CN113940918B - 一种药物组合物及制备方法 - Google Patents
一种药物组合物及制备方法 Download PDFInfo
- Publication number
- CN113940918B CN113940918B CN202010693600.6A CN202010693600A CN113940918B CN 113940918 B CN113940918 B CN 113940918B CN 202010693600 A CN202010693600 A CN 202010693600A CN 113940918 B CN113940918 B CN 113940918B
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- essence
- total weight
- mannitol
- sorbitol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title abstract description 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000375 suspending agent Substances 0.000 claims abstract description 12
- 239000000463 material Substances 0.000 claims abstract description 11
- 239000003085 diluting agent Substances 0.000 claims abstract description 10
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 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 17
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 17
- 229930195725 Mannitol Natural products 0.000 claims description 17
- 239000000594 mannitol Substances 0.000 claims description 17
- 235000010355 mannitol Nutrition 0.000 claims description 17
- 239000000600 sorbitol Substances 0.000 claims description 17
- 235000010356 sorbitol Nutrition 0.000 claims description 17
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 15
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 14
- 229920003082 Povidone K 90 Polymers 0.000 claims description 12
- 239000008187 granular material Substances 0.000 claims description 11
- 239000000853 adhesive Substances 0.000 claims description 9
- 230000001070 adhesive effect Effects 0.000 claims description 9
- 229960000913 crospovidone Drugs 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 9
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical group CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 8
- 229920001993 poloxamer 188 Polymers 0.000 claims description 8
- 229940044519 poloxamer 188 Drugs 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000004806 packaging method and process Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 6
- 229920000053 polysorbate 80 Polymers 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 6
- 239000007779 soft material Substances 0.000 claims description 6
- 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 5
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 5
- 229940068968 polysorbate 80 Drugs 0.000 claims description 5
- -1 2- (2-aminopyridin-4-yl) -5- (5- ((5- (2-ethyl-2H-tetrazol-5-yl) pyridin-2-yl) -oxy) -3, 3-dimethylpentyl) -1,2, 5-thiadiazolidine 1, 1-dioxide hydrochloride Chemical compound 0.000 claims description 4
- 240000008790 Musa x paradisiaca Species 0.000 claims description 2
- 235000018290 Musa x paradisiaca Nutrition 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000011361 granulated particle Substances 0.000 claims description 2
- 238000005469 granulation Methods 0.000 claims description 2
- 230000003179 granulation Effects 0.000 claims description 2
- 240000009088 Fragaria x ananassa Species 0.000 claims 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 abstract description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 abstract description 6
- 229940069328 povidone Drugs 0.000 abstract description 6
- 238000004090 dissolution Methods 0.000 abstract description 5
- 150000003839 salts Chemical class 0.000 abstract description 3
- LGLWQZQYCRSSPV-UHFFFAOYSA-N CCN1N=NC(=N1)C1=CN=C(OCCC(C)(C)CCN2CCN(C3=CC=NC(N)=C3)S2(=O)=O)C=C1 Chemical compound CCN1N=NC(=N1)C1=CN=C(OCCC(C)(C)CCN2CCN(C3=CC=NC(N)=C3)S2(=O)=O)C=C1 LGLWQZQYCRSSPV-UHFFFAOYSA-N 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 229940126062 Compound A Drugs 0.000 description 18
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 18
- 241000220223 Fragaria Species 0.000 description 14
- 238000012360 testing method Methods 0.000 description 10
- 238000013112 stability test Methods 0.000 description 9
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 7
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 6
- 238000011835 investigation Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000011975 tartaric acid Substances 0.000 description 6
- 235000002906 tartaric acid Nutrition 0.000 description 6
- 230000007774 longterm Effects 0.000 description 5
- 208000020061 Hand, Foot and Mouth Disease Diseases 0.000 description 4
- 208000025713 Hand-foot-and-mouth disease Diseases 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 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 4
- 241000700605 Viruses Species 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241001529459 Enterovirus A71 Species 0.000 description 3
- 229920003081 Povidone K 30 Polymers 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 208000030194 mouth disease Diseases 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 241000709661 Enterovirus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000006740 Aseptic Meningitis Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 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
- 206010019233 Headaches Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 206010027201 Meningitis aseptic Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 206010068319 Oropharyngeal pain Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 229940029893 carboxymethylcellulose / hypromellose Drugs 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 210000001624 hip Anatomy 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229940034008 mannitol / sorbitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Biophysics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提出了一种药物组合物,所述药物组合物包括:活性成分,包括2‑(2‑氨基吡啶‑4‑基)‑5‑(5‑((5‑(2‑乙基‑2H‑四唑‑5‑基)吡啶‑2‑基)‑氧基)‑3,3‑二甲基戊基)‑1,2,5‑噻二唑烷1,1‑二氧化物或其药学上可接受的盐;辅料,包括稀释剂、助悬剂;其中,所述助悬剂包括聚维酮。本发明的药物组合物溶解迅速、稳定性良好,且制备工艺简单,更适合工艺化大生产。
Description
技术领域
本发明属于药物制剂领域,更具体地说,涉及一种治疗儿童手足口病的药物组合物及制备方法。
背景技术
手足口病(HFMD)是一种由肠道病毒引起的全球性传染病,主要致病病毒包括肠道病毒71型(EV71)、科萨奇A16型(CoxA16)及其它一些肠道病毒,其中EV71引起的危害最为严重。手足口病多发于婴儿和儿童,特别是5岁以下的幼儿,而在成人人群中较少发病,但免疫缺陷的病人也可能被感染。发病时,以手部、足部和口部的水疱为典型特征,另外,还伴有发热、头疼、咽喉痛、皮疹等症状,严重者可能并发心肌炎、肺水肿、无菌性脑膜炎,甚至致死性肺栓塞或大出血,个别重症患儿病情发展快,死亡率高。
发明内容
本发明的目的在于提供一种稳定性良好、溶解迅速的治疗儿童手足口病的药物组合物及其制备方法。具体地,本发明提出的药物组合物包括:
活性成分,包括2-(2-氨基吡啶-4-基)-5-(5-((5-(2-乙基-2H-四唑-5-基)吡啶-2-基)-氧基)-3,3-二甲基戊基)-1,2,5-噻二唑烷1,1-二氧化物或其药学上可接受的盐;
辅料,包括稀释剂、助悬剂;其中,所述助悬剂包括聚维酮。
进一步地,所述助悬剂还包括羧甲基纤维素钠、卡拉胶或交联聚维酮(CL-M)中的一种或几种。
具体地,所述药学上可接受的盐包括盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
可选地,所述聚维酮包括聚维酮K30或聚维酮K90。
进一步地,所述助悬剂聚维酮K90含量选自基于组合物的总重量的0.3~2.0%,优选0.5~1.5%。
进一步地,所述助悬剂交联聚维酮(CL-M)含量选自基于组合物的总重量的0.5~2.0%,优选0.8~1.5%。
进一步地,所述药物组合物还包括增溶剂。所述增溶剂优选为泊洛沙姆188和/或聚山梨酯80和/或吐温80;所述增溶剂优选占所述药物组合物总重量的0.5%~2.0%,优选0.8~1.5%。
进一步地,所述稀释剂包括蔗糖、甘露醇、山梨醇、木糖醇中的一种或几种。
优选地,所述稀释剂包括甘露醇和山梨醇;所述甘露醇和山梨醇的重量比优选为1:1~3:1。
进一步地,所述辅料还包括香精,所述香精包括桔子香精、草莓香精、香蕉香精中的一种或几种;所述香精优选占所述药物组合物总重量的0%~1.0%,优选0.1~0.5%。
进一步地,所述活性成分占所述药物组合物总重量的1.0%~3.0%;所述稀释剂占所述药物组合物总重量的60%~98%;所述助悬剂占所述药物组合物总重量的0.3~2.0%。所述药物组合物为颗粒剂时,每袋活性成分含量具体重量为0.1~200mg,优选1~100mg,再优选10~100mg,更优选50mg。
进一步地,所述稀释剂占组合物总重量的80%~95%。
优选地,本发明中的药物组合物包括:化合物A1份、甘露醇26、山梨醇12份、聚维酮K30或聚维酮K90 0.2-0.3份。
进一步地,上述药物组合物还包括:波洛沙姆188 0.4份。
进一步地,上述药物组合物还包括:交联聚维酮(CL-M)0.4份。
进一步地,上述药物组合物还包括:草莓香精0.08份。
具体地,前述所述药物组合物为所述活性成分和所述辅料经过包括混合、制粒、干燥、整粒、总混、包装后得到的颗粒剂。
本发明还提出了一种药物组合物在治疗儿童手足口病中的用途。
本发明还提出一种制备如前任一所述的药物组合物的方法,该方法包括:
e)获得粘合剂;
f)将活性成分与填充剂按照混合,加入所述粘合剂进行制粒;
g)动态干燥;
h)整粒,总混。
具体地,所述干燥采用动态干燥。
进一步地,所述药物组合物选自颗粒剂时,该方法包括:
a)将0.4份泊洛沙姆188和0.3份聚维酮K90加入到80%乙醇溶液中混合均匀,作为粘合剂;
b)按重量比1:26:12:0.4份称取2-(2-氨基吡啶-4-基)-5-(5-((5-(2-乙基-2H-四唑-5-基)吡啶-2-基)-氧基)-3,3-二甲基戊基)-1,2,5-噻二唑烷1,1-二氧化物盐酸盐、甘露醇、山梨醇和交联聚维酮(CL-M),混合均匀后加入所述粘合剂,获得软材,过20目筛制粒;
c)50℃干燥;
d)20目筛整粒;将整粒后的颗粒加入香精总混;包装。
本发明对各辅料的种类和用量配比进行了筛选,最终得到具有溶解迅速、稳定性良好的药物组合物,且该药物组合物制备工艺简单,更适合工艺化大生产。
具体实施方式
本发明的活性物质(化合物A:2-(2-氨基吡啶-4-基)-5-(5-((5-(2-乙基-2H-四唑-5-基)吡啶-2-基)-氧基)-3,3-二甲基戊基)-1,2,5-噻二唑烷1,1-二氧化物盐酸盐)可通过进入EV71病毒核衣壳的口袋空腔,锁定病毒,阻止病毒衣壳分解释放病毒RNA,从而抑制病毒的进一步复制。结构式如下:
化学结构式:
分子式:C22H31N9O3S.HCl
分子量:538.07
对于增加难溶性药物的溶解度,现有技术中多采用添加表面活性剂、酸碱调节剂等。本发明在前期试验过程中发现,将化合物A与酸性调节剂(枸橼酸或酒石酸)能够实现将化合物A完全溶解;进一步的研究发现,当酸的加入量为化合物A的0.2~1.0时,能够提高化合物A在热水中的溶解度。然而,前期研究过程中得到的颗粒虽然能解决溶解性问题,但其稳定性不足。因此如何提高本发明活性物质的溶解性能,且同时保证其稳定性是成药技术上的难点。
有鉴于此,本发明提供了一种治疗儿童手足口病的药物组合物其它制剂方式,并通过合适的辅料选择,以解决化合物的溶解性和稳定性问题。
通过以下实施例和试验例进一步详细说明本发明。这些实施例和试验例仅用与说明性目的,而并不用于限制本发明的范围。
为了使得本领域技术人员能够更加清楚地了解本申请的技术方案,以下将结合具体的实施例详细说明本申请的技术方案。
本发明实施例中所用的试验材料均为本领域常规的试验材料,均可通过商业渠道购买得到或者通过现有技术方法制备得到。
实施例1:化合物A1份、甘露醇26、山梨醇12份、羧甲基纤维素钠0.2份、草莓香精0.08份;
实施例2:化合物A1份、甘露醇26、山梨醇12份、羟丙甲纤维素0.2份、草莓香精0.08份;
实施例3:化合物A1份、甘露醇26、山梨醇12份、聚维酮K30 0.2份、草莓香精0.08份;
实施例4:化合物A1份、甘露醇26、山梨醇12份、聚维酮K90 0.2份、草莓香精0.08份;
实施例5:化合物A1份、甘露醇26、山梨醇12份、聚维酮K90 0.2份、波洛沙姆1880.4份、草莓香精0.08份;
实施例6:化合物A1份、甘露醇26、山梨醇12份、聚维酮K90 0.3份、波洛沙姆1880.4份、草莓香精0.08份;
实施例7:化合物A1份、甘露醇26、山梨醇12份、聚维酮K90 0.3份、波洛沙姆1880.4份、交联聚维酮(CL-M)0.4份、草莓香精0.08份;
实施例8:化合物A1份、甘露醇26、山梨醇12份、聚维酮K90 0.2份、羧甲基纤维素钠0.1份、草莓香精0.08份;
实施例9:化合物A1份、甘露醇26、山梨醇12份、聚维酮K90 0.2份、交联聚维酮(CL-M)0.3份、聚山梨酯80 0.4份、草莓香精0.08份;
实施例1-9制备工艺:
①按照处方称取羧甲基纤维素钠/羟丙甲纤维素/聚维酮K30/聚维酮
K90/波洛沙姆188/聚山梨酯80,溶于80%乙醇中制得粘合剂。
②将化合物A与辅料甘露醇/山梨醇/交联聚维酮(CL-M)混合均匀,加粘合剂制软材。
③20目筛制粒。
④50℃干燥,水分控制小于2.0%。
⑤20目筛整粒,80目筛除去细粉。
⑥加入香精后总混。
⑦收集总混后颗粒。
⑧内包装。
对比例1:化合物A1份、蔗糖38份、酒石酸0.2份、草莓香精0.08份;
对比例1的制备工艺:
①称取酒石酸溶于80%乙醇中制得粘合剂。
②将化合物A与其它辅料(除酒石酸和香精外)混合均匀,加粘合剂制软材。
③20目筛制粒。
④50℃干燥,水分控制小于2.0%。
⑤20目筛整粒,80目筛除去细粉。
⑥加入香精后总混。
⑦收集总混后颗粒。
⑧内包装。
对比例2:化合物A1份、蔗糖38份、酒石酸0.6份、草莓香精0.08份;
对比例2的制备工艺同对比例1。
对比例3:化合物A1份、蔗糖38份、酒石酸0.6份、聚山梨酯80 0.4份、草莓香精0.08份;
对比例3的制备工艺同对比例1。
1、溶化性考察
取各实施例和对比例制备的颗粒剂,加入热水中考察溶化性,结果如表1所示。
表1:溶解性考察结果
根据溶化性考察结果,实施例1和2均有絮状沉淀,其它加入聚维酮的实施例或对比例均能呈混悬乳状溶液;其中实施例6和实施例7均呈分散均匀的半透明乳状溶液,且实施例7沉降后通过振摇能快速分散均匀,实施例9加入聚山梨酯80有微臭味,考虑到气味最终优选实施例7。
2、稳定性考察
按照《中国药典》2015年版二部附录XIXC原料药与药物制剂稳定性试验指导原则,对本发明实施例6和7混悬性颗粒剂和对比例2和3可溶性颗粒进行加速稳定性试验和长期稳定性试验考察(以下仅列出实施例7和对比例3)。
加速稳定性试验的条件:对上述施例7和对比例3制得的药物组合物分别按照聚酯/铝/聚乙烯药品包装用复合膜进行包装,在温度40℃、相对湿度75%的条件下放置6个月,在试验期间第0、1、3、6个月各取样1次,按稳定性考察项目检查。“有关物质”的加速试验检查结果如表2所示。结果显示对比例3杂质高于实施例7,这表明对比例处方虽然溶解性满足要求,但稳定性不足。同样地,实施例6的混悬颗粒有关物质变化也远小于对比例2和3。
表2加速稳定性试验有关物质检查结果
长期稳定性试验条件:对上述施例7和对比例3制得的药物组合物分别按照聚酯/铝/聚乙烯药品包装用复合膜进行包装,在温度25℃、相对湿度60%的条件下放置24个月,在试验期间第0、1、3、6、12、18、24个月各取样1次,目前完成12个月稳定性试验,按稳定性考察项目检查,其中,“有关物质”的长期试验检查结果如表3所示。
表3长期稳定性试验有关物质检查结果
根据长期及加速试验稳定性考察结果:实施例7较对比例3稳定性好。本品有关物质可能受温度湿度影响,故本品储藏条件为阴凉处保存。
以上所述仅为本申请的优选实施例而已,并不用于限制本申请,对于本领域的技术人员来说,本申请可以有各种更改和变化。凡在本申请的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (4)
1.一种药物组合物,其特征在于,所述药物组合物为颗粒剂,所述颗粒剂包括:
活性成分,选自2-(2-氨基吡啶-4-基)-5-(5-((5-(2-乙基-2H-四唑-5-基)吡啶-2-基)-氧基)-3,3-二甲基戊基)-1,2,5-噻二唑烷1,1-二氧化物盐酸盐,所述活性成分占所述药物组合物总重量的1.0%~3.0%;
辅料,包括稀释剂、助悬剂和增溶剂;其中,所述助悬剂选自聚维酮K90和/或交联聚维酮CL-M,所述助悬剂占所述药物组合物总重量的0.3~2.0%;
所述稀释剂选自甘露醇和山梨醇,甘露醇和山梨醇的重量比为1:1~3:1;所述稀释剂占所述药物组合物总重量的60%~98%;
所述增溶剂为泊洛沙姆188和/或聚山梨酯80,所述增溶剂占所述药物组合物总重量的0.5%~2.0%。
2.根据权利要求1所述的药物组合物,其特征在于,所述辅料还包括香精,所述香精选自桔子香精、草莓香精、香蕉香精中的一种或几种;所述香精占所述药物组合物总重量的0.1%~0.5%。
3.一种制备如权利要求1所述的药物组合物的方法,其特征在于,该方法包括:
a)获得粘合剂;
b)将活性成分与所述稀释剂、所述助悬剂和所述增溶剂按照比例混合,加入所述粘合剂进行制粒;
c)动态干燥;
d)整粒,总混。
4.一种制备如权利要求3所述的药物组合物的方法,其特征在于,该方法包括:
a)将0.4份泊洛沙姆188和0.3份聚维酮K90加入到80%乙醇溶液中混合均匀,作为粘合剂;
b)按重量比1:26:12:0.4份称取2-(2-氨基吡啶-4-基)-5-(5-((5-(2-乙基-2H-四唑-5-基)吡啶-2-基)-氧基)-3,3-二甲基戊基)-1,2,5-噻二唑烷1,1-二氧化物盐酸盐、甘露醇、山梨醇和交联聚维酮CL-M,混合均匀后加入所述粘合剂,获得软材,过20目筛制粒;
c)50℃干燥;
d)20目筛整粒;将整粒后的颗粒加入香精总混包装。
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010693600.6A CN113940918B (zh) | 2020-07-17 | 2020-07-17 | 一种药物组合物及制备方法 |
US18/005,237 US20230263789A1 (en) | 2020-07-17 | 2021-05-19 | Pharmaceutical composition and preparation method |
JP2023502916A JP7490883B2 (ja) | 2020-07-17 | 2021-05-19 | 医薬組成物及び調製方法 |
EP21841818.4A EP4159200A4 (en) | 2020-07-17 | 2021-05-19 | PHARMACEUTICAL COMPOSITION AND MANUFACTURING METHOD |
PCT/CN2021/094653 WO2022012152A1 (zh) | 2020-07-17 | 2021-05-19 | 一种药物组合物及制备方法 |
KR1020237001294A KR20230024374A (ko) | 2020-07-17 | 2021-05-19 | 약물 조성물 및 제조 방법 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010693600.6A CN113940918B (zh) | 2020-07-17 | 2020-07-17 | 一种药物组合物及制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113940918A CN113940918A (zh) | 2022-01-18 |
CN113940918B true CN113940918B (zh) | 2023-06-02 |
Family
ID=79326680
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010693600.6A Active CN113940918B (zh) | 2020-07-17 | 2020-07-17 | 一种药物组合物及制备方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20230263789A1 (zh) |
EP (1) | EP4159200A4 (zh) |
JP (1) | JP7490883B2 (zh) |
KR (1) | KR20230024374A (zh) |
CN (1) | CN113940918B (zh) |
WO (1) | WO2022012152A1 (zh) |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101278915A (zh) * | 2008-06-04 | 2008-10-08 | 宛六一 | 一种药物组合物颗粒及其制备方法 |
CN101862333B (zh) * | 2009-04-20 | 2013-07-24 | 天津药物研究院 | 左亚叶酸钠稳定的口服制剂及其制备方法 |
CN103893258B (zh) * | 2013-12-05 | 2017-09-29 | 人福医药集团股份公司 | 含有广金钱草总黄酮的口服固体制剂及其应用 |
CN103893247A (zh) * | 2013-12-05 | 2014-07-02 | 人福医药集团股份公司 | 药物组合物及其制备方法和用途 |
CN106661009B (zh) * | 2014-04-28 | 2019-11-26 | 江苏康缘药业股份有限公司 | 抗肠病毒71噻二唑烷衍生物 |
WO2015165340A1 (zh) * | 2014-04-28 | 2015-11-05 | 南京明德新药研发股份有限公司 | 抗肠病毒71噻二唑烷衍生物 |
JP6427695B2 (ja) | 2015-10-26 | 2018-11-21 | ジァンスー カニオン パーマスーティカル カンパニー リミテッド | 1,2,5−チアジアゾリジン−1,1−ジオキシドの塩形態、結晶形態及びその調製方法と中間体 |
CN112236146A (zh) * | 2018-04-24 | 2021-01-15 | 盐野义制药株式会社 | 稳定性优良的固体制剂 |
-
2020
- 2020-07-17 CN CN202010693600.6A patent/CN113940918B/zh active Active
-
2021
- 2021-05-19 JP JP2023502916A patent/JP7490883B2/ja active Active
- 2021-05-19 KR KR1020237001294A patent/KR20230024374A/ko unknown
- 2021-05-19 WO PCT/CN2021/094653 patent/WO2022012152A1/zh unknown
- 2021-05-19 US US18/005,237 patent/US20230263789A1/en active Pending
- 2021-05-19 EP EP21841818.4A patent/EP4159200A4/en active Pending
Also Published As
Publication number | Publication date |
---|---|
US20230263789A1 (en) | 2023-08-24 |
CN113940918A (zh) | 2022-01-18 |
JP2023533369A (ja) | 2023-08-02 |
JP7490883B2 (ja) | 2024-05-27 |
WO2022012152A1 (zh) | 2022-01-20 |
KR20230024374A (ko) | 2023-02-20 |
EP4159200A4 (en) | 2024-07-17 |
EP4159200A1 (en) | 2023-04-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5222841B2 (ja) | リン酸オセルタミビル顆粒剤及びその調製方法 | |
IE921568A1 (en) | Low solubility drug-coated bead compositions | |
JP5103173B2 (ja) | ジヒドロピリジン系化合物の分解を防止する方法 | |
PT1928459E (pt) | Preparação de libertação retardada na forma de comprimidos contendo cinarizina e dimenidrinato contra a vertigem | |
JP6641062B2 (ja) | テコビリマットの経口用医薬組成物及びその調製法 | |
JP6639024B2 (ja) | 化学的な安定性を改善した、非晶質体ソリフェナシン含有製剤 | |
CN109157517A (zh) | 一种利伐沙班颗粒剂及制备方法 | |
CN113940918B (zh) | 一种药物组合物及制备方法 | |
TW201130522A (en) | Dissolution-stable pharmaceutical agent | |
Chaudhary et al. | A technical approach of solubility enhancement of poorly soluble drugs: Liquisolid technique | |
JP7428356B2 (ja) | 高いバイオアベイラビリティを有するソラフェニブの医薬組成物、ソラフェニブ経口固形製剤、及びその使用 | |
IE20100799A1 (en) | Pharmaceutical composites of poorly water soluble drugs and polymers | |
EP3030224B1 (en) | Inhalable particles comprising tiotropium and indacaterol | |
US20070237828A1 (en) | Ziprasidone Dosage Form | |
RU2616500C2 (ru) | Композиция пазопаниба | |
CN108014079A (zh) | 一种氨己烯酸咀嚼片及其制备方法 | |
WO2022115055A1 (en) | Immediate release composition of favipiravir | |
CN107714653B (zh) | 一种稳定的可溶性甲氨蝶呤颗粒剂 | |
CN111714444B (zh) | 一种醋酸乌利司他口服固体制剂及其制备方法 | |
Ivone | Development of a Fast Dissolving Anti-HIV Formulation for Pediatrics | |
CN108938578A (zh) | 阿立哌唑分散片及其制备方法 | |
CN117653648A (zh) | 一种包含氘代核苷化合物的药物组合物及其在制备抗病毒药物中的应用 | |
BR102012027409B1 (pt) | composição farmacêutica e seu método de preparo | |
Verma et al. | Available Online Through Review Article www. ijptonline. com | |
CN115551484A (zh) | 一种法匹拉韦组合物及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40066776 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |