CN112294768B - Ezetimibe tablet and method for improving dissolution rate thereof - Google Patents
Ezetimibe tablet and method for improving dissolution rate thereof Download PDFInfo
- Publication number
- CN112294768B CN112294768B CN201910697163.2A CN201910697163A CN112294768B CN 112294768 B CN112294768 B CN 112294768B CN 201910697163 A CN201910697163 A CN 201910697163A CN 112294768 B CN112294768 B CN 112294768B
- Authority
- CN
- China
- Prior art keywords
- parts
- ezetimibe
- sanding
- dodecyl sulfate
- povidone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title claims abstract description 60
- 229960000815 ezetimibe Drugs 0.000 title claims abstract description 60
- 238000004090 dissolution Methods 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 29
- 239000000203 mixture Substances 0.000 claims description 35
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 32
- 239000000725 suspension Substances 0.000 claims description 28
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 25
- 229940083575 sodium dodecyl sulfate Drugs 0.000 claims description 22
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 20
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 20
- 229920003081 Povidone K 30 Polymers 0.000 claims description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 16
- 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 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 16
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 16
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 16
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 16
- 239000004576 sand Substances 0.000 claims description 16
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 14
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 14
- 229960001021 lactose monohydrate Drugs 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 11
- 239000012736 aqueous medium Substances 0.000 claims description 6
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 6
- 229940057948 magnesium stearate Drugs 0.000 claims description 6
- 229940024898 povidone k30 Drugs 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- 238000000227 grinding Methods 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229940069328 povidone Drugs 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 22
- 229940079593 drug Drugs 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 12
- 238000010902 jet-milling Methods 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000008187 granular material Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 12
- 238000009472 formulation Methods 0.000 description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000003801 milling Methods 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000007900 aqueous suspension Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 108010028554 LDL Cholesterol Proteins 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- IAZVVHPXBDEBOY-UHFFFAOYSA-L disodium dodecyl sulfate acetate Chemical compound C(C)(=O)[O-].[Na+].S(=O)(=O)(OCCCCCCCCCCCC)[O-].[Na+] IAZVVHPXBDEBOY-UHFFFAOYSA-L 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 239000007974 sodium acetate buffer Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 101710095342 Apolipoprotein B Proteins 0.000 description 2
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 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 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000011265 semifinished product Substances 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 208000030673 Homozygous familial hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000033227 intestinal cholesterol absorption Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 238000002616 plasmapheresis Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000005303 weighing 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- 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
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a method for improving dissolution rate of ezetimibe tablets. Compared with the method of granulating the crude drug after pretreatment by jet milling, the preparation process has the advantages that the dissolution speed of the obtained finished product is higher, especially in SDS medium with pH of 4.5+0.15%, and the curative effect of the product is improved.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a method for improving the dissolution rate of ezetimibe tablets.
Background
Chemical name of ezetimibe: 1- (4-fluorophenyl) -3 (R) - [3- (4-fluorophenyl) -3 (S) -hydroxypropyl ] -4 (S) - (4-hydroxyphenyl) -2-azetidine (azetidine) one having the following chemical structure:
the molecular formula is as follows: C24H21F2NO, molecular weight: 409.4.
ezetimibe is a white crystalline powder, soluble in ethanol, methanol, and acetone, practically insoluble in water, and stable at room temperature with a melting point of about 163 ℃. Ezetimibe is used clinically mainly for primary hypercholesterolemia, as an adjunct treatment to dietary management, can be used alone or in combination with HMG-CoA reductase inhibitors such as statins to treat hypercholesterolemia, can reduce Total Cholesterol (TC), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), or as an adjunct treatment to other lipid lowering therapies (such as LDL-C plasmapheresis), and can also be used to reduce TC and LDL-C levels in HoFH patients when other lipid lowering therapies are ineffective.
With the sustainable development of socioeconomic performance, the dietary level of people is continuously improved, and the blood lipid level of the national people is also increased. Many epidemiological studies on blood lipids carried out domestically have demonstrated that the incidence of hyperlipidemia in China is conservatively estimated to be 7% to 8%, whereas the actual average incidence may reach over 10%, and that more than one hundred million people are in need of lipid-regulating therapy nationally. With the upcoming aging society, there will be more population nationwide that will need to receive hypolipidemic therapy.
Ezetimibe tablet is a powerful hypolipidemic drug which is researched and developed by both first-aid and American moesadong company, is the only selective cholesterol absorption inhibitor on the market at present, and can effectively reduce intestinal cholesterol absorption and reduce plasma cholesterol level and liver cholesterol reserves by selectively inhibiting small intestine cholesterol transport proteins. Ezetimibe is used clinically primarily for the treatment of primary hypercholesterolemia, either alone or in combination with HMG-CoA reductase inhibitors. Ezetimibe mainly acts on the small intestine to inhibit cholesterol absorption, so that the ezetimibe can not influence the absorption of other nutrient substances, and patients have better tolerance than other lipid-lowering drugs and less adverse reaction.
Ezetimibe is insoluble in water and when a solid dosage form of ezetimibe is orally administered, the drug must be dissolved in gastric juice before it can be absorbed to exert its therapeutic effect. The bioavailability of a compressed solid oral dosage form, such as a tablet, is often limited by its dissolution rate, which affects the therapeutic efficacy of the drug. According to Ezetimibe tablet quality standard (standard number: JX 20030223) of national food and drug administration, dissolution of not less than 85% in 30 minutes under pH4.5+0.15% SDS/50r is required. Thus, the dissolution rate of ezetimibe is a very important quality measure. And ezetimibe tablets are mainly absorbed through the upper end of the duodenum after being orally taken, so that the dissolution curve of ezetimibe tablets in SDS medium with pH of 4.5+0.15% has a certain correlation with the in vivo absorption speed and degree, and important attention is paid to the ezetimibe tablets in experiments.
To increase the dissolution rate of oral solid formulations, generally the choice is to: the raw material medicines are pretreated in a jet milling mode to control the granularity of the raw material medicines, so that the solubility of the raw material medicines is increased. However, this method does not allow the dissolution of ezetimibe to a satisfactory extent, and thus requires further investigation into the formulation process.
The inventor finds that after ezetimibe and water are prepared into suspension in the research process, sanding is carried out by using a nano sand mill, and one-step granulation is used, so that the dissolution rate of the obtained product in SDS medium with pH of 4.5+0.15% is obviously improved compared with the prior reported preparation, the bioavailability of ezetimibe can be obviously increased, and the curative effect of the product is improved.
Disclosure of Invention
Accordingly, it is an object of the present invention to provide a composition, wherein each component of the composition is a semi-finished product for preparing ezetimibe solid preparation with high dissolution rate.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
the premix for preparing the ezetimibe solid preparation with high dissolution rate is characterized by comprising ezetimibe raw material, aqueous medium, sodium dodecyl sulfate and povidone k 30.
Further, the premix consists of the following components in parts by weight:
ezetimibe 8-10 parts
1-3 parts of sodium dodecyl sulfate
3-6 parts of povidone k30
A proper amount of aqueous medium; the aqueous medium refers to water sufficient for mixing and milling ezetimibe.
The second purpose of the invention is to provide a mixture which can be used as a semi-finished product raw material of the ezetimibe solid preparation with high dissolution rate after being treated by a special process.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
and (3) the sanding mixture prepared by the premix is prepared by arranging the ezetimibe with the formula amount in an aqueous medium, treating the ezetimibe with a nano sanding process to obtain ezetimibe suspension, adding the sodium dodecyl sulfate with the formula amount and povidone k30 into the suspension, and fully mixing the mixture to obtain the sanding mixture.
The sanding mixture is characterized in that the nano sanding process comprises the following steps: sanding with a nanometer sand mill with the frequency set at 8-27Hz, the rotational speed set at 600-1200rpm, the pressure set at 0.15-0.37mpa, and the sanding times at 7-20 times.
Further, the sanding mixture, the nano sanding process is specifically: sanding was performed with a nano-sander at a sanding frequency of 15Hz, a rotational speed of 1000rpm, a pressure of 0.28mpa, and a sanding frequency of 12 times.
The third object of the present invention is to provide a solid preparation. The solid preparation has better dissolution rate. In order to achieve the above purpose, the technical scheme of the invention is as follows:
solid formulations prepared with the sanding mixtures.
Further, in the solid preparation, the sand grinding mixture is mixed with auxiliary materials, and the solid preparation is prepared by a conventional preparation method.
Further, the auxiliary materials in the solid preparation comprise one or more of lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
The fourth object of the present invention is to provide a cereal-based food having a high dissolution rate. In order to achieve the above purpose, the technical scheme of the invention is as follows:
the high-dissolution ezetimibe prepared from the frosted mixture specifically comprises the following components in parts by weight: 8-10 parts of ezetimibe; 45-60 parts of lactose monohydrate; 1-3 parts of sodium dodecyl sulfate; 3-6 parts of povidone k; 6-10 parts of crosslinked sodium carboxymethylcellulose; 18-22 parts of microcrystalline cellulose; 0.5-1.5 parts of magnesium stearate;
and preparing the ezetimibe, sodium dodecyl sulfate, povidone k30 and a proper amount of water medium into a frosted mixture, fully mixing the lactose monohydrate, the croscarmellose sodium, the microcrystalline cellulose and the magnesium stearate in the frosted mixture, granulating and tabletting to obtain the ezetimibe with high dissolution.
Further, the high-dissolution ezetimibe comprises the following components in parts by weight: 10 parts of ezetimibe; 55 parts of lactose monohydrate; 2 parts of sodium dodecyl sulfate; povidone k30 parts; 8 parts of croscarmellose sodium; 20 parts of microcrystalline cellulose; 1 part of magnesium stearate.
According to the invention, ezetimibe bulk drug and water are prepared into suspension, a nano sand mill is used for sanding the suspension, sodium dodecyl sulfate and povidone K30 are added into the suspension after sanding to increase the hydrophilicity of ezetimibe, and the suspension is granulated to prepare granules by one-step granulation and then tabletting is carried out. The oral solid preparation is a tablet, and the preparation method comprises the following steps: preparing ezetimibe and water into suspension, and then performing sanding in a nano sand mill, wherein the frequency is set to 8-27Hz, the rotating speed is set to 600-1200rpm, the pressure is set to 0.15-0.37mpa, the sanding times are 7-20, and the ezetimibe-water suspension is obtained after the sanding is finished. And adding povidone K30 and sodium dodecyl sulfate into the suspension obtained by the process, and uniformly mixing. And mixing the auxiliary materials and adding the mixture into a fluidized bed. Spraying the obtained suspension into a fluidized bed for granulating and drying to obtain dry granules, mixing with the external auxiliary materials, and tabletting for shaping. Wherein the sanding frequency is preferably 15Hz, the rotating speed is preferably 1000rpm, the pressure is preferably 0.28mpa, and the sanding frequency is preferably 12 times. The auxiliary materials used in the preparation method are one or more of lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
Detailed Description
Hereinafter, preferred embodiments of the present invention will be described in detail. Experimental methods without specific conditions noted in the preferred embodiments, the present invention is better illustrated by the examples according to the conventional conditions, but the present invention is not limited to the examples. Those skilled in the art will appreciate that various modifications and adaptations of the embodiments described above are possible in light of the above teachings and are intended to be within the scope of the invention.
First part preparation
Example 1
1. Formulation recipe:
| sequence number | Composition of the components | mg/tablet |
| 1 | Ezetimibe | 10.0 |
| 2 | Lactose monohydrate | 55.0 |
| 3 | Sodium dodecyl sulfate | 2.00 |
| 4 | Povidone K30 | 4.00 |
| 5 | Croscarmellose sodium | 8.00 |
| 6 | Microcrystalline cellulose | 20.0 |
| 7 | Magnesium stearate | 1.00 |
| Totals to | 100 |
2. Preparation process
And adding ezetimibe into purified water, and uniformly mixing to obtain ezetimibe-water suspension.
The suspension is added into a nano sand mill for sand milling, the sand milling frequency is 15Hz, the rotating speed is 1000rpm, the pressure is 0.28mpa, and the sand milling times are 12 times. A suspension after sanding was obtained.
Lactose monohydrate is mixed with 1/3 amount of cross-linked sodium carboxymethyl cellulose in a fluidized bed, sodium dodecyl sulfate and povidone K30 are added into the suspension to be uniformly mixed, the mixed suspension is sprayed into the fluidized bed to be granulated and dried to obtain dry granules, the dry granules are mixed with 2/3 amount of cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate, and the mixture is pressed into proper size and weight on a proper tablet press.
Example 2
1. Formulation recipe:
| sequence number | Composition of the components | mg/tablet |
| 1 | Ezetimibe | 10.0 |
| 2 | Lactose monohydrate | 40.0 |
| 3 | Sodium dodecyl sulfate | 1.80 |
| 4 | Povidone K30 | 4.20 |
| 5 | Croscarmellose sodium | 8.00 |
| 6 | Microcrystalline cellulose | 35.0 |
| 7 | Magnesium stearate | 1.00 |
| Totals to | 100 |
2. The preparation process comprises the following steps: the same as in example 1.
Example 3
1. Formulation recipe: the same as in example 1.
2. Preparation process
And adding ezetimibe into purified water, and uniformly mixing to obtain ezetimibe-water suspension.
The suspension was added to a nano-sander for sanding at a frequency of 27Hz, a rotational speed of 1200rpm, a pressure of 0.37mpa, and a sanding time of 20 times. A suspension after sanding was obtained.
Lactose monohydrate is mixed with 1/3 amount of cross-linked sodium carboxymethyl cellulose in a fluidized bed, sodium dodecyl sulfate and povidone K30 are added into the suspension to be uniformly mixed, the mixed suspension is sprayed into the fluidized bed to be granulated and dried to obtain dry granules, the dry granules are mixed with 2/3 amount of cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate, and the mixture is pressed into proper size and weight on a proper tablet press.
Example 4
1. Formulation recipe: the same as in example 1.
2. Preparation process
And adding ezetimibe into purified water, and uniformly mixing to obtain ezetimibe-water suspension.
The suspension was added to a nano-sander for sanding at a frequency of 8Hz, a rotational speed of 600rpm, a pressure of 0.15mpa, and a sanding time of 7 times. A suspension after sanding was obtained.
Lactose monohydrate is mixed with 1/3 of sodium carboxymethyl cellulose in a fluidized bed, sodium dodecyl sulfate and povidone K30 are added into the suspension to be uniformly mixed, the mixed suspension is sprayed into the fluidized bed to be granulated and dried to obtain dry granules, the dry granules are mixed with 2/3 of sodium carboxymethyl cellulose, microcrystalline cellulose and magnesium stearate, and the mixture is pressed into proper size and weight on a proper tablet press.
Comparative example A
1. Formulation recipe: the same as in example 1.
2. Preparation process
And adding ezetimibe into purified water, and uniformly mixing to obtain ezetimibe-water suspension.
The suspension is added into a nano sand mill for sand milling, the sand milling frequency is 15Hz, the rotating speed is 1000rpm, the pressure is 0.28mpa, and the sand milling times are 12 times. A suspension after sanding was obtained. And standing the suspension, collecting a lower precipitate, and drying to obtain the ezetimibe bulk drug.
The ezetimibe crude drug obtained by the method is mixed with lactose monohydrate and 1/3 of croscarmellose sodium in a fluidized bed, and povidone K30, sodium dodecyl sulfate and purified water are prepared into an adhesive. The binder is sprayed into a fluid bed to granulate and dry to obtain dry granules, which are then mixed with 2/3 of the amount of croscarmellose sodium, microcrystalline cellulose, magnesium stearate, and the mixture is compressed to the appropriate size and weight on a suitable tablet press.
Comparative example B
1. Formulation recipe: the same as in example 1.
2. Preparation process
Ezetimibe is pretreated by common jet milling.
Lactose monohydrate and 1/3 of croscarmellose sodium are mixed in a fluidized bed, and the ezetimibe raw material after treatment and purified water are prepared into an adhesive. The binder is sprayed into a fluid bed to granulate and dry to obtain dry granules, which are then mixed with 2/3 of the amount of croscarmellose sodium, microcrystalline cellulose, magnesium stearate, and the mixture is compressed to the appropriate size and weight on a suitable tablet press.
Comparative example C
1. Formulation recipe: the same as in example 1.
2. Preparation process
Ezetimibe is pretreated by common jet milling.
The ezetimibe crude drug obtained by the method is mixed with lactose monohydrate and 1/3 of croscarmellose sodium in a fluidized bed, and povidone K30, sodium dodecyl sulfate and purified water are prepared into an adhesive. The binder is sprayed into a fluid bed to granulate and dry to obtain dry granules, which are then mixed with 2/3 of the amount of croscarmellose sodium, microcrystalline cellulose, magnesium stearate, and the mixture is compressed to the appropriate size and weight on a suitable tablet press.
Second part inspection and evaluation
Dissolution rate: taking the product, taking the product according to a dissolution rate measurement method (second method of appendix XC of 2000 edition of China), diluting the product to a scale with a sodium dodecyl sulfate-sodium acetate buffer solution (pH 4.5) (taking 1.5g of sodium dodecyl sulfate, 4.1g of anhydrous sodium acetate, adding 1000ml of water to dissolve the product, adjusting the pH to 4.5+/-0.1) with 1mol/L hydrochloric acid solution or 50% sodium hydroxide solution to 500ml as a solvent, operating at 50 revolutions per minute according to the method, taking a proper amount of solution, filtering, precisely measuring 5ml of a subsequent filtrate, placing the filtrate into a 10ml measuring flask, adding sodium dodecyl sulfate-sodium acetate buffer solution (pH 4.5), shaking the filtrate, and detecting the absorbance at a wavelength of 233nm according to a spectrophotometry (appendix IV A of 2000 edition of China); and (3) taking about 10mg of ezetimibe reference substance, precisely weighing, placing into a 500ml measuring flask, adding 5ml of methanol for dissolution, adding sodium dodecyl sulfate-sodium acetate buffer (pH 4.5) for dilution to scale, shaking uniformly, precisely measuring 5ml, placing into a 10ml measuring flask, adding sodium dodecyl sulfate-sodium acetate buffer (pH 4.5) for dilution to scale, shaking uniformly, taking as reference substance solution, measuring the absorbance by the same method, and calculating the leaching amount of each tablet. The limit is 85% of the indicated amount, which should be in compliance with the regulations.
Ezetimibe tablet dissolution (%)
By comparison of the above dissolution rates, the dissolution rates of examples 1, 2, 3, 4, in which sodium dodecyl sulfate and povidone K30 were added to the suspension after sanding as binders sprayed into the fluidized bed, were significantly higher than those of comparative example A, B, C, in which the above process was not employed. The dissolution of examples 1, 2, in which the preferred sanding parameters were used, was optimal.
Comparative example a used a sanding process, but the drug substance was added directly to the fluidized bed after sanding; comparative example B did not use the sanding process, but the drug substance, sodium dodecyl sulfate and povidone K30 were added to water and sprayed into the fluid bed for granulation, so comparative example A, B had a lower dissolution rate than examples 1-4, but was still better than comparative example C, where neither process was used.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (4)
1. A method for preparing ezetimibe tablets with high dissolution rate is characterized in that ezetimibe with a formula amount is arranged in an aqueous medium, a nano sanding process is used for processing the ezetimibe to obtain ezetimibe suspension, and sodium dodecyl sulfate and povidone k30 with the formula amount are added into the suspension and fully mixed to obtain a sanding mixture; adding the lactose monohydrate, croscarmellose sodium, microcrystalline cellulose and magnesium stearate to the sanding mixture, fully mixing, granulating and tabletting to obtain the tablet;
the tablet comprises the following components in parts by weight: 8-10 parts of ezetimibe; 45-60 parts of lactose monohydrate; 1-3 parts of sodium dodecyl sulfate; 3-6 parts of povidone k; 6-10 parts of crosslinked sodium carboxymethylcellulose; 18-22 parts of microcrystalline cellulose; 0.5-1.5 parts of magnesium stearate;
wherein, the sand grinding mixture comprises the following components in parts by weight: 8-10 parts of ezetimibe, 1-3 parts of sodium dodecyl sulfate, 3-6 parts of povidone k and an aqueous medium; the nano sand grinding process specifically comprises the following steps: sanding with a nanometer sand mill with the frequency set at 8-27Hz, the rotational speed set at 600-1200rpm, the pressure set at 0.15-0.37mpa, and the sanding times at 7-20 times.
2. The method according to claim 1, characterized in that the nano-sanding process is in particular: sanding was performed with a nano-sander at a sanding frequency of 15Hz, a rotational speed of 1000rpm, a pressure of 0.28mpa, and a sanding frequency of 12 times.
3. The method according to claim 1, wherein the tablet comprises the following components in parts by weight: 10 parts of ezetimibe; 55 parts of lactose monohydrate; 2 parts of sodium dodecyl sulfate; povidone k30 parts; 8 parts of croscarmellose sodium; 20 parts of microcrystalline cellulose; 1 part of magnesium stearate.
4. A tablet made by the method of claims 1-3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910697163.2A CN112294768B (en) | 2019-07-30 | 2019-07-30 | Ezetimibe tablet and method for improving dissolution rate thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910697163.2A CN112294768B (en) | 2019-07-30 | 2019-07-30 | Ezetimibe tablet and method for improving dissolution rate thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112294768A CN112294768A (en) | 2021-02-02 |
| CN112294768B true CN112294768B (en) | 2024-02-09 |
Family
ID=74486141
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910697163.2A Active CN112294768B (en) | 2019-07-30 | 2019-07-30 | Ezetimibe tablet and method for improving dissolution rate thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112294768B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115252565B (en) * | 2022-05-30 | 2023-09-19 | 国药集团致君（深圳）制药有限公司 | Ezetimibe tablet and preparation process and dissolution evaluation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103655453A (en) * | 2013-12-27 | 2014-03-26 | 华润赛科药业有限责任公司 | Preparation method of ezetimibe medicine composition |
| CN105832723A (en) * | 2016-04-15 | 2016-08-10 | 浙江巨泰药业有限公司 | Ezetimibe and atorvastatin calcium tablet and preparation method thereof |
| CN107397732A (en) * | 2017-09-25 | 2017-11-28 | 重庆华邦制药有限公司 | The method for improving Ezetimibe piece dissolution rate |
| CN109718215A (en) * | 2017-10-30 | 2019-05-07 | 海南皇隆制药股份有限公司 | A kind of Ezetimibe piece |
-
2019
- 2019-07-30 CN CN201910697163.2A patent/CN112294768B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103655453A (en) * | 2013-12-27 | 2014-03-26 | 华润赛科药业有限责任公司 | Preparation method of ezetimibe medicine composition |
| CN105832723A (en) * | 2016-04-15 | 2016-08-10 | 浙江巨泰药业有限公司 | Ezetimibe and atorvastatin calcium tablet and preparation method thereof |
| CN107397732A (en) * | 2017-09-25 | 2017-11-28 | 重庆华邦制药有限公司 | The method for improving Ezetimibe piece dissolution rate |
| CN109718215A (en) * | 2017-10-30 | 2019-05-07 | 海南皇隆制药股份有限公司 | A kind of Ezetimibe piece |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112294768A (en) | 2021-02-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3563036B2 (en) | Celecoxib composition | |
| EP2258394B1 (en) | Oral dosage form comprising a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient | |
| US10575537B2 (en) | Saury Maillard peptide and its preparation method and application | |
| KR20070085754A (en) | Stabilized ramipril compositions and methods of making | |
| KR20060019639A (en) | Valdecoxib compositions | |
| CN1440283A (en) | Combination of organic compounds | |
| WO2003082279A1 (en) | Solid preparation containing single crystal form | |
| CA2448456A1 (en) | Solid pharmaceutical formulations comprising modafinil | |
| US6911472B2 (en) | Pharmaceutical composition comprising a hmg-coa reductase inhibitor | |
| CN112294768B (en) | Ezetimibe tablet and method for improving dissolution rate thereof | |
| CN104013617A (en) | Composition containing ezetimibe and atorvastatin calcium and preparation method of composition | |
| CN117122570B (en) | Metamartan potassium tablet for improving stability and preparation method thereof | |
| KR100683876B1 (en) | Pharmaceutical agent comprising a benzamide derivative as active ingredient | |
| CA2498506A1 (en) | Novel pharmaceutical formulations of modafinil | |
| CN113230226A (en) | Tinidazole tablet and preparation method thereof | |
| CN106420646A (en) | Preparation method of ezetimibe tablets | |
| CN114340655A (en) | Method for producing tablets comprising GLP-1 peptides | |
| EP2361623A1 (en) | Composition comprising a polyphenol salt and corresponding use | |
| CN105213342A (en) | Ezetimibe sheet | |
| CN1757393A (en) | Fosfocina calcium disperser, and its prepn. method | |
| CN114432424B (en) | Stable aluminum-plastic package desmopressin tablet | |
| JP5713990B2 (en) | Pharmaceutical composition for the treatment of type 2 diabetes | |
| KR100788454B1 (en) | Rapid-acting fomulation containing nateglinide as an active ingredient | |
| CN103127131A (en) | Solid composition with valsartan and preparation method thereof | |
| CN117982495B (en) | Everolimus solid dispersion, preparation method thereof and everolimus tablet |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |