pressing roller pressure is 25bar, feeding speed is 18rpm, pressing roller speed is 8rpm, crushing speed is 100rpm, and granulating aperture is 1mm to obtain granules;
(3) and (3) mixing the granules obtained in the step (2), 5g of silicon dioxide and 4g of magnesium stearate to obtain the pharmaceutical composition containing dapagliflozin.
Example 2
The embodiment provides a pharmaceutical composition containing dapagliflozin, which is prepared from the following raw materials (1000 preparation units):
the preparation method of the pharmaceutical composition containing dapagliflozin comprises the following steps:
(1) adding 10g of dapagliflozin with the D90 of 20 mu m, 140g of lactose, 140g of microcrystalline cellulose, 13.5g of sodium carboxymethyl starch, 5g of colloidal silicon dioxide and 4g of magnesium stearate into a mixer, and uniformly mixing to obtain mixed powder;
(2) adding the mixed powder obtained in the step (1) into a dry-method granulator for granulation, wherein the equipment parameters are as follows: pressing roller pressure is 25bar, feeding speed is 18rpm, pressing roller speed is 8rpm, crushing speed is 100rpm, and granulating aperture is 1mm to obtain granules;
(3) and (3) mixing the granules obtained in the step (2), 13.5g of sodium carboxymethyl starch, 5g of silicon dioxide and 4g of magnesium stearate to obtain the pharmaceutical composition containing dapagliflozin.
Example 3
The embodiment provides a pharmaceutical composition containing dapagliflozin, which is prepared from the following raw materials (1000 preparation units):
the preparation method of the pharmaceutical composition containing dapagliflozin comprises the following steps:
(1) adding 10g of dapagliflozin with the D90 of 20 mu m, 140g of lactose, 140g of microcrystalline cellulose, 13.5g of sodium carboxymethyl starch, 5g of colloidal silicon dioxide and 4g of magnesium stearate into a mixer, and uniformly mixing to obtain mixed powder;
(2) adding the mixed powder obtained in the step (1) into a dry-method granulator for granulation, wherein the equipment parameters are as follows: pressing roller pressure is 45bar, feeding speed is 20rpm, pressing roller speed is 10rpm, crushing speed is 100rpm, and granulating aperture is 1mm to obtain granules;
(3) and (3) mixing the granules obtained in the step (2), 13.5g of sodium carboxymethyl starch, 5g of silicon dioxide and 4g of magnesium stearate to obtain the pharmaceutical composition containing dapagliflozin.
Example 4
The embodiment provides a pharmaceutical composition containing dapagliflozin, which is prepared from the following raw materials (1000 preparation units):
the preparation method of the pharmaceutical composition containing dapagliflozin comprises the following steps:
(1) adding 10g of dapagliflozin with the D90 of 20 mu m, 140g of lactose, 140g of microcrystalline cellulose, 5g of colloidal silicon dioxide and 4g of magnesium stearate into a mixer, and uniformly mixing to obtain mixed powder;
(2) adding the mixed powder obtained in the step (1) into a dry-method granulator for granulation, wherein the equipment parameters are as follows: pressing roller pressure is 25bar, feeding speed is 18rpm, pressing roller speed is 8rpm, crushing speed is 100rpm, and granulating aperture is 1mm to obtain granules;
(3) and (3) mixing the granules obtained in the step (2), 27g of sodium carboxymethyl starch, 5g of silicon dioxide and 4g of magnesium stearate to obtain the pharmaceutical composition containing dapagliflozin.
Example 5
The embodiment provides a pharmaceutical composition containing dapagliflozin, which is prepared from the following raw materials (1000 preparation units):
the preparation method of the pharmaceutical composition containing dapagliflozin comprises the following steps:
(1) adding 10g of dapagliflozin with the D90 of 20 mu m, 200g of lactose, 80g of microcrystalline cellulose, 5g of colloidal silicon dioxide and 4g of magnesium stearate into a mixer, and uniformly mixing to obtain mixed powder;
(2) adding the mixed powder obtained in the step (1) into a dry-method granulator for granulation, wherein the equipment parameters are as follows: pressing roller pressure is 25bar, feeding speed is 18rpm, pressing roller speed is 8rpm, crushing speed is 100rpm, and granulating aperture is 1mm to obtain granules;
(3) and (3) mixing the granules obtained in the step (2), 27g of sodium carboxymethyl starch, 5g of silicon dioxide and 4g of magnesium stearate to obtain the pharmaceutical composition containing dapagliflozin.
Example 6
The embodiment provides a pharmaceutical composition containing dapagliflozin, which is prepared from the following raw materials (1000 preparation units):
the preparation method of the pharmaceutical composition containing dapagliflozin comprises the following steps:
(1) adding 10g of dapagliflozin with the D90 of 15 mu m, 140g of lactose, 140g of microcrystalline cellulose, 27g of sodium carboxymethyl starch, 8g of colloidal silicon dioxide and 2g of magnesium stearate into a mixer, and uniformly mixing to obtain mixed powder;
(2) adding the mixed powder obtained in the step (1) into a dry-method granulator for granulation, wherein the equipment parameters are as follows: pressing roller pressure is 25bar, feeding speed is 18rpm, pressing roller speed is 8rpm, crushing speed is 100rpm, and granulating aperture is 1mm to obtain granules;
(3) and (3) mixing the granules obtained in the step (2), 2g of silicon dioxide and 6g of magnesium stearate to obtain the pharmaceutical composition containing dapagliflozin.
Example 7
The embodiment provides a pharmaceutical composition containing dapagliflozin, which is prepared from the following raw materials (1000 preparation units):
the preparation method of the pharmaceutical composition containing dapagliflozin comprises the following steps:
(1) adding 10g of dapagliflozin with the D90 of 15 mu m, 140g of lactose, 140g of microcrystalline cellulose, 27g of sodium carboxymethyl starch, 2g of colloidal silicon dioxide and 6g of magnesium stearate into a mixer, and uniformly mixing to obtain mixed powder;
(2) adding the mixed powder obtained in the step (1) into a dry-method granulator for granulation, wherein the equipment parameters are as follows: pressing roller pressure is 25bar, feeding speed is 18rpm, pressing roller speed is 8rpm, crushing speed is 100rpm, and granulating aperture is 1mm to obtain granules;
(3) and (3) mixing the granules obtained in the step (2), 8g of silicon dioxide and 2g of magnesium stearate to obtain the pharmaceutical composition containing dapagliflozin.
Example 8
The embodiment provides a pharmaceutical composition containing dapagliflozin, which is prepared from the following raw materials (1000 preparation units):
the preparation method of the pharmaceutical composition containing dapagliflozin comprises the following steps:
(1) adding 10g of dapagliflozin with the D90 of 15 mu m, 140g of lactose, 140g of microcrystalline cellulose, 27g of sodium carboxymethyl starch, 10g of colloidal silicon dioxide and 8g of magnesium stearate into a mixer, and uniformly mixing to obtain mixed powder;
(2) adding the mixed powder obtained in the step (1) into a dry-method granulator for granulation, wherein the equipment parameters are as follows: the compression roller pressure is 25bar, the feeding speed is 18rpm, the compression roller speed is 8rpm, the crushing speed is 100rpm, and the granulating aperture is 1mm, so as to obtain granules, and obtain the pharmaceutical composition containing the dapagliflozin.
Example 9
The embodiment provides a pharmaceutical composition containing dapagliflozin, which is prepared from the following raw materials (1000 preparation units):
the preparation method of the pharmaceutical composition containing dapagliflozin comprises the following steps:
(1) adding 10g of dapagliflozin with the D90 of 15 mu m, 140g of lactose, 140g of microcrystalline cellulose and 27g of carboxymethyl starch sodium into a mixer, and uniformly mixing to obtain mixed powder;
(2) adding the mixed powder obtained in the step (1) into a dry-method granulator for granulation, wherein the equipment parameters are as follows: pressing roller pressure is 25bar, feeding speed is 18rpm, pressing roller speed is 8rpm, crushing speed is 100rpm, and granulating aperture is 1mm to obtain granules;
(3) and (3) mixing the granules obtained in the step (2), 10g of silicon dioxide and 8g of magnesium stearate to obtain the pharmaceutical composition containing dapagliflozin.
Comparative example 1
This comparative example provides a pharmaceutical composition containing dapagliflozin, which differs from example 1 only in that the D90 particle size of dapagliflozin is 40 μm, the component content and the preparation method are the same as example 1.
Comparative example 2
The comparative example provides a pharmaceutical composition containing dapagliflozin, which is different from the example 1 only in that microcrystalline cellulose is replaced by starch with equal mass, and the contents of other components and the preparation method are the same as those in the example 1.
Comparative example 3
The comparative example provides a pharmaceutical composition containing dapagliflozin, and only differs from example 1 in that lactose is replaced by povidone K30 with equal mass, and the contents of other components and the preparation method are the same as those in example 1.
Comparative example 4
The comparative example provides a drug composition containing dapagliflozin, which is different from the drug composition in example 1 only in that sodium carboxymethyl starch is replaced by polyvinylpyrrolidone with equal mass, and the content of other components and the preparation method are the same as those in example 1.
Comparative example 5
This comparative example provides a pharmaceutical composition containing dapagliflozin, which differs from example 1 only in that colloidal silicon dioxide is not added in the internal addition, and the magnesium stearate content is increased to 9 g; and in addition, colloidal silicon dioxide is not added, the content of magnesium stearate is increased to 9g, and the content of other components and the preparation method are the same as those of the example 1.
Comparative example 6
This comparative example provides a pharmaceutical composition containing dapagliflozin, which differs from example 1 only in that magnesium stearate is not added in the internal addition, and the colloidal silicon dioxide content is increased to 9 g; and magnesium stearate is not added in the addition, the content of the colloidal silicon dioxide is increased to 9g, and the content of other components and the preparation method are the same as those of the example 1.
Performance testing
The dissolution rate of dapagliflozin in the pharmaceutical composition is determined according to the second method (paddle method) of dissolution determination method X C in the second part of the 2010 version of the Chinese pharmacopoeia. Dissolution medium: 900mL of degassed pH 4.5 acetate buffer. Water bath temperature: (37 ± 0.5) ° c, rotation speed: 50 rpm;
samples in examples 1-9 and comparative examples 1-6 were respectively added, and appropriate amount of solution was taken at 5, 10, 15, 20, and 30min according to the method, and filtered to obtain filtrate as sample solution. Detecting the dissolution rate by a high performance liquid chromatography, calculating the concentration of dapagliflozin in a dissolution medium, and calculating the accumulated dissolution rate;
the specific test results are shown in table 1 below:
TABLE 1
As shown in the test data in Table 1, the cumulative dissolution rate of the pharmaceutical composition containing dapagliflozin can reach more than 90% in 30 min. Therefore, the preparation method of the pharmaceutical composition containing dapagliflozin can improve the physicochemical quality of the dapagliflozin tablet practically and ensure that qualified products can be produced smoothly in each production process by optimizing the preparation process. The process preparation process is simple and controllable, and the reproducibility is good; can effectively control the particle size of the raw material medicine and ensure the in vitro dissolution.
The applicant states that the pharmaceutical composition containing dapagliflozin and the preparation method and application thereof are illustrated by the above examples, but the invention is not limited to the above examples, that is, the invention is not limited to the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. The pharmaceutical composition containing dapagliflozin is characterized in that the raw materials for preparing the pharmaceutical composition containing dapagliflozin comprise: dapagliflozin with D90 of less than 30 μm, lactose, microcrystalline cellulose, silicon dioxide, sodium starch glycolate and magnesium stearate.
2. The dapagliflozin-containing pharmaceutical composition according to claim 1, characterized in that the preparation raw materials of the dapagliflozin-containing pharmaceutical composition comprise, in parts by weight: 5-10 parts of dapagliflozin with the D90 smaller than 30 mu m, 45-100 parts of lactose, 90-270 parts of microcrystalline cellulose, 5-15 parts of silicon dioxide, 4.5-45 parts of carboxymethyl starch sodium and 2-13.5 parts of magnesium stearate.
3. The dapagliflozin containing pharmaceutical composition according to claim 1 or 2, characterized in that the dosage form of the dapagliflozin containing pharmaceutical composition comprises any one or a combination of at least two of tablets, hard capsules, soft capsules, pills, powders or pastes.
4. The preparation method of the dapagliflozin containing pharmaceutical composition according to any one of claims 1 to 3, characterized in that the preparation method of the dapagliflozin containing pharmaceutical composition comprises the following steps:
(1) mixing dapagliflozin with the D90 of less than 30 mu m, lactose, microcrystalline cellulose, part of sodium carboxymethyl starch, part of silicon dioxide and part of magnesium stearate to obtain mixed powder;
(2) performing dry granulation on the mixed powder obtained in the step (1) to obtain granules;
(3) and (3) mixing the granules obtained in the step (2) with the residual sodium carboxymethyl starch, the residual silicon dioxide and the residual magnesium stearate to obtain the pharmaceutical composition containing dapagliflozin.
5. The method for preparing the dapagliflozin-containing pharmaceutical composition according to claim 4, characterized in that, in the step (1), the dapagliflozin with the D90 smaller than 30 μm is prepared by a pulverization method.
6. The method for preparing the dapagliflozin-containing pharmaceutical composition according to claim 4 or 5, characterized in that, in the step (1), the rotation speed of the mixing is 5-30rpm, and the mixing time is 3-15 min.
7. The method for preparing the dapagliflozin-containing pharmaceutical composition according to any one of claims 4-6, characterized in that, in step (1), the part of the sodium carboxymethyl starch accounts for 0-100% of the total mass of the sodium carboxymethyl starch;
preferably, in the step (1), the mass of the partial silica accounts for 0.5-10% of the total mass of the silica;
preferably, in the step (1), the part of magnesium stearate accounts for 0.5-10% of the total mass of magnesium stearate.
8. The process for the preparation of the pharmaceutical composition containing dapagliflozin according to any one of claims 4-7, characterized in that, in step (2), the dry granulation is carried out in a dry granulator, the equipment parameters being in particular: the pressure of the press roll is 20-70bar, the feeding speed is 10-40rpm, the speed of the press roll is 5-30rpm, and the crushing speed is 50-150 rpm;
preferably, in the step (2), the dry granulation is performed to obtain particles with the particle size of 20-80 meshes, and the particles account for 40-70% of the total mass.
9. The method for preparing the dapagliflozin containing pharmaceutical composition according to any one of claims 4-8, characterized in that, in the step (3), the rotation speed of the mixing is 5-30rpm, and the mixing time is 3-15 min.
10. Use of the pharmaceutical composition containing dapagliflozin according to any one of claims 1 to 3 in the preparation of a medicament for treating diabetes.
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