CN112315903A - Rupatadine fumarate oral solution and preparation method thereof - Google Patents
Rupatadine fumarate oral solution and preparation method thereof Download PDFInfo
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- CN112315903A CN112315903A CN202011313135.5A CN202011313135A CN112315903A CN 112315903 A CN112315903 A CN 112315903A CN 202011313135 A CN202011313135 A CN 202011313135A CN 112315903 A CN112315903 A CN 112315903A
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- Prior art keywords
- rupatadine fumarate
- oral solution
- solution
- fumarate oral
- rupatadine
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- JYBLCDXVHQWMSU-WLHGVMLRSA-N (e)-but-2-enedioic acid;8-chloro-11-[1-[(5-methylpyridin-3-yl)methyl]piperidin-4-ylidene]-5,6-dihydrobenzo[1,2]cyclohepta[2,4-b]pyridine Chemical compound OC(=O)\C=C\C(O)=O.CC1=CN=CC(CN2CCC(CC2)=C2C3=NC=CC=C3CCC3=CC(Cl)=CC=C32)=C1 JYBLCDXVHQWMSU-WLHGVMLRSA-N 0.000 title claims abstract description 190
- 229940100688 oral solution Drugs 0.000 title claims abstract description 144
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000000796 flavoring agent Substances 0.000 claims abstract description 30
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000000022 bacteriostatic agent Substances 0.000 claims abstract description 17
- 239000003086 colorant Substances 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 239000000706 filtrate Substances 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 15
- 238000002156 mixing Methods 0.000 claims abstract description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 90
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 80
- 229930189775 mogroside Natural products 0.000 claims description 48
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 43
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 43
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 43
- 239000000811 xylitol Substances 0.000 claims description 43
- 235000010447 xylitol Nutrition 0.000 claims description 43
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 43
- 229960002675 xylitol Drugs 0.000 claims description 43
- 241000234295 Musa Species 0.000 claims description 41
- 235000018290 Musa x paradisiaca Nutrition 0.000 claims description 41
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 28
- 229940051201 quinoline yellow Drugs 0.000 claims description 24
- 235000012752 quinoline yellow Nutrition 0.000 claims description 24
- IZMJMCDDWKSTTK-UHFFFAOYSA-N quinoline yellow Chemical compound C1=CC=CC2=NC(C3C(C4=CC=CC=C4C3=O)=O)=CC=C21 IZMJMCDDWKSTTK-UHFFFAOYSA-N 0.000 claims description 24
- 239000004172 quinoline yellow Substances 0.000 claims description 24
- 239000008213 purified water Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 13
- 239000003002 pH adjusting agent Substances 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 3
- 235000005979 Citrus limon Nutrition 0.000 claims description 3
- 244000131522 Citrus pyriformis Species 0.000 claims description 3
- 235000000177 Indigofera tinctoria Nutrition 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- ALSPKRWQCLSJLV-UHFFFAOYSA-N azanium;acetic acid;acetate Chemical compound [NH4+].CC(O)=O.CC([O-])=O ALSPKRWQCLSJLV-UHFFFAOYSA-N 0.000 claims description 3
- 235000012730 carminic acid Nutrition 0.000 claims description 3
- 239000012153 distilled water Substances 0.000 claims description 3
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 3
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 3
- 229940097275 indigo Drugs 0.000 claims description 3
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- LJSOLTRJEQZSHV-UHFFFAOYSA-L potassium;sodium;hydron;hydroxide;phosphate Chemical compound [OH-].[Na+].[K+].OP(O)([O-])=O LJSOLTRJEQZSHV-UHFFFAOYSA-L 0.000 claims description 3
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 3
- 229960003415 propylparaben Drugs 0.000 claims description 3
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 235000019640 taste Nutrition 0.000 abstract description 29
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 6
- 206010011224 Cough Diseases 0.000 abstract description 3
- 210000000936 intestine Anatomy 0.000 abstract description 3
- 210000004072 lung Anatomy 0.000 abstract description 3
- 230000002040 relaxant effect Effects 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 description 48
- 239000012535 impurity Substances 0.000 description 28
- 229960004063 propylene glycol Drugs 0.000 description 26
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 20
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 20
- 229960002216 methylparaben Drugs 0.000 description 20
- 230000000052 comparative effect Effects 0.000 description 15
- 239000000126 substance Substances 0.000 description 8
- 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 description 6
- 235000003599 food sweetener Nutrition 0.000 description 5
- 229940085605 saccharin sodium Drugs 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- 235000019658 bitter taste Nutrition 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 235000019634 flavors Nutrition 0.000 description 4
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 3
- 108010003541 Platelet Activating Factor Proteins 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 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 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 229960004793 sucrose Drugs 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- 235000016623 Fragaria vesca Nutrition 0.000 description 2
- 240000009088 Fragaria x ananassa Species 0.000 description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 239000000605 aspartame Substances 0.000 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 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000011194 food seasoning agent Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 239000008123 high-intensity sweetener Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 235000019614 sour taste Nutrition 0.000 description 2
- QLSJOGIENLKPTF-WLHGVMLRSA-N (e)-but-2-enedioic acid;pyridine Chemical compound C1=CC=NC=C1.OC(=O)\C=C\C(O)=O QLSJOGIENLKPTF-WLHGVMLRSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 1
- 108700023400 Platelet-activating factor receptors Proteins 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea 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
- 238000010521 absorption reaction Methods 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 229960001342 dinoprost Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 102000030769 platelet activating factor receptor Human genes 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- PXGPLTODNUVGFL-YNNPMVKQSA-N prostaglandin F2alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O PXGPLTODNUVGFL-YNNPMVKQSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229960005328 rupatadine Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- 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
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Botany (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicines, and particularly relates to rupatadine fumarate oral solution and a preparation method thereof, wherein the preparation method of the rupatadine fumarate oral solution comprises the following steps: preparing rupatadine fumarate, a flavoring agent, an alcohol solvent, a bacteriostatic agent, a pH regulator and a coloring agent according to the formula amount; dissolving the rupatadine fumarate and the bacteriostatic agent in an alcohol solvent to obtain a solution A; dissolving the flavoring agent, the pH regulator and the coloring agent in water to obtain a solution B; and mixing the solution A and the solution B, adding water to fix the volume to the volume of the rupatadine fumarate oral solution specified by the formula, filtering, and collecting filtrate to obtain the rupatadine fumarate oral solution. The rupatadine fumarate oral solution has good taste, can improve the medication safety and compliance of patients, especially children, and also has certain effects of clearing heat, moistening lung, relieving cough, moistening intestine and relaxing bowels.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to rupatadine fumarate oral solution and a preparation method thereof.
Background
Rupatadine Fumarate (FR, Rupatadine Fumarate) is chemically 8-chloro-6, 11-dihydro-11- [1- [ (5-methyl-3-pyridine) methyl ] -4-piperidinyl ] -5H-benzocyclohepta [1,2-b ] pyridine Fumarate. It was successfully developed by Uriach pharmaceutical, Spain, and first marketed in Spain in 2003. It is a new generation of tricyclic antihistamine medicine, has the dual effects of resisting histamine and antagonizing Platelet Activating Factor (PAF), and is the only strong and efficient antiallergic medicine which has the antihistaminic effect and antagonizing PAF activity and is on the market at present. The medicine can selectively block H1 receptor, has weak blocking effect on 5-hydroxytryptamine, acetylcholine, prostaglandin F2 and leukotriene D4, can be non-competitively combined with platelet activating factor receptor, and can inhibit sensitized cell degranulation. The traditional Chinese medicine composition has the advantages of definite action mechanism, good bioavailability, stable curative effect and the like and a good safe treatment window, so that the traditional Chinese medicine composition is in a more advantageous position in treating allergic inflammatory diseases.
Until now, the rupatadine fumarate preparation for children is only sold in the market abroad, the product dosage form on the market is oral liquid, the specification is 1mg/mL, and the indication is allergic rhinitis and persistent rhinorrhea of children of 2-11 years old. In order to mask the bitter taste, the prior art generally adopts the mode that saccharin sodium is added into a rupatadine fumarate preparation as a sweetening agent so as to improve the taste of the rupatadine fumarate preparation. But saccharin sodium salt has no nutritive value to human body except for causing sweet feeling in taste. When the food is eaten more, the normal secretion of digestive enzymes in intestines and stomach can be influenced, the absorption capacity of small intestines is reduced, the appetite is reduced, and the food threatens the health of human bodies greatly.
Therefore, research and development of the rupatadine fumarate oral solution which does not contain saccharin sodium, has better mouthfeel, is beneficial to the physical health of patients and improves the medication safety and the compliance of the patients, particularly children, are urgent.
Disclosure of Invention
In order to overcome the defects in the prior art and solve the problem that the rupatadine fumarate preparation in the prior art is not enough in safety and taste in the aspect of taking medicines by patients, particularly children, the invention aims to provide the rupatadine fumarate oral solution and the preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a rupatadine fumarate oral solution, which comprises the following components in every 100ml of rupatadine fumarate oral solution:
wherein the flavoring agent comprises at least one of mogroside, xylitol and banana essence.
Preferably, the oral solution of rupatadine fumarate comprises per 100 ml:
wherein the flavoring agent is a mixture of mogroside, xylitol and banana essence.
In any of the above embodiments, preferably, the alcoholic solvent includes at least one of propylene glycol, isopropyl alcohol, ethanol, and polyethylene glycol; the mass ratio of the mogroside to the xylitol to the banana essence is 1: (500-1500): (2-30); the pH regulator comprises one of acetic acid-sodium acetate, acetic acid-ammonium acetate, citric acid-disodium hydrogen phosphate, and potassium dihydrogen phosphate-sodium hydroxide; the bacteriostatic agent comprises at least one of methyl hydroxybenzoate, ethylparaben, propyl hydroxybenzoate and butyl hydroxybenzoate; the colorant comprises at least one of sunset yellow, lemon yellow, quinoline yellow, carmine and indigo; the water includes one of purified water and distilled water.
In any of the above schemes, preferably, the mass ratio of mogroside, xylitol and banana essence is 1: (800-1100): (10-20).
In any of the above embodiments, preferably, when the pH adjuster is citric acid-disodium hydrogen phosphate, the mass ratio of the citric acid to the disodium hydrogen phosphate is 0.4 to 2.
In any of the above schemes, the pH of the rupatadine fumarate oral solution is preferably 5.0-6.0.
According to the rupatadine fumarate oral solution provided by the invention, the mogroside, the xylitol and the banana essence are used for replacing other corrigents such as saccharin sodium and the like, so that the oral solution has better taste, the medication safety and compliance of patients, particularly children, can be improved, and the rupatadine fumarate oral solution also has certain effects of clearing heat, moistening lung, relieving cough and relaxing bowel due to the mogroside.
In another aspect, the present invention further provides a method for preparing rupatadine fumarate oral solution according to any one of the above schemes, comprising the following steps:
preparing rupatadine fumarate, a flavoring agent, an alcohol solvent, a bacteriostatic agent, a pH regulator and a coloring agent according to the formula amount;
dissolving the rupatadine fumarate and the bacteriostatic agent in the alcohol solvent to obtain a solution A;
dissolving the flavoring agent, the pH regulator and the coloring agent in water to obtain a solution B;
and mixing the solution A and the solution B, adding water to fix the volume to the volume of the rupatadine fumarate oral solution specified by the formula, filtering, and collecting filtrate to obtain the rupatadine fumarate oral solution.
Preferably, in the step of dissolving the rupatadine fumarate and the bacteriostatic agent in the alcohol solvent to obtain the solution a, the dissolving temperature is 40 to 70 ℃.
In any of the above embodiments, preferably, in the step of dissolving the flavoring agent, the pH adjuster, and the coloring agent in water to obtain the B solution, the temperature of the dissolution is 40 to 70 ℃.
In any of the above schemes, preferably, after the step of mixing the solution a and the solution B, adding water to a volume of the rupatadine fumarate oral solution specified by the formula, filtering, and collecting the filtrate to obtain the rupatadine fumarate oral solution, the method further comprises:
and filling the rupatadine fumarate oral solution.
The preparation method of the rupatadine fumarate oral solution provided by the invention is convenient to operate, has low requirements on equipment conditions, is easy to realize, has simple post-treatment, and is suitable for industrial production.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more apparent, the present invention is further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The experimental reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments, equipment and the like used in the following examples are either commercially available or available by existing methods; the dosage of the experimental reagent is the dosage of the reagent in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
In one aspect, an embodiment of the present invention provides a rupatadine fumarate oral solution, which includes, per 100ml of rupatadine fumarate oral solution:
wherein the flavoring agent comprises at least one of mogroside, xylitol and banana essence.
According to the rupatadine fumarate oral solution provided by the embodiment of the invention, the mogroside, the xylitol and the banana essence are used for replacing other corrigents such as saccharin sodium and the like, so that the oral solution has better taste, and the medication safety and the compliance of patients, particularly children, can be improved.
Further, in each 100ml of rupatadine fumarate oral solution comprising:
wherein the flavoring agent is a mixture of mogroside, xylitol and banana essence.
The rupatadine fumarate oral solution provided by the embodiment of the invention has better taste, and has certain effects of clearing heat, moistening lung, relieving cough, moistening intestine and relaxing bowels due to the inclusion of mogroside.
Further, the alcohol solvent comprises at least one of propylene glycol, isopropanol, ethanol and polyethylene glycol, preferably, the alcohol solvent is propylene glycol, namely 1, 2-propylene glycol, and the solubility of rupatadine fumarate in the propylene glycol is the maximum.
Further, the mass ratio of the mogroside to the xylitol to the banana essence is 1: (500-1500): (2-30), for example, the mass ratio of the mogroside to the xylitol to the banana essence can be 1: 500: 2. 1: 600: 10. 1: 800: 15. 1: 1000: 20. 1: 1200: 25 or 1: 1500: 30, etc. The sweetness of the mogroside is released quickly, the duration time of the taste in the oral cavity is short, the xylitol is slightly cool after the mouth is entered, the mogroside has a synergistic effect with the sweetness of the mogroside, the three flavoring agents of the mogroside, the xylitol and the banana essence are mutually matched and are mutually synergistic, the bitterness of the rupatadine fumarate is perfectly covered, the taste of the oral solution of the rupatadine fumarate is better than that of the oral solution of the rupatadine fumarate disclosed in the prior art, and the medication compliance of patients, particularly children, is improved. Preferably, the mass ratio of the mogroside to the xylitol to the banana essence is 1: (800-1100): (10-20), for example, the mass ratio of the mogroside to the xylitol to the banana essence can be 1: 800: 10. 1: 900: 10. 1: 1000:16 or 1: 1100: 20, and the like, under the mass ratio, the oral solution of the rupatadine fumarate has the best taste.
Further, the pH regulator comprises one of acetic acid-sodium acetate, acetic acid-ammonium acetate, citric acid-disodium hydrogen phosphate and potassium dihydrogen phosphate-sodium hydroxide. The pH regulator is used for controlling the pH value of the rupatadine fumarate oral solution within the range of 5.0-6.0, and the dosage of the pH regulator can be determined according to the pH value of the rupatadine fumarate oral solution to be reached. Preferably, when the pH adjuster is citric acid-disodium hydrogen phosphate, the mass ratio of the citric acid to the disodium hydrogen phosphate is 0.4 to 2, for example, the mass ratio of the citric acid to the disodium hydrogen phosphate may be 0.4, 1, 1.5, 2, or the like. The proper citric acid increases a certain sour taste, the sour and sweet taste is more acceptable for patients, especially children, and the taste of the rupatadine fumarate oral solution is improved.
Further, the bacteriostatic agent comprises at least one of methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate and butyl hydroxybenzoate.
Further, the colorant comprises at least one of sunset yellow, lemon yellow, quinoline yellow, carmine and indigo.
Further, the water includes one of purified water and distilled water.
Further, the pH of the rupatadine fumarate oral solution is 5.0-6.0, for example, the pH of the rupatadine fumarate oral solution can be 5.0, 5.52 or 6.0. When the pH value of the rupatadine fumarate oral solution is too low, the stability of the rupatadine fumarate is reduced, and more impurities can be generated in the oral solution; when the pH value of the rupatadine fumarate oral solution is too high, the solubility of the rupatadine fumarate is reduced, and precipitates can be separated out from the oral solution. The pH value of the rupatadine fumarate oral solution is controlled within the range of 5.0-6.0, so that the stability of the rupatadine fumarate oral solution can be ensured, and the maximum bioavailability of the rupatadine fumarate oral solution can be ensured.
In a second aspect, an embodiment of the present invention further provides a method for preparing the rupatadine fumarate oral solution according to any one of the first aspect, including the following steps:
(1) preparing rupatadine fumarate, a flavoring agent, an alcohol solvent, a bacteriostatic agent, a pH regulator and a coloring agent according to the formula amount;
(2) dissolving the rupatadine fumarate and the bacteriostatic agent in the alcohol solvent to obtain a solution A;
(3) dissolving the flavoring agent, the pH regulator and the coloring agent in water to obtain a solution B;
(4) and mixing the solution A and the solution B, adding water to fix the volume to the volume of the rupatadine fumarate oral solution specified by the formula, filtering, and collecting filtrate to obtain the rupatadine fumarate oral solution.
The preparation method of the rupatadine fumarate oral solution provided by the embodiment of the invention is convenient to operate, has low requirements on equipment conditions, is easy to realize, has simple post-treatment, and is suitable for industrial production.
Further, in the step of dissolving the rupatadine fumarate and the bacteriostatic agent in the alcohol solvent to obtain the solution A, the dissolving temperature is 40-70 ℃, and the solubility of the rupatadine fumarate and the bacteriostatic agent is higher at the temperature. For example, the temperature may be 40 ℃, 50 ℃, 60 ℃, or 70 ℃, etc.
Further, in the step of dissolving the flavoring agent, the pH regulator and the coloring agent in water to obtain the solution B, the dissolving temperature is 40-70 ℃, and the solubility of the flavoring agent, the pH regulator and the coloring agent is higher at the temperature. For example, the temperature may be 40 ℃, 50 ℃, 60 ℃, or 70 ℃, etc.
Further, after the steps of mixing the solution A and the solution B, adding water to a constant volume of the rupatadine fumarate oral solution specified by the formula, filtering, and collecting filtrate to obtain the rupatadine fumarate oral solution, the method further comprises the following steps:
the rupatadine fumarate oral solution is filled, for example, by filling the rupatadine fumarate oral solution with a plastic bottle.
The rupatadine fumarate oral solution of the embodiment of the invention preferably comprises the following components in every 100 milliliters of the rupatadine fumarate oral solution:
wherein the flavoring agent is a mixture of mogroside, xylitol and banana essence.
The preferable steps of the preparation method of the rupatadine fumarate oral solution provided by the embodiment of the invention are as follows:
(1) preparing rupatadine fumarate, a flavoring agent, an alcohol solvent, a bacteriostatic agent, a pH regulator and a coloring agent according to the formula amount;
(2) dissolving the rupatadine fumarate and the bacteriostatic agent in propylene glycol at 40-70 ℃ to obtain a solution A;
(3) dissolving citric acid-disodium hydrogen phosphate, mogroside, xylitol, banana essence and a coloring agent in a proper amount of purified water at 40-70 ℃ to obtain a solution B;
(4) and mixing the solution A and the solution B, adding purified water to a constant volume of the rupatadine fumarate oral solution specified by the formula, filtering, and collecting filtrate to obtain the rupatadine fumarate oral solution.
The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.
Test example 1
In this test example, the high-intensity sweetener was screened, and the contents of the components of each sample are shown in table 1 based on 100ml of rupatadine fumarate oral solution, and the preparation method was:
(1) weighing the components according to the formula;
(2) dissolving rupatadine fumarate and methylparaben in propylene glycol at 50 ℃ to obtain a solution A;
(3) dissolving citric acid, disodium hydrogen phosphate, high-sweetness sweetening agent and cane sugar in proper amount of purified water at 50 ℃ to obtain a solution B;
(4) and mixing the solution A and the solution B, adding purified water to a constant volume of 100mL, filtering, and collecting filtrate to obtain the rupatadine fumarate oral solution.
TABLE 1 component content of each sample
200 subjects with the ages ranging from 10 years to 50 years are selected, wherein 100 men and 100 women respectively select a sample with the best taste, and the test results are shown in table 2.
TABLE 2 high intensity sweetener test results
| Sample numbering | 1-1 | 1-2 | 1-3 | 1-4 | 1-5 | 1-6 | 1-7 |
| Number of people | 30 | 15 | 9 | 10 | 5 | 8 | 123 |
From the results of the tests, 123 subjects considered samples 1-7 to be the best tasting, and therefore mogroside was selected as the flavoring agent in the present invention.
Test example 2
In this test example, low-intensity sweeteners were screened, and the contents of each component in each sample based on 100ml of rupatadine fumarate oral solution are shown in table 3, and the preparation method was different from that in test example 1 in that: in the step (3), citric acid, disodium hydrogen phosphate, mogroside, and a low-sweetness sweetener were dissolved in an appropriate amount of purified water at 50 ℃ to obtain a solution B, and the remaining steps were the same as in test example 1.
TABLE 3 component content of each sample
200 subjects with the ages ranging from 10 years to 50 years are selected, wherein 100 men and 100 women respectively select a sample with the best taste, and the test results are shown in table 4.
TABLE 4 Low sweetness sweetener test results
| Sample numbering | 1-7 | 2-1 | 2-2 | 2-3 |
| Number of people | 42 | 135 | 15 | 8 |
From the test results, 135 subjects considered sample 2-1 to have the best mouthfeel, and therefore, xylitol could be selected as the flavoring agent in the present invention.
Test example 3
In this test example, flavor seasonings were screened, and the contents of the components of each sample in 100ml of rupatadine fumarate oral solution are shown in table 5, which was different from that in test example 1 in that: in step (3), citric acid, disodium hydrogen phosphate, mogroside, xylitol, and a flavor seasoning were dissolved in an appropriate amount of purified water at 50 ℃ to obtain a solution B, and the remaining steps were the same as in test example 1.
TABLE 5 component content of each sample
200 subjects with the ages ranging from 10 years to 50 years are selected, wherein 100 men and 100 women respectively select a sample with the best taste, and the test results are shown in table 6.
Table 6 flavor testing results
| Sample numbering | 3-1 | 3-2 | 3-3 | 3-4 |
| Number of people | 95 | 47 | 39 | 19 |
From the test results, 95 subjects considered the sample 3-1 to have the best mouthfeel, and therefore, banana essence can be selected as a flavoring agent in the invention.
Test example 4
In this test example, the ratio of the flavoring agent was examined, and the contents of the components in each sample based on 100ml of rupatadine fumarate oral solution are shown in table 7, and the preparation method is different from that in test example 1 in that: in the step (3), citric acid, disodium hydrogen phosphate, mogroside, xylitol, banana essence and quinoline yellow are dissolved in a proper amount of purified water at 50 ℃ to obtain a solution B, and the rest steps are the same as those in the test example 1.
TABLE 7 component content of each sample
200 subjects with the ages ranging from 10 years to 50 years are selected, wherein 100 men and 100 women respectively select a sample with the best taste, and the test results are shown in Table 8.
Table 8 flavor ratio test results
| Sample numbering | 4-1 | 4-2 | 4-3 | 4-4 | 4-5 | 4-6 | 4-7 | 4-8 |
| Number of people | 15 | 20 | 12 | 28 | 24 | 20 | 50 | 31 |
According to the test result, 50 subjects consider that the samples 4-7 have the best mouthfeel, and the formula flavoring agent is composed of mogroside: xylitol: banana essence is 1: 1000:16, moderate sweetness, short duration in the oral cavity and minimal bitterness.
Test example 5
In this test example, the ratio of the pH adjusting agent was examined, and the contents of the components of each sample based on 100ml of rupatadine fumarate oral solution are shown in table 9, and the preparation method is different from that of test example 1 in that: in the step (3), citric acid, disodium hydrogen phosphate, mogroside, xylitol, banana essence and quinoline yellow are dissolved in a proper amount of purified water at 50 ℃ to obtain a solution B, and the rest steps are the same as those in the test example 1.
TABLE 9 content of each sample component
200 subjects with the ages ranging from 10 years to 50 years are selected, wherein 100 men and 100 women respectively select a sample with the best taste, and the test results are shown in a table 10.
TABLE 10 test results of pH modifier ratio
| Sample numbering | 4-7 | 5-1 | 5-2 | 5-3 | 5-4 |
| Number of people | 45 | 25 | 33 | 60 | 37 |
From the results of the tests, 60 subjects considered samples 5-3 to have the best mouthfeel, the formulation pH adjuster ratio was 0.57, the appropriate citric acid added some sourness, and the sour-sweet taste made the subjects more acceptable.
Test example 6
The test example investigates the influence of different pH values on the stability of the main drug of the rupatadine fumarate oral solution, wherein the content of each sample component is shown in table 11 based on 100ml of the rupatadine fumarate oral solution, and the preparation method is the same as that of the test example 5.
TABLE 11 component content of each sample
Putting each sample into a transparent colorless glass bottle, sealing, placing at 40 ℃, sampling for detection on the 30 th day after lofting, and determining the content of impurities in the rupatadine fumarate oral solution according to high performance liquid chromatography (China pharmacopoeia 2020 edition four ministry of general rules 0512), wherein the determination results are shown in Table 12.
TABLE 12 measurement results of impurity content of each sample
According to the quality standard of rupatadine fumarate in European pharmacopoeia and British pharmacopoeia and the detection results of foreign market samples and homemade samples, the limit of related substances is drawn up: impurity A should not exceed 1.0%, impurity B should not exceed 0.5%, impurity C should not exceed 0.2%, other individual impurities should not exceed 0.2%, and the total amount of impurities should not exceed 2.0%.
Impurities A-C are impurities of known structure, also called related species, the largest unknown single impurity is an impurity of unknown specific structure and molecular formula, and the total impurity is the sum of all impurities in the sample. According to the self-proposed standard, each impurity needs to be less than the limit to ensure the safety of medication.
From the measurement results, it was found that: when each sample is placed at 40 ℃ for 30 days, the detection of related substances meets the quality standard limit; the amount of impurity A decreases with increasing pH, and the amount of impurity B is substantially unchanged from that of impurity C.
When the sample 5-1 is placed at 40 ℃ for 30 days, the amount of the impurity A is 0.852%, the total impurity is 0.962%, and the related substance amount is increased more than that of the sample at 0 day; when the sample 5-2 is placed at 40 ℃ for 30 days, the amount of the impurity A is 0.645 percent, the total impurities are 0.752 percent, and the related substance amount is increased more than that of the sample for 0 day; when the samples 4 to 7 are placed at 40 ℃ for 30 days, the amount of the impurity A is 0.238 percent, the total impurities are 0.334 percent, and the change of related substances is relatively stable compared with 0 day; when the sample 6-2 is placed at 40 ℃ for 30 days, the amount of the impurity A is 0.194 percent, the total impurities are 0.301 percent, and the change of related substances is relatively stable in comparison with 0 day; when the sample 5-3 is placed at 40 ℃ for 30 days, the amount of the impurity A is 0.125 percent, the total impurities are 0.320 percent, and the change of related substances is relatively stable in comparison with 0 day; when the sample 5-4 is placed at 40 ℃ for 30 days, the amount of the impurity A is 0.066%, the total impurities are 0.308%, and the change of related substances is relatively stable compared with 0 day.
When the pH value of the rupatadine fumarate oral solution is controlled to be more than 6.0, the raw material can be separated out, and further investigation is not carried out.
In conclusion, the pH value of the oral liquid influences the stability of the main medicine, the pH is controlled within the range of 5.0-6.0, and the rupatadine fumarate oral liquid is most stable.
The contents of the components of the rupatadine fumarate oral solutions of examples 1-5 and the contents of the components of the rupatadine fumarate oral solutions of examples 6-10 are shown in table 13 and table 14, respectively, based on 100ml of the rupatadine fumarate oral solution.
TABLE 13 examples 1-5 Rupatadine fumarate oral solution component content
TABLE 14 examples 6-10 Rupatadine fumarate oral solution component content
Example 1
The contents of the components of the rupatadine fumarate oral solution provided in this example are shown in table 13.
The preparation method of the rupatadine fumarate oral solution provided by the embodiment comprises the following steps:
(1) preparing 0.128g of rupatadine fumarate, 0.050g of mogroside, 30.000g of xylitol, 0.200g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.323g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow;
(2) dissolving rupatadine fumarate and methylparaben in propylene glycol at 50 ℃ to obtain a solution A;
(3) dissolving citric acid, disodium hydrogen phosphate, mogroside, xylitol, banana essence and quinoline yellow in a proper amount of purified water at 50 ℃ to obtain a solution B;
(4) and mixing the solution A and the solution B, adding purified water to a constant volume of 100mL, filtering, collecting filtrate to obtain the rupatadine fumarate oral solution, wherein the pH value of the rupatadine fumarate oral solution is 5.52, and then filling.
Example 2
The contents of the components of the rupatadine fumarate oral solution provided in this example are shown in table 13.
The difference between the preparation method of the rupatadine fumarate oral solution provided by the embodiment and the preparation method of the rupatadine fumarate oral solution provided by the embodiment 1 is that: in the step (1), 0.128g of rupatadine fumarate, 0.050g of mogroside, 40.000g of xylitol, 0.200g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.323g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow are prepared, and the rest steps are the same as in the example 1.
Example 3
The contents of the components of the rupatadine fumarate oral solution provided in this example are shown in table 13.
The preparation method of the rupatadine fumarate oral solution provided by the embodiment comprises the following steps:
(1) preparing 0.128g of rupatadine fumarate, 0.050g of mogroside, 50.000g of xylitol, 0.200g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.323g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow;
(2) dissolving rupatadine fumarate and methylparaben in propylene glycol at 40 ℃ to obtain a solution A;
(3) dissolving citric acid, disodium hydrogen phosphate, mogroside, xylitol, banana essence and quinoline yellow in a proper amount of purified water at 40 ℃ to obtain a solution B;
(4) and mixing the solution A and the solution B, adding purified water to a constant volume of 100mL, filtering, collecting filtrate to obtain the rupatadine fumarate oral solution, wherein the pH value of the rupatadine fumarate oral solution is 5.52, and then filling.
Example 4
The contents of the components of the rupatadine fumarate oral solution provided in this example are shown in table 13.
The difference between the preparation method of the rupatadine fumarate oral solution provided by the embodiment and the preparation method of the rupatadine fumarate oral solution provided by the embodiment 3 is that: in the step (1), 0.128g of rupatadine fumarate, 0.050g of mogroside, 50.000g of xylitol, 0.400g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.323g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow are prepared, and the rest steps are the same as in the example 3.
Example 5
The contents of the components of the rupatadine fumarate oral solution provided in this example are shown in table 13.
The difference between the preparation method of the rupatadine fumarate oral solution provided by the embodiment and the preparation method of the rupatadine fumarate oral solution provided by the embodiment 1 is that: in the step (1), 0.128g of rupatadine fumarate, 0.050g of mogroside, 50.000g of xylitol, 0.800g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.323g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow are prepared, and the rest steps are the same as in the example 1.
Example 6
The contents of the components of the rupatadine fumarate oral solution provided in this example are shown in table 14.
The difference between the preparation method of the rupatadine fumarate oral solution provided by the embodiment and the preparation method of the rupatadine fumarate oral solution provided by the embodiment 1 is that: in the step (1), 0.128g of rupatadine fumarate, 0.050g of mogroside, 50.000g of xylitol, 1.200g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.323g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow are prepared, and the rest steps are the same as in the example 1.
Example 7
The contents of the components of the rupatadine fumarate oral solution provided in this example are shown in table 14.
The difference between the preparation method of the rupatadine fumarate oral solution provided by the embodiment and the preparation method of the rupatadine fumarate oral solution provided by the embodiment 1 is that: in the step (1), 0.128g of rupatadine fumarate, 0.030g of mogroside, 36.000g of xylitol, 0.300g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.397g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow are prepared; in the step (4), the pH value of the rupatadine fumarate oral solution is 5.04; the rest of the procedure was the same as in example 1.
Example 8
The contents of the components of the rupatadine fumarate oral solution provided in this example are shown in table 14.
The preparation method of the rupatadine fumarate oral solution provided by the embodiment comprises the following steps:
(1) preparing 0.128g of rupatadine fumarate, 0.050g of mogroside, 50.000g of xylitol, 0.800g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.768g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow;
(2) dissolving rupatadine fumarate and methylparaben in propylene glycol at 60 ℃ to obtain a solution A;
(3) dissolving citric acid, disodium hydrogen phosphate, mogroside, xylitol, banana essence and quinoline yellow in a proper amount of purified water at 60 ℃ to obtain a solution B;
(4) and mixing the solution A and the solution B, adding purified water to a constant volume of 100mL, filtering, collecting filtrate to obtain the rupatadine fumarate oral solution, wherein the pH value of the rupatadine fumarate oral solution is 4.01, and then filling.
Example 9
The contents of the components of the rupatadine fumarate oral solution provided in this example are shown in table 14.
The difference between the preparation method of the rupatadine fumarate oral solution provided by the embodiment and the preparation method of the rupatadine fumarate oral solution provided by the embodiment 8 is that: in the step (1), 0.128g of rupatadine fumarate, 0.050g of mogroside, 50.000g of xylitol, 0.800g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.558g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow are prepared; in the step (4), the pH value of the rupatadine fumarate oral solution is 4.50; the remaining procedure was the same as in example 8.
Example 10
The contents of the components of the rupatadine fumarate oral solution provided in this example are shown in table 14.
The difference between the preparation method of the rupatadine fumarate oral solution provided by the embodiment and the preparation method of the rupatadine fumarate oral solution provided by the embodiment 1 is that: in the step (1), 0.128g of rupatadine fumarate, 0.050g of mogroside, 50.000g of xylitol, 0.800g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.246g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow are prepared; in the step (4), the pH value of the rupatadine fumarate oral solution is 5.99; the rest of the procedure was the same as in example 1.
Comparative example 1
Selecting a commercial rupatadine fumarate oral solution containing saccharin sodium, wherein the commercial Rupafin fumarate oral solution is sold by Vifor PHarma
S.L.。
Comparative example 2
The rupatadine fumarate oral solution comprises the following components in percentage by 100 milliliters of the rupatadine fumarate oral solution:
the preparation method of the rupatadine fumarate oral solution provided by the embodiment comprises the following steps:
(1) preparing 0.128g of rupatadine fumarate, 0.050g of aspartame, 50.000g of xylitol, 0.800g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.323g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow;
(2) dissolving rupatadine fumarate and methylparaben in propylene glycol at 50 ℃ to obtain a solution A;
(3) dissolving citric acid, disodium hydrogen phosphate, aspartame, xylitol, banana essence and quinoline yellow in a proper amount of purified water at 50 ℃ to obtain a solution B;
(4) and mixing the solution A and the solution B, adding purified water to a constant volume of 100mL, filtering, collecting filtrate to obtain the rupatadine fumarate oral solution, wherein the pH value of the rupatadine fumarate oral solution is 5.52, and then filling.
Comparative example 3
The rupatadine fumarate oral solution comprises the following components in percentage by 100 milliliters of the rupatadine fumarate oral solution:
the preparation method of the rupatadine fumarate oral solution provided by the embodiment comprises the following steps:
(1) preparing 0.128g of rupatadine fumarate, 0.050g of mogroside, 50.000g of cane sugar, 0.800g of banana essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.323g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow;
(2) dissolving rupatadine fumarate and methylparaben in propylene glycol at 50 ℃ to obtain a solution A;
(3) dissolving citric acid, disodium hydrogen phosphate, mogroside, sucrose, banana essence and quinoline yellow in a proper amount of purified water at 50 ℃ to obtain a solution B;
(4) and mixing the solution A and the solution B, adding purified water to a constant volume of 100mL, filtering, collecting filtrate to obtain the rupatadine fumarate oral solution, wherein the pH value of the rupatadine fumarate oral solution is 5.52, and then filling.
Comparative example 4
The rupatadine fumarate oral solution comprises the following components in percentage by 100 milliliters of the rupatadine fumarate oral solution:
the preparation method of the rupatadine fumarate oral solution provided by the embodiment comprises the following steps:
(1) preparing 0.128g of rupatadine fumarate, 0.050g of mogroside, 50.000g of xylitol, 0.800g of strawberry essence, 20.000g of propylene glycol, 0.1g of methylparaben, 0.323g of citric acid, 0.568g of disodium hydrogen phosphate and 0.0001g of quinoline yellow;
(2) dissolving rupatadine fumarate and methylparaben in propylene glycol at 50 ℃ to obtain a solution A;
(3) dissolving citric acid, disodium hydrogen phosphate, mogroside, xylitol, strawberry essence and quinoline yellow in a proper amount of purified water at 50 ℃ to obtain a solution B;
(4) and mixing the solution A and the solution B, adding purified water to a constant volume of 100mL, filtering, collecting filtrate to obtain the rupatadine fumarate oral solution, wherein the pH value of the rupatadine fumarate oral solution is 5.52, and then filling.
Rupatadine fumarate oral solution taste testing
500 subjects were selected, aged from 10 years to 50 years, 250 men and 250 women, and example 1, example 2 and example 5 were randomly selected from 10 examples and tested together with comparative example, and each subject was tasted for example 1, example 2, example 5, comparative example 1, comparative example 2, comparative example 3 and comparative example 4, respectively, and given 5 points, 4 points, 3 points, 2 points and 1 point, respectively, according to the taste. The mouthfeel was best at 5 min and the mouthfeel was worst at 1 min, and the test results are shown in the following table.
Results of taste testing of different examples and comparative examples
As can be seen from the results of the mouthfeel tests of the different examples and comparative examples: when the taste test was performed on example 1, the number of people scored 5 was 349, the number of people scored 4 was 143, the number of people scored 3 was 7, and the number of people scored 2 was 1; when the taste test was performed on example 2, the number of people scored 5 was 378, the number of people scored 4 was 110, and the number of people scored 3 was 12; when the taste test was performed on example 5, the number of people scored 5 was 391, the number of people scored 4 was 98, the number of people scored 3 was 10, and the number of people scored 2 was 1; when the taste test was performed on comparative example 1, the number of people scored 5 was 70, the number of people scored 4 was 100, the number of people scored 3 was 300, the number of people scored 2 was 25, and the number of people scored 1 was 5; when the taste test was performed on comparative example 2, the number of people scored 5 was 100, the number of people scored 4 was 224, the number of people scored 3 was 173, and the number of people scored 2 was 3; when the taste test of comparative example 3 was performed, the number of people who rated 5 was 150, the number of people who rated 4 was 170, the number of people who rated 3 was 178, and the number of people who rated 2 was 2; when the taste test was performed on comparative example 4, the number of people scored 5 was 170, the number of people scored 4 was 210, the number of people scored 3 was 119, and the number of people scored 2 was 1. Therefore, the taste of the rupatadine fumarate oral solution is far better than that of other rupatadine fumarate oral solutions, the mogroside, the xylitol and the banana essence are synergistic, the bitter taste of the rupatadine fumarate is improved and covered together, any one component is replaced by other components, and the taste is reduced.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A rupatadine fumarate oral solution comprising, per 100 milliliters of rupatadine fumarate oral solution:
wherein the flavoring agent comprises at least one of mogroside, xylitol and banana essence.
2. The rupatadine fumarate oral solution of claim 1, comprising per 100 milliliters of rupatadine fumarate oral solution:
wherein the flavoring agent is a mixture of mogroside, xylitol and banana essence.
3. The rupatadine fumarate oral solution of any of claims 1-2,
the alcohol solvent comprises at least one of propylene glycol, isopropanol, ethanol and polyethylene glycol;
the mass ratio of the mogroside to the xylitol to the banana essence is 1: (500-1500): (2-30);
the pH regulator comprises one of acetic acid-sodium acetate, acetic acid-ammonium acetate, citric acid-disodium hydrogen phosphate, and potassium dihydrogen phosphate-sodium hydroxide;
the bacteriostatic agent comprises at least one of methyl hydroxybenzoate, ethylparaben, propyl hydroxybenzoate and butyl hydroxybenzoate;
the colorant comprises at least one of sunset yellow, lemon yellow, quinoline yellow, carmine and indigo;
the water includes one of purified water and distilled water.
4. The rupatadine fumarate oral solution of any of claims 1-2, wherein the mass ratio of mogroside, xylitol, and banana essence is 1: (800-1100): (10-20).
5. The rupatadine fumarate oral solution of any of claims 1-2, wherein when the pH adjuster is citric acid-disodium hydrogen phosphate, the mass ratio of the citric acid to the disodium hydrogen phosphate is 0.4-2.
6. The rupatadine fumarate oral solution of any of claims 1-2, wherein the rupatadine fumarate oral solution has a pH of 5.0 to 6.0.
7. The process for the preparation of rupatadine fumarate oral solution according to any of claims 1-2, comprising the steps of:
preparing rupatadine fumarate, a flavoring agent, an alcohol solvent, a bacteriostatic agent, a pH regulator and a coloring agent according to the formula amount;
dissolving the rupatadine fumarate and the bacteriostatic agent in the alcohol solvent to obtain a solution A;
dissolving the flavoring agent, the pH regulator and the coloring agent in water to obtain a solution B;
and mixing the solution A and the solution B, adding water to fix the volume to the volume of the rupatadine fumarate oral solution specified by the formula, filtering, and collecting filtrate to obtain the rupatadine fumarate oral solution.
8. The method for preparing rupatadine fumarate oral solution of claim 7, wherein in the step of dissolving said rupatadine fumarate and said bacteriostatic agent in said alcoholic solvent to obtain solution A:
the dissolving temperature is 40-70 ℃.
9. The method for preparing rupatadine fumarate oral solution of claim 7, wherein in the step of dissolving the flavoring agent, the pH adjusting agent and the coloring agent in water to obtain B solution:
the dissolving temperature is 40-70 ℃.
10. The method for preparing rupatadine fumarate oral solution of claim 7, wherein after the steps of mixing the solution A and the solution B, adding water to a volume of the rupatadine fumarate oral solution specified by a formula, filtering, and collecting filtrate to obtain the rupatadine fumarate oral solution, the method further comprises the following steps:
and filling the rupatadine fumarate oral solution.
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| CN116898799A (en) * | 2023-08-30 | 2023-10-20 | 哈尔滨圣泰生物制药有限公司 | Desloratadine oral preparation and preparation method thereof |
| CN116983309A (en) * | 2022-04-25 | 2023-11-03 | 北京阳光德美医药科技有限公司 | Insoluble antiallergic medicinal preparation and preparation method thereof |
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| CN116898799B (en) * | 2023-08-30 | 2024-04-30 | 哈尔滨圣泰生物制药有限公司 | Desloratadine oral preparation and preparation method thereof |
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