CN114588123B - High-stability cetirizine hydrochloride tablet and preparation method thereof - Google Patents
High-stability cetirizine hydrochloride tablet and preparation method thereof Download PDFInfo
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- CN114588123B CN114588123B CN202210385008.9A CN202210385008A CN114588123B CN 114588123 B CN114588123 B CN 114588123B CN 202210385008 A CN202210385008 A CN 202210385008A CN 114588123 B CN114588123 B CN 114588123B
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- cetirizine hydrochloride
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- 229960004342 cetirizine hydrochloride Drugs 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 title claims abstract 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 33
- 239000007962 solid dispersion Substances 0.000 claims abstract description 31
- 238000002156 mixing Methods 0.000 claims abstract description 29
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 18
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 18
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 18
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 18
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 18
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 18
- 229960004853 betadex Drugs 0.000 claims abstract description 18
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 18
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 18
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000009474 hot melt extrusion Methods 0.000 claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 6
- 239000011812 mixed powder Substances 0.000 claims description 48
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- 239000002245 particle Substances 0.000 claims description 18
- 235000006708 antioxidants Nutrition 0.000 claims description 17
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 15
- 239000000945 filler Substances 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000853 adhesive Substances 0.000 claims description 10
- 230000001070 adhesive effect Effects 0.000 claims description 10
- 239000012943 hotmelt Substances 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229940083542 sodium Drugs 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
- 229940009662 edetate Drugs 0.000 claims description 2
- 229960001484 edetic acid Drugs 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- 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 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 235000010384 tocopherol Nutrition 0.000 claims description 2
- 229960001295 tocopherol Drugs 0.000 claims description 2
- 229930003799 tocopherol Natural products 0.000 claims description 2
- 239000011732 tocopherol Substances 0.000 claims description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 2
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 9
- 235000019640 taste Nutrition 0.000 abstract description 6
- 238000005886 esterification reaction Methods 0.000 abstract description 5
- 230000007774 longterm Effects 0.000 abstract description 4
- 230000000873 masking effect Effects 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- PGLIUCLTXOYQMV-UHFFFAOYSA-N Cetirizine hydrochloride Chemical compound Cl.Cl.C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PGLIUCLTXOYQMV-UHFFFAOYSA-N 0.000 description 68
- 239000003826 tablet Substances 0.000 description 36
- 239000008119 colloidal silica Substances 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 6
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 6
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 6
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 6
- 239000007916 tablet composition Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 235000019658 bitter taste Nutrition 0.000 description 3
- 150000005846 sugar alcohols Polymers 0.000 description 3
- 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
- 239000004480 active ingredient Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000009477 glass transition Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 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 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 description 1
- 206010039094 Rhinitis perennial Diseases 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 206010046751 Urticaria physical Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- -1 amine salts Chemical class 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 208000030949 chronic idiopathic urticaria Diseases 0.000 description 1
- 206010072757 chronic spontaneous urticaria Diseases 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical class C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000022719 perennial allergic rhinitis Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 201000002881 physical urticaria Diseases 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 208000017022 seasonal allergic rhinitis Diseases 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
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/2022—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical preparations, and discloses a long-acting cetirizine hydrochloride tablet with improved stability and a preparation method thereof. The tablet is prepared by uniformly mixing cetirizine hydrochloride, beta-cyclodextrin, polyvinylpyrrolidone, an alkaline agent and an antioxidant, preparing a solid dispersion by a hot melt extrusion process, mixing with other pharmaceutically acceptable auxiliary materials, and directly tabletting. The hydroxyl groups in the polyvinylpyrrolidone and the beta-cyclodextrin in the tablet can be combined with the medicine in a hydrogen bond mode to prevent the cetirizine hydrochloride from undergoing esterification reaction, so that the stability of the medicine is improved, the bioavailability of the medicine is improved, the taste masking effect is achieved, and the developed tablet can maintain long-term medicine effect.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a long-acting cetirizine hydrochloride tablet with improved stability and a preparation method thereof.
Background
Cetirizine hydrochloride is a metabolite of hydroxyzine, is a selective histamine H1 receptor antagonist, is used as a novel antihistamine, is mainly used for relieving allergic symptoms of allergic diseases, and is clinically used for treating symptoms of perennial or seasonal allergic rhinitis, chronic idiopathic urticaria, physical urticaria, allergic asthma and atopic dermatitis. Proved by researches, the cetirizine hydrochloride has the advantages of rapid oral absorption, high receptor selectivity, strong clinical curative effect, small side effect, good safety and the like.
Cetirizine hydrochloride is white crystalline powder, has slight bitter taste, has no other peculiar smell, is easy to dissolve in water and ethanol, is insoluble in diethyl ether, has chemical name of (+/-) -2- [2- [4- [ (4-chlorophenyl) benzyl ] -1-piperazinyl ] ethoxy ] acetic acid dihydrochloride, is a racemization compound, and has the structural formula:
because cetirizine hydrochloride raw material is bitter in taste, belongs to water-soluble acidic compounds, and is extremely easy to degrade by esterification reaction with polyalcohol, the medicine preparation is prepared by considering how to coexist with polyalcohol so as to keep the original shape of the medicine and play a role of masking taste. The cetirizine hydrochloride preparation which is marketed at present has various types, including common tablets, dry suspension, dispersible tablets, chewable tablets, granules, capsules, compressed orally disintegrating tablets and the like, and mainly takes tablets. Wherein the tablet is compression molded, and has the problems of slower disintegration, lower bioavailability, bitter taste and easy degradation.
CN104887635B discloses a cetirizine hydrochloride tablet and a preparation process thereof, the technology prepares cetirizine hydrochloride into liposome, and then prepares a tablet containing the liposome, although the technology improves the stability of cetirizine hydrochloride, spray drying is needed, and the preparation process is complex.
CN1768752a discloses a double-layer slow release preparation made of cetirizine and pseudoephedrine hydrochloride, which consists of a pseudoephedrine hydrochloride slow release layer and a cetirizine hydrochloride quick release layer, wherein the pseudoephedrine hydrochloride slow release layer comprises 120g of pseudoephedrine hydrochloride; HPMC60RT1000020g; HPMC60RT100000180g; 60g of microcrystalline cellulose; 10% polyvinylpyrrolidone absolute ethanol solution with proper amount; 2g of magnesium stearate; prescription of cetirizine hydrochloride quick release layer, cetirizine hydrochloride 5g; 80g of microcrystalline cellulose; 80g of lactose; 20g of sodium carboxymethyl starch; a proper amount of polyvinylpyrrolidone absolute ethyl alcohol solution; magnesium stearate 1g. The quick-release part containing the cetirizine hydrochloride and the slow-release part containing the pseudoephedrine hydrochloride are combined together, so that the medicine substitution characteristic of the pseudoephedrine hydrochloride which is required to be administrated for 4 times a day is improved while the quick-acting and long half-life period of the cetirizine hydrochloride are maintained, and the double-layer slow-release preparation is prepared for 2 times a day, so that the two preparations achieve the best synergistic curative effect. However, the formulation does not take into account the instability problem of cetirizine hydrochloride.
By searching the literature, the existing cetirizine hydrochloride preparation is mainly concentrated on quick release of medicines, the problem of long-term maintenance of the medicine effect is not considered, and besides, the existing cetirizine hydrochloride quick release medicine layer is directly exposed on the outermost layer, so that the existing cetirizine hydrochloride preparation is bitter in taste and easy to cause medicine degradation.
Disclosure of Invention
In view of the defects existing in the prior art, the invention aims to provide a long-acting cetirizine hydrochloride tablet with improved stability and a preparation method thereof, so as to solve the problems of bitter taste, easy degradation and incapability of long-time drug release of the existing preparation.
In order to achieve the technical purpose, the inventor adopts a solid dispersion method in the process development of a tablet prescription, the solid dispersion is prepared by uniformly mixing cetirizine hydrochloride, beta-cyclodextrin, polyvinylpyrrolidone, an alkaline agent and an antioxidant and then carrying out hot melt extrusion, then the solid dispersion is directly tabletted after being mixed with polyethylene oxide, a filling agent, a disintegrating agent, a glidant and the like, hydroxyl groups in water-soluble matrix polyvinylpyrrolidone and beta-cyclodextrin in the tablet are combined with the medicine in a hydrogen bond form to prevent the esterification reaction of the cetirizine hydrochloride, so that the stability of the cetirizine hydrochloride is improved, the bioavailability of the medicine is improved, the taste masking effect is achieved, and the developed tablet has a slow release effect and can maintain a long-term medicine effect.
Specifically, the invention aims at adopting the following technical scheme: a cetirizine hydrochloride tablet with high stability is prepared by uniformly mixing cetirizine hydrochloride, beta-cyclodextrin, polyvinylpyrrolidone, an alkaline agent and an antioxidant, preparing a solid dispersion by a hot melt extrusion process, mixing with other pharmaceutically acceptable auxiliary materials, and directly tabletting; the other pharmaceutically acceptable auxiliary materials comprise polyethylene oxide, a filling agent, a disintegrating agent and a glidant.
Rather, the polyvinylpyrrolidone K30 employed in the present invention is a water-soluble controlled release matrix with a moderate glass transition temperature (Tg) of 168 ℃) which allows cetirizine hydrochloride to exist in a stable amorphous form in solid dispersion without the risk of reversion of the amorphous form. The polyethylene oxide used in the present invention has a number average molecular weight of 10 to 500 tens of thousands, a particle diameter of 150 to 800 μm and a bulk density of about 1.10 to 1.45g/ml.
Further preferably, the high-stability cetirizine hydrochloride tablet as described above, wherein the solid dispersion consists of 10 parts of cetirizine hydrochloride, 2-4 parts of beta-cyclodextrin, 25-35 parts of polyvinylpyrrolidone, 3-6 parts of alkaline agent and 0.03-0.10 part of antioxidant; still further preferably, the solid dispersion therein is composed of 10 parts of cetirizine hydrochloride, 3-4 parts of beta-cyclodextrin, 29-32 parts of polyvinylpyrrolidone, 4-5 parts of alkaline agent and 0.03-0.07 part of antioxidant.
Further preferably, the high stability cetirizine hydrochloride tablet as described above, wherein the mass ratio of the solid dispersion to polyethylene oxide is 1: (0.35-0.50).
Further preferred is a highly stable cetirizine hydrochloride tablet as described above wherein the alkaline agent is meant to balance the tertiary amino groups of cetirizine hydrochloride such that it is susceptible to oxidation or other forms of degradation that can be inhibited by protonated amine salts, which inhibits the esterification reaction while maintaining the protonation of the tertiary amine groups, leaving their stability unaffected; the proper alkaline agent is selected from sodium bicarbonate or/and sodium citrate, and the antioxidant is selected from one or more than two of tocopherol, ascorbic acid, sodium metabisulfite, butyl hydroxy toluene, butyl hydroxy anisole, edetic acid and edetate.
Further preferably, the high stability cetirizine hydrochloride tablet as described above, wherein the filler is selected from one or more of lactose monohydrate, microcrystalline cellulose, cellulose lactose and corn starch, accounting for 17-36% of the weight of the cetirizine hydrochloride tablet; the disintegrating agent is selected from sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose, and accounts for 10-18% of the weight of the cetirizine hydrochloride tablet; the glidant is selected from one or more of colloidal silicon dioxide, talcum powder and magnesium stearate; the best results are obtained with colloidal silica having a bulk density of 0.03-0.05g/ml.
Further preferably, the cetirizine hydrochloride tablet with high stability as described above, wherein the pharmaceutically acceptable other excipients further comprise a binder and a lubricant, wherein the binder is hydroxypropyl methylcellulose, the hydroxypropyl methylcellulose has a number average molecular weight of 40 to 120 ten thousand and a viscosity of 7500 to 14000cp (measured in a 2% w/V solution at 20 ℃), and the lubricant is one or more selected from magnesium stearate, sodium stearyl fumarate and talc.
In addition, the invention also provides a preparation method of the cetirizine hydrochloride tablet with high stability, which comprises the following steps:
1) Adding the cetirizine hydrochloride, beta-cyclodextrin, polyvinylpyrrolidone, alkaline agent and antioxidant with the prescription amount into a low-shear V-shaped mixer for mixing to obtain mixed powder;
2) Preparing solid dispersion particles from the mixed powder obtained in the step 1) through hot melt extrusion;
3) Adding a prescribed amount of filler, a disintegrating agent, an adhesive, polyethylene oxide and a glidant into the solid dispersion particles obtained in the step 2), and mixing in a low-shear V-shaped mixer to obtain mixed powder;
4) Adding the prescribed amount of lubricant into the mixed powder obtained in the step 3), and mixing in a low-shear V-shaped mixer to obtain total mixed powder;
5) And (3) directly tabletting and coating the total mixed powder obtained in the step (4).
Further preferably, the preparation method of the cetirizine hydrochloride tablet with high stability as described above comprises the following process parameters in the hot-melt extrusion in the step 2): the hot melting temperature is 115-130 ℃, the screw rotating speed is 80-100 rpm, and the extrudate is crushed after being cooled.
Compared with the prior art, the cetirizine hydrochloride tablet and the preparation method thereof provided by the invention have the following advantages and remarkable progress:
(1) The hydroxyl and active ingredients in the water-soluble matrix are combined in a hydrogen bond form to prevent the esterification reaction of cetirizine hydrochloride, so that the stability of the cetirizine hydrochloride is improved, and the bioavailability of the medicine is improved.
(2) The alkaline agent is added in the hot-melt extrusion process, so that cetirizine hydrochloride and polyalcohol auxiliary materials can coexist and play a role in taste masking;
(3) The tablet developed by the invention has a slow release effect and can maintain a long-term drug effect.
Drawings
FIG. 1 is a graph showing the dissolution of cetirizine hydrochloride tablets prepared according to the present invention in 0.01mol/L hydrochloric acid.
Detailed Description
The technical scheme and technical effects of the present invention are further described in detail below through specific preparation examples and test examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. In addition, the specific technical operation steps or conditions are not noted in the examples, and are carried out according to the techniques or conditions described in the literature in the field or according to the product specifications. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The polyvinylpyrrolidone K30 employed in the examples of the present invention is a water-soluble controlled release matrix with a moderate glass transition temperature (Tg) of 168 ℃) which can enable cetirizine hydrochloride to exist in a solid dispersion in a stable amorphous form without the risk of reversion of the amorphous form. The polyethylene oxide used in the present invention has a number average molecular weight of 10 to 500 tens of thousands, a particle diameter of 150 to 800 μm and a bulk density of about 1.10 to 1.45g/ml. The colloidal silica employed in the present invention has a bulk density of 0.03 to 0.05g/ml. The hydroxypropyl methylcellulose used in the present invention has a number average molecular weight of 40 to 120 tens of thousands and a viscosity of 7500-14000cp (measured in a 2% w/V solution at 20 ℃).
Example 1: preparation of cetirizine hydrochloride tablets
1) Adding the cetirizine hydrochloride, the alkaline agent, the antioxidant, the beta-cyclodextrin and the polyvinylpyrrolidone with the prescription amount into a low-shear V-shaped mixer for mixing for 30min to obtain mixed powder;
2) Adding the mixed powder obtained in the step 1) into a hot-melt extruder preheated to 120 ℃, setting the rotating speed of a screw to 100 revolutions per minute, cooling the extrudate, and crushing to obtain solid dispersion particles;
3) Adding a prescribed amount of filler, a disintegrating agent, an adhesive, polyethylene oxide and colloidal silica into the solid dispersion particles obtained in the step 2), mixing in a low-shear V-shaped mixer for 15min to obtain mixed powder;
4) Adding the magnesium stearate with the prescription amount into the mixed powder obtained in the step 3), mixing in a low-shear V-shaped mixer for 5min to obtain total mixed powder;
5) And (3) directly tabletting the total mixed powder obtained in the step (4). The prescription composition is shown in Table 1.
Table 1: cetirizine hydrochloride tablet formulation of example 1
Example 2: preparation of cetirizine hydrochloride tablets
1) Adding the cetirizine hydrochloride, the alkaline agent, the antioxidant, the beta-cyclodextrin and the polyvinylpyrrolidone with the prescription amount into a low-shear V-shaped mixer for mixing for 30min to obtain mixed powder;
2) Adding the mixed powder obtained in the step 1) into a hot-melt extruder preheated to 120 ℃, setting the rotating speed of a screw to 100 revolutions per minute, cooling the extrudate, and crushing to obtain solid dispersion particles;
3) Adding a prescribed amount of filler, a disintegrating agent, an adhesive, polyethylene oxide and colloidal silica into the solid dispersion particles obtained in the step 2), mixing in a low-shear V-shaped mixer for 15min to obtain mixed powder;
4) Adding the magnesium stearate with the prescription amount into the mixed powder obtained in the step 3), mixing in a low-shear V-shaped mixer for 5min to obtain total mixed powder;
5) And (3) directly tabletting the total mixed powder obtained in the step (4). The prescription composition is shown in Table 2.
Table 2: cetirizine hydrochloride tablet formulation of example 2
Example 3: preparation of cetirizine hydrochloride tablets
1) Adding the cetirizine hydrochloride, the alkaline agent, the antioxidant, the beta-cyclodextrin and the polyvinylpyrrolidone with the prescription amount into a low-shear V-shaped mixer for mixing for 30min to obtain mixed powder;
2) Adding the mixed powder obtained in the step 1) into a hot-melt extruder preheated to 120 ℃, setting the rotating speed of a screw to 100 revolutions per minute, cooling the extrudate, and crushing to obtain solid dispersion particles;
3) Adding a prescribed amount of filler, a disintegrating agent, an adhesive, polyethylene oxide and colloidal silica into the solid dispersion particles obtained in the step 2), mixing in a low-shear V-shaped mixer for 15min to obtain mixed powder;
4) Adding the magnesium stearate with the prescription amount into the mixed powder obtained in the step 3), mixing in a low-shear V-shaped mixer for 5min to obtain total mixed powder;
5) And (3) directly tabletting the total mixed powder obtained in the step (4). The prescription composition is shown in Table 3.
Table 3: cetirizine hydrochloride tablet formulation of example 3
Example 4: preparation of cetirizine hydrochloride tablets
1) Adding the cetirizine hydrochloride, the alkaline agent, the antioxidant, the beta-cyclodextrin and the polyvinylpyrrolidone with the prescription amount into a low-shear V-shaped mixer for mixing for 30min to obtain mixed powder;
2) Adding the mixed powder obtained in the step 1) into a hot-melt extruder preheated to 120 ℃, setting the rotating speed of a screw to 100 revolutions per minute, cooling the extrudate, and crushing to obtain solid dispersion particles;
3) Adding a prescribed amount of filler, a disintegrating agent, an adhesive, polyethylene oxide and colloidal silica into the solid dispersion particles obtained in the step 2), mixing in a low-shear V-shaped mixer for 15min to obtain mixed powder;
4) Adding the magnesium stearate with the prescription amount into the mixed powder obtained in the step 3), mixing in a low-shear V-shaped mixer for 5min to obtain total mixed powder;
5) And (3) directly tabletting the total mixed powder obtained in the step (4). The prescription composition is shown in Table 4.
Table 4: cetirizine hydrochloride tablet formulation of example 4
Example 5: preparation of cetirizine hydrochloride tablets
1) Adding the cetirizine hydrochloride, the alkaline agent, the antioxidant, the beta-cyclodextrin and the polyvinylpyrrolidone with the prescription amount into a low-shear V-shaped mixer for mixing for 30min to obtain mixed powder;
2) Adding the mixed powder obtained in the step 1) into a hot-melt extruder preheated to 120 ℃, setting the rotating speed of a screw to 100 revolutions per minute, cooling the extrudate, and crushing to obtain solid dispersion particles;
3) Adding a prescribed amount of filler, a disintegrating agent, an adhesive, polyethylene oxide and colloidal silica into the solid dispersion particles obtained in the step 2), mixing in a low-shear V-shaped mixer for 15min to obtain mixed powder;
4) Adding the magnesium stearate with the prescription amount into the mixed powder obtained in the step 3), mixing in a low-shear V-shaped mixer for 5min to obtain total mixed powder;
5) And (3) directly tabletting the total mixed powder obtained in the step (4). The recipe composition is shown in Table 5.
Table 5: cetirizine hydrochloride tablet formulation of example 5
Example 6: preparation of cetirizine hydrochloride tablet (beta-cyclodextrin is not added in the prescription)
1) Adding the cetirizine hydrochloride, the alkaline agent, the antioxidant and the polyvinylpyrrolidone with the prescription amount into a low-shear V-shaped mixer for mixing for 30min to obtain mixed powder;
2) Adding the mixed powder obtained in the step 1) into a hot-melt extruder preheated to 120 ℃, setting the rotating speed of a screw to 100 revolutions per minute, cooling the extrudate, and crushing to obtain solid dispersion particles;
3) Adding a prescribed amount of filler, a disintegrating agent, an adhesive, polyethylene oxide and colloidal silica into the solid dispersion particles obtained in the step 2), mixing in a low-shear V-shaped mixer for 15min to obtain mixed powder;
4) Adding the magnesium stearate with the prescription amount into the mixed powder obtained in the step 3), mixing in a low-shear V-shaped mixer for 5min to obtain total mixed powder;
5) And (3) directly tabletting the total mixed powder obtained in the step (4). The recipe composition is shown in Table 6.
Table 6: cetirizine hydrochloride tablet formulation of example 6
Example 7: cetirizine hydrochloride tablet dissolution rate determination and stability test research
1. Cetirizine hydrochloride tablet dissolution assay:
taking the product, taking a dissolution rate and release rate measuring method (second method of the fourth edition of the 2015 edition of Chinese pharmacopoeia) and taking 0.01mol/L hydrochloric acid as a dissolution medium, wherein the rotation speed is 50 revolutions per minute, and the method is operated according to the method, and measuring the dissolution rate of the medicine by a high-performance liquid phase method respectively for 1, 3 and 10 hours, wherein the dissolution rate of each tablet of the product respectively reaches 20-40%, 45-65% and more than 85% of the marked amount, and the dissolution rate of each tablet of the product respectively accords with the regulations. See fig. 1.
2. Stability test
The prepared cetirizine hydrochloride tablet is put under an acceleration condition (40 ℃/75% RH) for stability investigation. Samples were taken at months 0, 1, 3 and 6 to examine the content of the active ingredient, and the results are shown in Table 7.
Table 7: stability investigation result of cetirizine hydrochloride tablet
| Examples | Month 0 | Month 1 | Month 3 | Month 6 |
| Example 1 | 99.6 | 99.7 | 99.4 | 99.3 |
| Example 2 | 96.3 | 96.1 | 95.9 | 95.3 |
| Example 3 | 92.4 | 92.3 | 91.5 | 91.1 |
| Example 4 | 93.1 | 93.0 | 92.8 | 92.5 |
| Example 5 | 96.1 | 95.8 | 95.6 | 95.2 |
| Example 6 | 95.4 | 91.1 | 89.0 | 86.3 |
Claims (3)
1. The high-stability cetirizine hydrochloride tablet is characterized in that cetirizine hydrochloride, beta-cyclodextrin, polyvinylpyrrolidone K30, an alkaline agent and an antioxidant are uniformly mixed, a solid dispersion is prepared through a hot melt extrusion process, and then the solid dispersion is directly tabletted after being mixed with other pharmaceutically acceptable auxiliary materials;
the solid dispersion consists of 10 parts of cetirizine hydrochloride, 2-4 parts of beta-cyclodextrin, 30-35 parts of polyvinylpyrrolidone K, 3-6 parts of alkaline agent and 0.03-0.10 part of antioxidant; the alkaline agent is selected from sodium bicarbonate or/and sodium citrate; the antioxidant is one or more than two selected from tocopherol, ascorbic acid, sodium metabisulfite, butyl hydroxy toluene, butylated hydroxyanisole, edetic acid and edetate;
the pharmaceutically acceptable other auxiliary materials consist of polyethylene oxide, a filling agent, a disintegrating agent, a glidant, an adhesive and a lubricant; the mass ratio of the solid dispersion to the polyethylene oxide is 1: (0.35-0.50); the filler is microcrystalline cellulose and accounts for 17-36% of the weight of the cetirizine hydrochloride tablet; the disintegrating agent is selected from sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose, and accounts for 10-18% of the weight of the cetirizine hydrochloride tablet; the glidant is colloidal silicon dioxide, and the bulk density is 0.03-0.05g/ml; the adhesive is hydroxypropyl methyl cellulose; the lubricant is one or more than two of magnesium stearate, sodium stearyl fumarate and talcum powder;
the parameters of the hot melt extrusion process are that the hot melt temperature is 115-130 ℃, the screw rotating speed is 80-100 rpm, and the extrudate is crushed after being cooled.
2. The high-stability cetirizine hydrochloride tablet according to claim 1, wherein the solid dispersion consists of 10 parts of cetirizine hydrochloride, 3-4 parts of beta-cyclodextrin, 29-32 parts of polyvinylpyrrolidone K, 4-5 parts of alkaline agent and 0.03-0.07 part of antioxidant.
3. A process for the preparation of a highly stable cetirizine hydrochloride tablet according to claim 1, characterized in that it comprises the steps of:
1) Adding the cetirizine hydrochloride, beta-cyclodextrin, polyvinylpyrrolidone K30, alkaline agent and antioxidant with the prescription amount into a low-shear V-shaped mixer for mixing to obtain mixed powder;
2) Preparing solid dispersion particles from the mixed powder obtained in the step 1) through hot melt extrusion;
3) Adding a prescribed amount of filler, a disintegrating agent, an adhesive, polyethylene oxide and a glidant into the solid dispersion particles obtained in the step 2), and mixing in a low-shear V-shaped mixer to obtain mixed powder;
4) Adding the prescribed amount of lubricant into the mixed powder obtained in the step 3), and mixing in a low-shear V-shaped mixer to obtain total mixed powder;
5) And (3) directly tabletting and coating the total mixed powder obtained in the step (4).
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| EP1158962B1 (en) * | 1999-03-12 | 2002-12-04 | Basf Aktiengesellschaft | Method for producing solid dosage forms containing cyclodextrin |
| WO2011110939A2 (en) * | 2010-03-11 | 2011-09-15 | Rubicon Research Private Limited | Pharmaceutical compositions of substituted benzhydrylpiperazines |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1158962B1 (en) * | 1999-03-12 | 2002-12-04 | Basf Aktiengesellschaft | Method for producing solid dosage forms containing cyclodextrin |
| WO2011110939A2 (en) * | 2010-03-11 | 2011-09-15 | Rubicon Research Private Limited | Pharmaceutical compositions of substituted benzhydrylpiperazines |
Non-Patent Citations (2)
| Title |
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| 热熔挤出技术在药物制剂领域的应用进展;王艳宏;姜霁洺;张智慧;李雪虹;;中国实验方剂学杂志(第23期) * |
| 王艳宏 ; 姜霁洺 ; 张智慧 ; 李雪虹 ; .热熔挤出技术在药物制剂领域的应用进展.中国实验方剂学杂志.2013,(23),第327-334页. * |
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