CN114129512B - Naproxen solution preparation for oral administration and preparation method and application thereof - Google Patents
Naproxen solution preparation for oral administration and preparation method and application thereof Download PDFInfo
- Publication number
- CN114129512B CN114129512B CN202111530754.4A CN202111530754A CN114129512B CN 114129512 B CN114129512 B CN 114129512B CN 202111530754 A CN202111530754 A CN 202111530754A CN 114129512 B CN114129512 B CN 114129512B
- Authority
- CN
- China
- Prior art keywords
- naproxen
- citrate
- phosphate
- sodium
- solution preparation
- 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.)
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- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 title claims abstract description 109
- 229960002009 naproxen Drugs 0.000 title claims abstract description 109
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 title claims abstract description 109
- 238000002360 preparation method Methods 0.000 title claims abstract description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 239000008213 purified water Substances 0.000 claims abstract description 17
- 239000000686 essence Substances 0.000 claims abstract description 16
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 14
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 13
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 13
- 239000010452 phosphate Substances 0.000 claims abstract description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 9
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 9
- 239000003765 sweetening agent Substances 0.000 claims abstract description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 7
- 238000009472 formulation Methods 0.000 claims description 15
- 229940001468 citrate Drugs 0.000 claims description 10
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 8
- 229940085605 saccharin sodium Drugs 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- 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 4
- 235000011083 sodium citrates Nutrition 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 3
- 206010037660 Pyrexia Diseases 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- RQALKBLYTUKBFV-UHFFFAOYSA-N 1,4-dioxa-7-thiaspiro[4.4]nonane Chemical compound O1CCOC11CSCC1 RQALKBLYTUKBFV-UHFFFAOYSA-N 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 2
- 239000004376 Sucralose Substances 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- UZLGHNUASUZUOR-UHFFFAOYSA-L dipotassium;3-carboxy-3-hydroxypentanedioate Chemical compound [K+].[K+].OC(=O)CC(O)(C([O-])=O)CC([O-])=O UZLGHNUASUZUOR-UHFFFAOYSA-L 0.000 claims description 2
- 239000002526 disodium citrate Substances 0.000 claims description 2
- 235000019262 disodium citrate Nutrition 0.000 claims description 2
- 229940079896 disodium hydrogen citrate Drugs 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- HWPKGOGLCKPRLZ-UHFFFAOYSA-M monosodium citrate Chemical compound [Na+].OC(=O)CC(O)(C([O-])=O)CC(O)=O HWPKGOGLCKPRLZ-UHFFFAOYSA-M 0.000 claims description 2
- 239000002524 monosodium citrate Substances 0.000 claims description 2
- 235000018342 monosodium citrate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 229920003023 plastic Polymers 0.000 claims description 2
- 239000004033 plastic Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 239000001508 potassium citrate Substances 0.000 claims description 2
- 229960002635 potassium citrate Drugs 0.000 claims description 2
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 claims description 2
- 235000011082 potassium citrates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 235000019353 potassium silicate Nutrition 0.000 claims description 2
- 229940081974 saccharin Drugs 0.000 claims description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019204 saccharin Nutrition 0.000 claims description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229960001790 sodium citrate Drugs 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 229940013618 stevioside Drugs 0.000 claims description 2
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019202 steviosides Nutrition 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 150000005323 carbonate salts Chemical class 0.000 claims 1
- 229940109275 cyclamate Drugs 0.000 claims 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 claims 1
- 230000028709 inflammatory response Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 239000007788 liquid Substances 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 239000002244 precipitate Substances 0.000 abstract description 2
- 230000003381 solubilizing effect Effects 0.000 abstract 1
- 230000000087 stabilizing effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 65
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 24
- 238000004090 dissolution Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000003085 diluting agent Substances 0.000 description 14
- 239000011259 mixed solution Substances 0.000 description 14
- 235000021317 phosphate Nutrition 0.000 description 10
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 8
- 230000001954 sterilising effect Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 229960003940 naproxen sodium Drugs 0.000 description 7
- 239000011148 porous material Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 235000005976 Citrus sinensis Nutrition 0.000 description 5
- 240000002319 Citrus sinensis Species 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 4
- 229960002303 citric acid monohydrate Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- ASTWEMOBIXQPPV-UHFFFAOYSA-K trisodium;phosphate;dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]P([O-])([O-])=O ASTWEMOBIXQPPV-UHFFFAOYSA-K 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 230000009747 swallowing Effects 0.000 description 3
- 208000019505 Deglutition disease Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- NSIKFNOYIGGILA-UHFFFAOYSA-N [Na].[Na].[K] Chemical compound [Na].[Na].[K] NSIKFNOYIGGILA-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000012567 medical material Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- NHWXRQNADJPTQC-UHFFFAOYSA-N [K].[Na].[Na].[Na] Chemical compound [K].[Na].[Na].[Na] NHWXRQNADJPTQC-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical group OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 231100000206 health hazard Toxicity 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000012858 packaging process Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 150000007519 polyprotic acids Polymers 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 239000002699 waste material Substances 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61K9/08—Solutions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an orally taken naproxen solution preparation and application thereof, wherein the orally taken naproxen solution preparation comprises naproxen, carbonate, phosphate, citrate or a mixture thereof, sweetener, essence and purified water; the pH value of the naproxen solution preparation for oral administration prepared by the invention is 7.0-8.5, and the carbonate, the phosphate and the citrate have the functions of solubilizing and stabilizing, and simultaneously have the effect of inhibiting the taste of naproxen, and the addition of polyvinylpyrrolidone can further ensure that no precipitate is generated. The naproxen solution preparation for oral administration is colorless, clear and transparent liquid, has uniform naproxen content distribution and good chemical stability, has the advantages of faster medicine absorption, more accurate dosage, higher bioavailability and the like, and is more beneficial to clinical application.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an orally taken naproxen solution preparation and a preparation method and application thereof.
Background
Naproxen (Naproxen) is also known as (+) -alpha-methyl-6-methoxy-2-naphthalene acetic acid, is a non-steroidal drug widely used for treating pain, fever and inflammation, can inhibit prostaglandin synthesis to play a role of anti-inflammatory and analgesic, has a stronger effect than aspirin, is rapidly and completely absorbed, reaches the highest blood concentration in 2 hours, is suitable for rheumatoid arthritis, osteoarthritis, acute ventilation and the like, has good effect and smaller side effect, and is one of non-prescription drugs which are popular worldwide. Among naproxen oral preparation products, tablets, capsules and granules are main products widely applied clinically in the market for a long time. Besides the dosage forms, the naproxen suspension is clinically applied in European and American markets, compared with an oral solid preparation product, the oral suspension is faster to absorb, brings convenience to children, old people and dysphagia patients, and has obvious advantages that the dosage of the suspension is easy to adjust by measuring different volumes.
The naproxen suspension is in a form of solid-liquid mixed metastable state, the naproxen exists in the form of solid particles, the suspension balance is achieved by adding a plurality of necessary auxiliary agents, and the preparation process is complex. Particularly, solid particles with relatively uniform content in the original suspension can be settled at the bottom of liquid due to the actions of gravity, vibration and the like in the storage or transportation process, so that the content of the product is unevenly distributed, the accuracy of medicine taking dosage can be influenced, and the medication safety and the curative effect of a patient are finally influenced; various suspension auxiliary agents which do not generate drug effects have potential health hazard to human bodies, increase unnecessary metabolic burden of the human bodies, and are also waste of resources.
In view of this, a solution formulation of naproxen for oral administration having a simple composition was developed to solve the above-mentioned problems, and more effective and safer treatment can be provided to patients.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides an orally taken naproxen solution preparation for the first time.
In order to obtain a naproxen solution formulation for oral administration, the problem of poor solubility of naproxen in water must be solved so that the dosage of naproxen for clinical use is reached in 5ml or 10ml of oral liquid. The solubility of the derived naproxen sodium in water can meet the requirement, but the uncomfortable effect of the naproxen sodium in oral cavity stimulating taste and swallowing is another difficult problem to be solved in clinical application, and the naproxen sodium aqueous solution is more alkaline, has relatively poor stability in a medium with relatively high pH value, generates decomposition products when stored for a long time, and is unfavorable for clinical application.
The naproxen solution preparation for oral administration prepared by the invention can improve the total concentration of naproxen in the solution to 25-50 mg/mL within the pH range of less than 8.0, and meanwhile, the naproxen solution preparation for oral administration is a colorless, clear and transparent solution, the naproxen and the naproxen sodium are dissolved in the solution in a molecular state, are uniformly distributed, do not generate sedimentation and precipitation phenomena, and have good physical stability; the pH value is reduced to a near neutral range, the chemical stability is good, and the preparation method has the advantages of faster drug absorption, more accurate dosage, higher bioavailability and the like.
It is an object of the present invention to provide an orally administered naproxen solution formulation.
An orally taken naproxen solution preparation, which comprises naproxen, at least one of carbonate, phosphate and citrate, sweetener, essence and purified water, wherein the total content of the naproxen is 1.5-6.0% (W/V).
Further, the total content of naproxen is preferably 2.5% (W/V) and 5.0% (W/V).
Further, the naproxen solution preparation for oral administration further comprises polyvinylpyrrolidone, and the weight ratio of the total amount of at least one or more of the carbonate, the phosphate and the citrate to the naproxen is (0.3-3): 1, wherein the content of the sweetener is 0.05-30% (W/V), the content of the essence is 0.05-3% (W/V), and the content of the polyvinylpyrrolidone is 0-3.0% (W/V).
Further, the carbonate is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
Further, the phosphate is selected from one or more of sodium phosphate, potassium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate and potassium dihydrogen phosphate;
further, the citrate is selected from one or more of sodium citrate, potassium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate and potassium dihydrogen citrate.
Further, the sweetener is selected from one or more of saccharin sodium, saccharin, stevioside, aspartame, sucralose, sucrose, sorbitol and sodium cyclamate, the essence is selected from one or more of orange essence and orange essence, and the polyvinylpyrrolidone is selected from one or more of K17, K30 and K90.
Further, the pH value of the naproxen solution preparation for oral administration is 7.0-8.5, preferably 7.5-8.2.
In the invention, carbonate, phosphate or citrate is polybasic acid salt, mono-or disodium (potassium) salt of carbonate (sodium salt or potassium salt), tri-or disodium (potassium) salt of phosphate (sodium salt or potassium salt) or tri-sodium (potassium) salt of citrate (sodium salt or potassium salt), and the aqueous solutions of the carbonate, the phosphate or the citrate are alkaline, so that the solubility of naproxen in water can be improved; on one hand, carbonate, phosphate and citrate form a diversified composite buffer system with naproxen and naproxen sodium, so that the dissolution performance of naproxen is enhanced, and meanwhile, the pH value of the whole naproxen solution preparation oral liquid is stable, the oral liquid can be kept stable for a long time in a near neutral range, and no solid is separated out; on the other hand, the inventors found that carbonates, citrates and phosphates also have a taste-modifying effect on naproxen and naproxen sodium, which can improve the mouthfeel and inhibit the taste, and reduce or eliminate the uncomfortable feeling upon swallowing; the polyvinylpyrrolidone-medical material has solubilization, can further ensure that no solid precipitate is precipitated in the long-term storage process of the naproxen solution preparation oral liquid, and the sweetener and the essence can further improve the taste of the naproxen solution preparation oral liquid, so that the polyvinylpyrrolidone-medical material is particularly suitable for the old and the children, has good compliance, and can also be added with medicinal pigment to prepare the oral preparation more suitable for children. Through the synergistic effect of the components, the prepared naproxen solution preparation for oral administration has good chemical stability, high naproxen solubility and good taste, and is more beneficial to clinical application.
The naproxen solution preparation for oral administration, disclosed by the invention, is simple in preparation method, and can be prepared by the method described below.
The method for preparing the naproxen solution preparation for oral administration according to any one of the above claims, comprising the following steps:
s1, adding at least one of carbonate, phosphate or citrate into purified water for dissolution, then adding naproxen, adjusting the pH value of the solution to 10-12 by using sodium hydroxide or potassium hydroxide, continuing to dissolve, and then adding sweetener, essence and polyvinylpyrrolidone for dissolution to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 by using an acid-base regulator, and adding purified water to a required volume to obtain a diluent;
and S3, filtering and sterilizing the diluent obtained in the step S2, and sub-packaging to obtain the naproxen solution for oral administration.
Further, in step S2, the acid-base modifier is one or more of sodium hydroxide, potassium hydroxide and hydrochloric acid.
Further, in step S3, the pore size of the filter membrane in the filter sterilization is 0.22 μm.
Further, in step S3, the packaging container used in the packaging process is a medicinal liquid glass bottle or a plastic bottle, and the volume of the packaging container is 20-500 mL, preferably 30mL,50mL,100mL,250mL.
It is a final object of the present invention to provide the use of a naproxen solution formulation for oral administration.
Use of an orally administered naproxen solution formulation according to any one of the preceding claims for the preparation of a medicament for the treatment of pain, fever and some inflammatory reactions.
Compared with the prior art, the invention has the following advantages:
1) The naproxen solution preparation for oral administration prepared by the invention is a homogeneous transparent liquid, naproxen and naproxen sodium exist in the solution in a molecular form, the collapse and dissolution processes of solid oral agents are not needed, the dissolution processes of suspension agents are avoided, the naproxen solution preparation can be directly absorbed, the occurrence of the drug effect is faster, and the bioavailability is higher;
2) The naproxen content of the orally taken naproxen solution preparation prepared by the invention is uniformly distributed in the solution, and the medicament has more accurate administration dosage, better curative effect and higher safety;
3) The naproxen solution preparation for oral administration prepared by the invention is a solution with stable physical state, but not the metastable state of a suspension, and does not have precipitation phenomenon; the pH of the solution is close to neutral, the chemical stability is good, and the solution is easy to store for a long time; the carbonate, the phosphate and the citrate in the naproxen solution preparation for oral administration prepared by the invention have the effects of inhibiting the peculiar smell and the stimulation of naproxen, have no uncomfortable feeling during swallowing, have good mouthfeel and are beneficial to clinical application;
4) The naproxen solution preparation for oral administration prepared by the invention has the advantages of less material consumption, simple preparation process, environmental protection and easy mass production;
5) The naproxen solution preparation for oral administration prepared by the invention has no preservative, and avoids the side effects of toxicity and irritation of the preservative on human bodies;
6) The naproxen solution preparation for oral administration prepared by the invention is suitable for children, the elderly and patients with dysphagia.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below. It is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments, and that all other embodiments obtained by persons of ordinary skill in the art without making creative efforts based on the embodiments in the present invention are within the protection scope of the present invention.
Example 1
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, weighing 8.3g of sodium phosphate dodecahydrate, adding the sodium phosphate dodecahydrate into 70mL of purified water for dissolution, then adding 5.0g of naproxen for continuous dissolution, and then adding 0.3g of saccharin sodium, 0.1g of sweet orange essence and 0.5g of polyvinylpyrrolidone-K30 for dissolution to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 8.1 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 by using a pore diameter of 0.22 mu m to obtain a colorless clear orally taken naproxen solution preparation with the naproxen concentration of 5% (W/V).
Example 2
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, weighing 5.8g of sodium phosphate dodecahydrate, adding the sodium phosphate dodecahydrate into 70mL of purified water for dissolution, then adding 2.5g of naproxen for continuous dissolution, and then adding 0.1g of saccharin sodium and 10g of sucrose, and dissolving 0.1g of sweet orange essence to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 7.4 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 by using a pore diameter of 0.22 mu m to obtain a colorless clear orally taken naproxen solution preparation with the naproxen concentration of 2.5% (W/V).
Example 3
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, weighing 6.3g of citric acid monohydrate, adding the citric acid monohydrate into 70mL of purified water for dissolution, neutralizing with 1.6g of sodium hydroxide for reaction to generate sodium citrate, then adding 2.5g of naproxen, adding 1.0mol/L of sodium hydroxide to the pH value of the solution to be 10-12, and then adding 0.2g of saccharin sodium, 0.1g of orange essence and 0.5g of polyvinylpyrrolidone-K30 for dissolution to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 7.7 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 by using a pore diameter of 0.22 mu m to obtain a colorless clear orally taken naproxen solution preparation with the naproxen concentration of 2.5% (W/V).
Example 4
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, weighing 3.1g of citric acid monohydrate, adding the citric acid monohydrate into 70mL of purified water for dissolution, neutralizing with 2.2g of excessive sodium hydroxide for reaction to generate sodium citrate, adding 3g of sodium bicarbonate, then adding 2.5g of naproxen, adding 1.0mol/L of sodium hydroxide to the pH value of the solution to be 10-12, and then adding 0.2g of saccharin sodium and 0.1g of sweet orange essence for dissolution to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 7.8 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 by adopting a pore diameter of 0.22 mu m to obtain a colorless clear oral naproxen solution preparation with the naproxen concentration of 2.5% (W/V).
Example 5
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, weighing 6.5g of sodium bicarbonate, adding the sodium bicarbonate into 70mL of purified water for dissolution, adding 0.5g of sodium hydroxide for dissolution, then adding 2.5g of naproxen for continuous dissolution, adding 1.0mol/L of sodium hydroxide to the pH value of the solution to be 10-12, and then adding 0.1g of saccharin sodium and 0.3g of sweet orange essence for dissolution to obtain a mixed solution;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 8.0 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 with a pore diameter of 0.22 mu m, and subpackaging to obtain 100mL of colorless clear orally taken naproxen solution preparation with the naproxen concentration of 2.5% (W/V).
Example 6
The preparation method of the naproxen solution preparation for oral administration comprises the following steps:
s1, 2.5g of naproxen is added into 40ml of purified water, 1.0mol/L sodium hydroxide is used for dissolving the naproxen into sodium naproxen, 1.0g of sodium carbonate and 1.0g of polyvinylpyrrolidone-K30 are added, then 0.5g of saccharin sodium and 0.1g of sweet orange essence are added for dissolving, and a mixed solution is obtained;
s2, adjusting the pH value of the mixed solution obtained in the step S1 to 7.8 by using 1.0mol/L sodium hydroxide, 1.0mol/L potassium hydroxide or 1.0mol/L hydrochloric acid, and adding purified water to dilute to 100mL to obtain a diluent;
s3, filtering and sterilizing the diluent obtained in the step S2 by using a pore diameter of 0.22 mu m to obtain 100mL of colorless clear orally taken naproxen solution preparation with the naproxen concentration of 2.5% (W/V).
Example 7
The oral naproxen solution formulations prepared in examples 1-6 were subjected to stability testing at room temperature in the absence of light, and the test results are shown in table 1:
TABLE 1 physical stability test results of orally administered naproxen solution formulations
As can be seen from the results in Table 1, the orally taken naproxen solution preparations prepared in examples 1 to 6 have no phenomena of discoloration, turbidity, precipitation and the like when being stored for 12 months under the condition of being protected from light at room temperature, and have the advantages of unchanged pH value and good stability;
example 8
The total content of naproxen in the orally taken naproxen solution preparations prepared in examples 1 to 6 was tested under the condition of keeping the orally taken naproxen solution preparation in a dark place at room temperature, and the results show that the total content of naproxen in the orally taken naproxen solution preparations prepared in examples 1 to 6 is not changed at all under the condition of keeping the orally taken naproxen solution preparation in a dark place at room temperature for 12 months.
Example 9
The oral naproxen solution formulations prepared in examples 1 to 6 were subjected to taste tests, and as a result, the oral naproxen solution formulations prepared in examples 1 to 6 were found to have no irritating taste, no uncomfortable feeling when swallowed, and good taste.
The above examples are only specific embodiments of the present invention for illustrating the technical solution of the present invention, but not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the foregoing examples, it will be understood by those skilled in the art that the present invention is not limited thereto: any person skilled in the art may modify or easily conceive of the technical solution described in the foregoing embodiments, or perform equivalent substitution of some of the technical features, while remaining within the technical scope of the present disclosure; such modifications, changes or substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention, and are intended to be included in the scope of the present invention.
Claims (8)
1. An orally taken naproxen solution preparation is characterized by comprising naproxen, at least one of carbonate, phosphate and citrate, polyvinylpyrrolidone, sweetener, essence and purified water;
wherein the total content of naproxen is 1.5-6.0% (W/V); the weight ratio of the total amount of at least one or more of carbonate, phosphate and citrate to naproxen is (0.3-3): 1, a step of;
the content of the sweetener is 0.05-30% (W/V), the content of the essence is 0.05-3% (W/V), and the content of the polyvinylpyrrolidone is 0-3.0% (W/V);
the pH value of the naproxen solution preparation for oral administration is 7.5-8.2.
2. The orally administered naproxen solution formulation of claim 1, wherein the total naproxen content is 2.5% (W/V) or 5.0% (W/V).
3. The orally administered naproxen solution formulation of claim 1, wherein the carbonate salt is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
4. The orally administered naproxen solution formulation of claim 1, wherein the phosphate salt is selected from one or more of sodium phosphate, potassium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate.
5. The orally administered naproxen solution formulation of claim 1, wherein the citrate salt is selected from one or more of sodium citrate, potassium citrate, disodium hydrogen citrate, sodium dihydrogen citrate, dipotassium hydrogen citrate, and potassium dihydrogen citrate.
6. The orally administered naproxen solution formulation of claim 1, wherein the sweetener is selected from one or more of saccharin sodium, saccharin, stevioside, aspartame, sucralose, sucrose, sorbitol, and cyclamate, and the flavoring is selected from one or more of orange flavoring, orange flavoring.
7. The orally administered naproxen solution preparation according to claim 1, wherein the split charging container for the orally administered naproxen solution preparation is a medicinal liquid glass bottle or a plastic bottle, and the volume of the split charging container is 20-500 mL.
8. The clinical use of an orally administered naproxen solution formulation according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of pain, fever and inflammatory response.
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