CN114085237A - 左氧氟沙星新化合物及其脂质体纳米药物 - Google Patents
左氧氟沙星新化合物及其脂质体纳米药物 Download PDFInfo
- Publication number
- CN114085237A CN114085237A CN202010848185.7A CN202010848185A CN114085237A CN 114085237 A CN114085237 A CN 114085237A CN 202010848185 A CN202010848185 A CN 202010848185A CN 114085237 A CN114085237 A CN 114085237A
- Authority
- CN
- China
- Prior art keywords
- temperature
- minutes
- freeze
- new compound
- hours
- 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.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 72
- 239000002502 liposome Substances 0.000 title claims abstract description 36
- 229960003376 levofloxacin Drugs 0.000 title claims abstract description 26
- 229940079593 drug Drugs 0.000 title claims description 37
- -1 levofloxacin compound Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims abstract description 20
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960000711 alprostadil Drugs 0.000 claims abstract description 15
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 13
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 241001465754 Metazoa Species 0.000 claims abstract description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 7
- 229930195725 Mannitol Natural products 0.000 claims abstract description 7
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 7
- 239000000594 mannitol Substances 0.000 claims abstract description 7
- 235000010355 mannitol Nutrition 0.000 claims abstract description 7
- 231100000419 toxicity Toxicity 0.000 claims abstract description 7
- 230000001988 toxicity Effects 0.000 claims abstract description 7
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 5
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims abstract description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims abstract description 3
- 231100000518 lethal Toxicity 0.000 claims abstract description 3
- 230000001665 lethal effect Effects 0.000 claims abstract description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims abstract description 3
- 230000001954 sterilising effect Effects 0.000 claims description 36
- 239000007788 liquid Substances 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 229930182555 Penicillin Natural products 0.000 claims description 28
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 28
- 229940049954 penicillin Drugs 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 27
- 238000004108 freeze drying Methods 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000011049 filling Methods 0.000 claims description 22
- 238000005406 washing Methods 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 20
- 238000002347 injection Methods 0.000 claims description 18
- 239000007924 injection Substances 0.000 claims description 18
- 238000004659 sterilization and disinfection Methods 0.000 claims description 18
- 239000000463 material Substances 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000004140 cleaning Methods 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 239000004033 plastic Substances 0.000 claims description 12
- 239000013067 intermediate product Substances 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- 239000008121 dextrose Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000008055 phosphate buffer solution Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 239000008213 purified water Substances 0.000 claims description 8
- 229910001220 stainless steel Inorganic materials 0.000 claims description 8
- 239000010935 stainless steel Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000012546 transfer Methods 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 7
- 239000002131 composite material Substances 0.000 claims description 6
- 239000006185 dispersion Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 5
- 241000894006 Bacteria Species 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 230000002924 anti-infective effect Effects 0.000 claims description 4
- 238000007796 conventional method Methods 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 238000005096 rolling process Methods 0.000 claims description 4
- 238000005070 sampling Methods 0.000 claims description 4
- 238000007789 sealing Methods 0.000 claims description 4
- 238000000859 sublimation Methods 0.000 claims description 4
- 230000008022 sublimation Effects 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 239000008215 water for injection Substances 0.000 claims description 4
- 150000001263 acyl chlorides Chemical group 0.000 claims description 3
- 150000003904 phospholipids Chemical class 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 241000792859 Enema Species 0.000 claims description 2
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- AHANXAKGNAKFSK-PDBXOOCHSA-N all-cis-icosa-11,14,17-trienoic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCCCC(O)=O AHANXAKGNAKFSK-PDBXOOCHSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 229960001275 dimeticone Drugs 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims description 2
- 210000002969 egg yolk Anatomy 0.000 claims description 2
- PRHHYVQTPBEDFE-UHFFFAOYSA-N eicosatrienoic acid Natural products CCCCCC=CCC=CCCCCC=CCCCC(O)=O PRHHYVQTPBEDFE-UHFFFAOYSA-N 0.000 claims description 2
- 238000005485 electric heating Methods 0.000 claims description 2
- 239000007920 enema Substances 0.000 claims description 2
- 229940095399 enema Drugs 0.000 claims description 2
- 229910001447 ferric ion Inorganic materials 0.000 claims description 2
- 238000005429 filling process Methods 0.000 claims description 2
- 238000007710 freezing Methods 0.000 claims description 2
- 230000008014 freezing Effects 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- CXQXSVUQTKDNFP-UHFFFAOYSA-N octamethyltrisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 238000005192 partition Methods 0.000 claims description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000003825 pressing Methods 0.000 claims description 2
- 239000002510 pyrogen Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 238000005475 siliconizing Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 238000005507 spraying Methods 0.000 claims description 2
- 238000003892 spreading Methods 0.000 claims description 2
- 238000005092 sublimation method Methods 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 230000000172 allergic effect Effects 0.000 claims 1
- 208000010668 atopic eczema Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 206010002198 Anaphylactic reaction Diseases 0.000 abstract description 5
- 208000003455 anaphylaxis Diseases 0.000 abstract description 5
- 230000036783 anaphylactic response Effects 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- CAOOISJXWZMLBN-PPHPATTJSA-N htn0d03vrz Chemical compound Cl.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 CAOOISJXWZMLBN-PPHPATTJSA-N 0.000 abstract description 2
- 229940119744 dextran 40 Drugs 0.000 abstract 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 210000000056 organ Anatomy 0.000 abstract 1
- 239000008363 phosphate buffer Substances 0.000 abstract 1
- 208000015181 infectious disease Diseases 0.000 description 16
- 244000000010 microbial pathogen Species 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 206010035664 Pneumonia Diseases 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000002458 infectious effect Effects 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 206010006451 bronchitis Diseases 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 206010005940 Bone and joint infections Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 2
- 229960000282 metronidazole Drugs 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- PUQSUZTXKPLAPR-KSSYENDESA-N 4-(beta-D-Glucopyranosyloxy) benzyl alcohol Natural products O([C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1)c1ccc(CO)cc1 PUQSUZTXKPLAPR-KSSYENDESA-N 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 206010048946 Anal abscess Diseases 0.000 description 1
- 208000004429 Bacillary Dysentery Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010051548 Burn infection Diseases 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 241000193163 Clostridioides difficile Species 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- PUQSUZTXKPLAPR-UJPOAAIJSA-N Gastrodin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(CO)C=C1 PUQSUZTXKPLAPR-UJPOAAIJSA-N 0.000 description 1
- 206010017914 Gastroenteritis salmonella Diseases 0.000 description 1
- 206010017915 Gastroenteritis shigella Diseases 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010021531 Impetigo Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022678 Intestinal infections Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 206010033971 Paratyphoid fever Diseases 0.000 description 1
- 206010034686 Peritonsillar abscess Diseases 0.000 description 1
- 206010034960 Photophobia Diseases 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 206010036410 Postoperative wound infection Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010049677 Salpingo-oophoritis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010042343 Subcutaneous abscess Diseases 0.000 description 1
- 208000031650 Surgical Wound Infection Diseases 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043248 Tendon rupture Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000008344 egg yolk phospholipid Substances 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 229930193974 gastrodin Natural products 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- PUQSUZTXKPLAPR-NZEXEKPDSA-N helicidol Natural products O([C@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](CO)O1)c1ccc(CO)cc1 PUQSUZTXKPLAPR-NZEXEKPDSA-N 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000013469 light sensitivity Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 206010025226 lymphangitis Diseases 0.000 description 1
- 208000004396 mastitis Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 231100000668 minimum lethal dose Toxicity 0.000 description 1
- 208000017445 musculoskeletal system disease Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 238000000275 quality assurance Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000000697 sensory organ Anatomy 0.000 description 1
- 201000005113 shigellosis Diseases 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- 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
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
Abstract
发明一种左氧氟沙星分子与前列地尔分子酸酐的新化合物M.并制成其纳米脂质体药物。原料重量比:高纯度新化合物M 600‑800,亚硫酸氢钠16‑20,甘露醇与低分子右旋糖酐‑40重量比1∶1.5混合物2240‑2800,0.015M磷酸盐缓冲液pH值4.0‑6.5 16000‑20000,蛋黄卵磷脂3200‑4000,胆固醇640‑800;并公开了制备方法;经动物试验与现有盐酸左氧氟沙星药物比较:剂量小,疗效高,安全性好,消除致死过敏毒性,对器官毒性非常小。
Description
技术领域
本发明涉及左氧氟沙星新化合物及其脂质体纳米药物创新领域。
背景技术
现有市场上左氧氟沙星药物,适用于敏感细菌引起的下列中、重度感染:
1.呼吸系统感染:急性支气管炎、慢性支气管炎急性发作、弥漫性支气管炎、支气管扩张合并感染、肺炎、扁桃体炎(扁桃体周围脓肿)。
2.泌尿系统感染:肾盂肾炎、复杂性尿路感染等。
3.生殖系统感染:急性前列腺炎、急性副睾炎、宫腔感染、子宫附件炎、盆腔炎(疑有厌氧菌感染时可合用甲硝唑)。
4.皮肤软组织感染:传染性脓疱病、蜂窝组织炎、淋巴管(结)炎、皮下脓肿、肛脓肿等。
5.肠道感染:细菌性痢疾、感染性肠炎、沙门菌属肠炎、伤寒及副伤寒。
6.败血症、粒细胞减少及免疫功能低下患者的各种感染。
7.其它感染:乳腺炎、外伤、烧伤及手术后伤口感染、腹腔感染(必要时合用甲硝唑)、胆囊炎、胆管炎、骨与关节感染以及五官科感染等。
但是,现有市场似乎左氧氟沙星药物疗效存在耐药反应,安全性问题很大问题多:
肌腱炎和肌腱断裂、重症肌无力恶化、超敏反应、其他严重和有时致命的过敏反应、肝毒性、中枢神经系统效应、难辨梭菌相关性腹泻、周围神经病、QT间期延长、儿科患者中的肌肉骨骼疾病、血糖紊乱、光敏感性/光毒性和耐药细菌产生。左氧氟沙星快速静脉滴注或者推注可能导致低血压。
发明内容
一.发明内容
1.发明左氧氟沙星分子与前列地尔酰氯分子缩合,合成为左氧氟沙星与前列地尔形成酸酐的新化合物M。M分子结构见说明书附图1.
用经典合成反应原理,实现新化合物M制造,进一步制造其纳米脂质体药物,本发明的这个药物保持并增强左氧氟沙星药物疗效,减少药物剂量,消除左氧氟沙星的致命过敏反应、光过敏反应毒性;消除对肝、神经系统和骨骼及血液系统毒性;消除用药过程中低血压不良反应。
2.新化合物M把左氧氟沙星羧基变为酸酐,消除左氧氟沙星羧基影响对人体细胞释药不良反应和毒性,本发明用鸡蛋卵磷脂做成纳米脂质体药物,靶向病原微生物释药,这又大大减少左氧氟沙星药物剂量。
3.把含有左氧氟沙星分子的新化合物M纳米脂质体药物进入人体内,水解出的前列地尔可以提高人体免疫力,提高人体抗体与病原微生物形成免疫复合物能力,前列地尔又有清除人体血液中免疫复合物作用,使病原微生物进入人体产生不了繁殖和达不到产生炎症浓度。
4.通过动物实验计算,新化合物M纳米药物可以把左氧氟沙星现在每次500毫克用药剂量减少到新化合物M纳米药物10-50毫克剂量等效,致死性过敏反应和光过敏毒性及其它左氧氟沙星原来所有对人体毒性,都从根本上消除。
5.创新了抗感染药物脂质体纳米药物从研制到上市的艰难过程和要素:
抗感染药物的脂质体纳米药物要素:
5.1.选择的药物必须对抗病原微生物有效;
5.2.比有效更重要的是安全,无毒,无明显副作用,在体内不积累并且身体无依赖性;
5.3对人体细胞没有杀死、毒死,对人体病细胞是修复转化为正常细胞,对病原微生物因为细胞壁磷脂相同而融合病原微生物细胞再释药,把病原微生物细胞毒死;
5.4.药物的载体,脂质体能被动靶向病原微生物细胞,脂质体材料有靶向性带动药物和病原微生物细胞融合,专门向病原微生物细胞释药;
不要认为做到以上四点就了不起了,要做得更优秀的还在下面:
5.5保证药物是在脂质体载体包裹条件下从毛细血管筛孔能中出来并保证是脂质体药物和病原微生物细胞融合;
5.6这就要求脂质体药物在保存、运输、储存、使用过程中和在从毛细血管筛孔中出去到和病原微生物细胞融合95%以上是保持脂质体药物,有的脂质体药物粒子粒径大,在毛细血管中出不来,等到脂质体在血管内分解,还是自然药物分子游离到血管外,对病原微生物细胞和人体细胞都释药,制造的是靶向药物,却不是纳米药物靶向病原微生物胞释药。避免这毛病,要求质量标准要求脂质体包裹率99.5%以上,总的泄漏率在3%以下;
5.7脂质体包裹率99.5%以上,总的泄漏率在3%以下,还不能保证是脂质体释药,更重要的是要求脂质体药物是纳米粒径的药物,而且是保证纳米药物的粒径99.5%是在80至150 纳米范围,保证99.5%脂质体药物可以在毛细血管筛孔中出来向病原微生物细胞融合,我在激光检测粒径设备制造单位检测我的样品时,检测员讲当时国内只有我的纳米药物样品可以达到这范围;
5.8更重要的是要建立保证以上条件都能保证的配方、工艺、质量控制、检验方法的质量保证体系和制订质量标准。这些都要有授权的发明专利保护;还要注册国家新药,有新药批准文号。
二.创新化合物M制备:
1.反应方程式见说明书附图1。
附图说明:
图1是制备新化合物M反应原理图。
反应式1:前列地尔分子中羧基生成酰氯基。
反应式2:前列地尔酰氯基与左氧氟沙星羧基反应生成新化合物M。
2.经物理性质测定和新化合物M分子结构分析鉴定,确定为左氧氟沙星和前列地尔分子两者形成的酸酐分子结构。
3.制备方法:
将前列地尔,即二十碳三烯酸350克溶于3000ml至10000ml四氢呋喃中,冰浴,在搅拌的条件下,缓慢滴加氯化亚飒240克,继续搅拌1个小时后。加热回流1个小时后,冷却至常温后滴加380克左氧氟沙星溶于4000ml-10000ml的四氢呋喃溶液,完全滴加完后继续搅拌5个小时。加入560克的碳酸钾,搅拌半个小时后,过滤。滤液旋转蒸干后在戊烷和四氢味喃的复合溶剂中重结晶得到所需产物M,即前列地尔羧基生成酰氯基后再与左氧氟沙星羧基缩合形成的酸酐新化合物M。戊烷∶四氢呋喃的体积比是3∶2。
三.创新化合物M纳米脂质体药物制备
(一)原料重量比
(二)操作过程及工艺条件:
(1)西林瓶理瓶、清洗、灭菌
将5ml西林瓶由传递柜经紫外灯灭菌后运入理瓶室,在理瓶室进行理瓶,把理好的西林瓶放到洗瓶室的固定位置;把GMSU-400W隧道式灭菌烘箱后面出现的排风口挡板开至一半,启动电加热按钮,预热区、高温区、冷却区温度开始逐渐上升;当烘箱内预热区温度达到 25CTC、高温区温度达到预置温度35CTC、冷却区温度达到220℃,洗瓶机即可投入生产。PCX-IV型洗瓶机用热纯化水,XCQ-VI型洗瓶机用注射用水,启动PLC程控器,完成粗洗、精洗的全部过程,取精洗后的西林瓶,检测西林瓶是否洗净、有无可见异物;烘箱在运行过程中,温度保持在350±5℃;西林瓶洗净后至灭菌放置时间不超过4小时,西林瓶灭菌后至使用放置时间不超过16小时;
(2)胶塞清洗、灭菌
将装5ml胶塞小盒打开,将盒内的合格证取出,并剔除不合格胶塞之后,将胶塞装入料桶中;纯化水、注射用水压力0.1-0.2MPa,真空压力-0.06MPa以下,压缩空气0.4-0.6MPa,纯蒸汽0.2MPa以上。真空进料,待所有胶塞被吸入后,盖上“加料、取样口盖”;纯化水喷淋粗洗10分钟,超声波漂洗15分钟,注射用水精洗25分钟,取样进行可见异物检测,如检测不合格,则点动“重新精洗”按钮,继续自动精洗全过程;加入二甲硅油,二甲硅油加入量为10ml,温度上升至加热温度85℃后,硅化10分钟,冲洗时间5分钟;当灭菌温度逐渐上升到设置的123℃后,灭菌开始计时,灭菌时间30分钟;真空干燥8分钟,当烘干温度逐渐上升至105℃后,热风干燥10分钟,再真空干燥5分钟,当逐步降温冷却至60℃后,出料;胶塞灭菌后至使用放置时间不超过16小时;
(3)铝塑盖清洗、轧盖
将5ml铝塑盖拿到铝盖清洗间,先剔除不合格的铝盖,将合格铝塑盖放入清洗槽中,用热纯化水进行清洗;将已清洗的铝塑盖平铺于盘中放入JRSH型净化热风循环烘箱,110℃干燥灭菌3小时后放置备用,其灭菌后至使用放置时间不超过16小时;
(4)配液
活性炭和右旋糖酢40与甘露醇混合物的处理:
将针剂用活性炭放入1000ml烧杯中,在烘箱中于180℃温度下保温2.5小时除菌、除热原、除水,降温至室温并密封备用;
按配方量称取右旋糖酢40与甘露醇混合物重量,加入磷酸盐缓冲液,搅拌溶解,按右旋糖酢40重量加入10%(w%w)活性炭,不需搅拌,于121℃灭菌15分钟,下步配料用需用的磷酸盐缓冲液或注射用水也一同灭菌;冷却至60±5℃,趁热用0.15μm滤膜的滤芯过滤,滤器、滤筒、管件、滤芯应在滤前放在注射用水中灭菌后才可使用;过滤后,滤液密封,冷却20℃±2℃,制得辅料液;
(5)将灭菌和滤过后的20℃±2℃辅料液放入316L不锈钢料桶中,加入灭菌磷酸盐缓冲液,调至辅料液重量等于配方中磷酸盐缓冲液、右旋糖酢40与甘露醇混合物混合物重量之和(调药液体积受温度波动误差较大,调药液重量只要车间在地球上地址不变,温度不同重量不变,批与批间含量均匀度好),搅拌均匀,先用8%的氢氧化钠溶液调溶液pH值至6.5-7.0,用0.15μm膜滤芯过滤,除去辅料、活性炭带入辅料液中的金属离子沉淀物、不溶性粒子,尤其是三价铁离子沉淀物;滤过后的辅料液再用8%盐酸溶液调pH值4.5-5.5,在搅拌下加入亚硫酸氢钠,搅拌溶解完全,待下步制备用;
(6)将蛋黄卵磷脂溶解于无水乙醇中,蛋黄卵磷脂∶无水乙醇比为1∶100(W/V);在700-1000转/分搅拌转速中,将蛋黄磷脂乙醇液在30分钟内滴加在(5)步制得的辅料液中,用40Hz频率(在常温下)超声波超声至空白脂质体粒子粒径经检测无大于0.15微米空白脂质体粒子止,制得空白脂质体分散液;称量配方用量新化合物M原料药,用1∶80(w/v)药用注射剂级无水乙醇将其溶解后,30分钟内搅拌下滴加加入至上述空白脂质体分散液中,搅拌均匀,溶解完全;将胆固醇溶于无水乙醇中,胆固醇重量∶无水乙醇体积为1∶80,将胆固醇乙醇溶液在700-1000转/分搅拌转速中,30分钟内滴加前列地尔脂质体分散液中,滴加完后,再常温搅拌孵化40分钟;到将COMPACT-200型过滤器串连安装好,用0.15um滤芯进行除菌过滤,滤过完毕,送样检测新化合物M中间产品含量,加入无水乙醇后至检测完毕的配液的时间不能超过2.5小时;
(7)灌装、半加塞
生产前将硅胶灌液管、灌液针用配制好的2%NaOH溶液浸泡30分钟后用注射用水冲洗干净,然后用灭菌袋包好,放入湿热灭菌柜中于121℃灭菌30分钟;按药剂学允许的新化合物剂量,确定灌装量,正式灌装前调好灌装体积(称重法),灌装过程中每10分钟测定一次装量差异;灌装好药液的西林瓶经过机器自动半加塞后进入316L不锈钢托盘内;将316L不锈钢托盘沿百级通道送入冻干机组的冻干箱内;整个灌装时间不能超过4小时;
(8)冻干
灌装好药液的西林瓶都进入冻干箱内,开冷冻干燥机冷冻,当制品温度达到预冻温度 -35℃以下,保温时间达到2小时,对捕水器进行预冷,待到“捕水器”温度达到-50℃,维持 30分钟,对系统抽真空,当冷冻干燥箱内真空度达到10Pa以下时,开始加热升华,升华过程中,每1小时隔板升温2℃,升温至36℃,并保持系统真空度不高于20Pa;当制品温度达到 36℃且冷冻干燥箱内达到极限真空(小于2.0Pa)6小时后,水分残留小于1%,升华结束;真空下压塞,使西林瓶内药物及辅料在真空状态下,不被氧气,不被水分、细菌破坏,冻干周期20-26小时;
(9)轧盖
打开冷冻干燥箱门(此时冻干箱内压与外压一致),从冷冻干燥箱中取出已压塞的注射用新化合物M中间产品,放入传递柜中,关闭传递柜门,打开轧盖室内的传递柜门,取出注射用新化合物M中间产品。把铝塑盖加入料斗里,将新化合物M冻干中间产品装满送瓶盘,铝塑盖充满轨道,开始轧盖;轧盖过程中每5分钟检查一次轧盖是否轧紧,制得新化合物M脂质体组合药物的冻干针剂;
(10)取(6)步制得的药液分装到316L不锈钢托盘中,放入冷冻干燥箱中冷冻干燥,达水分残留小于1%后出箱,将冷冻干燥固体无菌粉碎至60-80目,再按常法,配加其它辅料或溶液,按药剂学允许的新化合物M脂质体组合药物的剂量,按常法操作可制新化合物M脂质体组合药物的口服制剂,或喷雾剂,或拴剂、或灌肠剂。
具体实施方式
实施例1
原料重量比
操作过程及工艺条件:同上所述。
实施例2
原料重量比
操作过程及工艺条件:同上所述。
实施例3
原料重量比
操作过程及工艺条件:同上所述。
实施例4
原料重量比
操作过程及工艺条件:同上所述。
实施例5
原料重量比
操作过程及工艺条件:同上所述。
四.药效学验证试验
抗感染药物药效学试验:
(1)动物选择:选择由实验动物中心制备的感染动物实验模型的小鼠,体重18-22g,雌雄各半,随机分组,每组动物50只。
(2)感染菌种:金黄色葡萄球菌致肺炎的模型小鼠、肺炎链球菌致肺炎的模型小鼠二个组。
(3)感染菌量:由实验动物中心测出所试菌株的100%最小致死量(100%MLD),作为感染菌量。
(4)感染途径:菌原液用5%胃膜素稀释至所需浓度(实验动物中心确定),经尾静脉注射。
(5)试验方法:将小鼠分:A.金黄色葡萄球菌致肺炎的模型小鼠组、B.肺炎链球菌致肺炎的模型小鼠组二个组。进行不给药对照、现有技术制备的注射用盐酸左氧氟沙星对发明药物对照。每组模型动物50只。感染后立即静注给药或口服,每隔6小时再给药一次。观察动物物反应,连续7天,记录小鼠死亡数。
所用药物及剂量、效果见试验结果表:
通过上述药效学试验结果可见,本发明的脂质体组合药物药物在安全性、稳定性、疗效都全面优于现有技术制备的现售对应药物。
Claims (4)
2.以权利要求1所书的一种新化合物M,其特征是,制备方法如下:
将前列地尔,即二十碳三烯酸350克溶于3000ml至10000ml四氢呋喃中,冰浴,在搅拌的条件下,缓慢滴加氯化亚飒240克,继续搅拌1个小时后。加热回流1个小时后,冷却至常温后滴加380克左氧氟沙星溶于4000ml-10000ml的四氢呋喃溶液,完全滴加完后继续搅拌5个小时。加入560克的碳酸钾,搅拌半个小时后,过滤。滤液旋转蒸干后在戊烷和四氢味喃的复合溶剂中重结晶得到所需产物M,即前列地尔羧基生成酰氯基后再与左氧氟沙星羧基缩合形成的酸酐新化合物M。戊烷∶四氢呋喃的体积比是3∶2。
3.依权利要求1所述的新化合物M,其特征是,其纳米脂质体药物,其制备方法如下:
(一)原料重量比
(二)操作过程及工艺条件:
(1)西林瓶理瓶、清洗、灭菌
将5ml西林瓶由传递柜经紫外灯灭菌后运入理瓶室,在理瓶室进行理瓶,把理好的西林瓶放到洗瓶室的固定位置;把GMSU-400W隧道式灭菌烘箱后面出现的排风口挡板开至一半,启动电加热按钮,预热区、高温区、冷却区温度开始逐渐上升;当烘箱内预热区温度达到25CTC、高温区温度达到预置温度35CTC、冷却区温度达到220℃,洗瓶机即可投入生产。PCX-IV型洗瓶机用热纯化水,XCQ-VI型洗瓶机用注射用水,启动PLC程控器,完成粗洗、精洗的全部过程,取精洗后的西林瓶,检测西林瓶是否洗净、有无可见异物;烘箱在运行过程中,温度保持在350±5℃;西林瓶洗净后至灭菌放置时间不超过4小时,西林瓶灭菌后至使用放置时间不超过16小时;
(2)胶塞清洗、灭菌
将装5ml胶塞小盒打开,将盒内的合格证取出,并剔除不合格胶塞之后,将胶塞装入料桶中;纯化水、注射用水压力0.1-0.2MPa,真空压力-0.06MPa以下,压缩空气0.4-0.6MPa,纯蒸汽0.2MPa以上。真空进料,待所有胶塞被吸入后,盖上“加料、取样口盖”;纯化水喷淋粗洗10分钟,超声波漂洗15分钟,注射用水精洗25分钟,取样进行可见异物检测,如检测不合格,则点动“重新精洗”按钮,继续自动精洗全过程;加入二甲硅油,二甲硅油加入量为10ml,温度上升至加热温度85℃后,硅化10分钟,冲洗时间5分钟;当灭菌温度逐渐上升到设置的123℃后,灭菌开始计时,灭菌时间30分钟;真空干燥8分钟,当烘干温度逐渐上升至105℃后,热风干燥10分钟,再真空干燥5分钟,当逐步降温冷却至60℃后,出料;胶塞灭菌后至使用放置时间不超过16小时;
(3)铝塑盖清洗、轧盖
将5ml铝塑盖拿到铝盖清洗间,先剔除不合格的铝盖,将合格铝塑盖放入清洗槽中,用热纯化水进行清洗;将已清洗的铝塑盖平铺于盘中放入JRSH型净化热风循环烘箱,110℃干燥灭菌3小时后放置备用,其灭菌后至使用放置时间不超过16小时;
(4)配液
活性炭和右旋糖酢40与甘露醇混合物的处理:
将针剂用活性炭放入1000ml烧杯中,在烘箱中于180℃温度下保温2.5小时除菌、除热原、除水,降温至室温并密封备用;
按配方量称取右旋糖酢40与甘露醇混合物重量,加入磷酸盐缓冲液,搅拌溶解,按右旋糖酢40重量加入10%(w%w)活性炭,不需搅拌,于121℃灭菌15分钟,下步配料用需用的磷酸盐缓冲液或注射用水也一同灭菌;冷却至60±5℃,趁热用0.15μm滤膜的滤芯过滤,滤器、滤筒、管件、滤芯应在滤前放在注射用水中灭菌后才可使用;过滤后,滤液密封,冷却20℃±2℃,制得辅料液;
(5)将灭菌和滤过后的20℃±2℃辅料液放入316L不锈钢料桶中,加入灭菌磷酸盐缓冲液,调至辅料液重量等于配方中磷酸盐缓冲液、右旋糖酢40与甘露醇混合物混合物重量之和(调药液体积受温度波动误差较大,调药液重量只要车间在地球上地址不变,温度不同重量不变,批与批间含量均匀度好),搅拌均匀,先用8%的氢氧化钠溶液调溶液pH值至6.5-7.0,用0.15μm膜滤芯过滤,除去辅料、活性炭带入辅料液中的金属离子沉淀物、不溶性粒子,尤其是三价铁离子沉淀物;滤过后的辅料液再用8%盐酸溶液调pH值4.5-5.5,在搅拌下加入亚硫酸氢钠,搅拌溶解完全,待下步制备用;
(6)将蛋黄卵磷脂溶解于无水乙醇中,蛋黄卵磷脂∶无水乙醇比为1∶100(W/V);在700-1000转/分搅拌转速中,将蛋黄磷脂乙醇液在30分钟内滴加在(5)步制得的辅料液中,用40Hz频率(在常温下)超声波超声至空白脂质体粒子粒径经检测无大于0.15微米空白脂质体粒子止,制得空白脂质体分散液;称量配方用量新化合物M原料药,用1∶80(w/v)药用注射剂级无水乙醇将其溶解后,30分钟内搅拌下滴加加入至上述空白脂质体分散液中,搅拌均匀,溶解完全;将胆固醇溶于无水乙醇中,胆固醇重量∶无水乙醇体积为1∶80,将胆固醇乙醇溶液在700-1000转/分搅拌转速中,30分钟内滴加前列地尔脂质体分散液中,滴加完后,再常温搅拌孵化40分钟;到将COMPACT-200型过滤器串连安装好,用0.15um滤芯进行除菌过滤,滤过完毕,送样检测新化合物M中间产品含量,加入无水乙醇后至检测完毕的配液的时间不能超过2.5小时;
(7)灌装、半加塞
生产前将硅胶灌液管、灌液针用配制好的2% NaOH溶液浸泡30分钟后用注射用水冲洗干净,然后用灭菌袋包好,放入湿热灭菌柜中于121℃灭菌30分钟;按药剂学允许的新化合物剂量,确定灌装量,正式灌装前调好灌装体积(称重法),灌装过程中每10分钟测定一次装量差异;灌装好药液的西林瓶经过机器自动半加塞后进入316L不锈钢托盘内;将316L不锈钢托盘沿百级通道送入冻干机组的冻干箱内;整个灌装时间不能超过4小时;
(8)冻干
灌装好药液的西林瓶都进入冻干箱内,开冷冻干燥机冷冻,当制品温度达到预冻温度-35℃以下,保温时间达到2小时,对捕水器进行预冷,待到“捕水器”温度达到-50℃,维持30分钟,对系统抽真空,当冷冻干燥箱内真空度达到10Pa以下时,开始加热升华,升华过程中,每1小时隔板升温2℃,升温至36℃,并保持系统真空度不高于20Pa;当制品温度达到36℃且冷冻干燥箱内达到极限真空(小于2.0Pa)6小时后,水分残留小于1%,升华结束;真空下压塞,使西林瓶内药物及辅料在真空状态下,不被氧气,不被水分、细菌破坏,冻干周期20-26小时;
(9)轧盖
打开冷冻干燥箱门(此时冻干箱内压与外压一致),从冷冻干燥箱中取出已压塞的注射用新化合物M中间产品,放入传递柜中,关闭传递柜门,打开轧盖室内的传递柜门,取出注射用新化合物M中间产品。把铝塑盖加入料斗里,将新化合物M冻干中间产品装满送瓶盘,铝塑盖充满轨道,开始轧盖;轧盖过程中每5分钟检查一次轧盖是否轧紧,制得新化合物M脂质体组合药物的冻干针剂;
(10)取(6)步制得的药液分装到316L不锈钢托盘中,放入冷冻干燥箱中冷冻干燥,达水分残留小于1%后出箱,将冷冻干燥固体无菌粉碎至60-80目,再按常法,配加其它辅料或溶液,按药剂学允许的新化合物M脂质体组合药物的剂量,按常法操作可制新化合物M脂质体组合药物的口服制剂,或喷雾剂,或拴剂、或灌肠剂。
4.依权利要求1所述的新化合物M,其特征是,用于抗感染动物试验结果是,比左氧氟沙星剂量小,疗效高,消除左氧氟沙星致死过敏毒性。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010848185.7A CN114085237A (zh) | 2020-08-24 | 2020-08-24 | 左氧氟沙星新化合物及其脂质体纳米药物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010848185.7A CN114085237A (zh) | 2020-08-24 | 2020-08-24 | 左氧氟沙星新化合物及其脂质体纳米药物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114085237A true CN114085237A (zh) | 2022-02-25 |
Family
ID=80295289
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010848185.7A Pending CN114085237A (zh) | 2020-08-24 | 2020-08-24 | 左氧氟沙星新化合物及其脂质体纳米药物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114085237A (zh) |
-
2020
- 2020-08-24 CN CN202010848185.7A patent/CN114085237A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPH06298768A (ja) | ヘリコバクター・ピロリに起因する胃性消化不良を治療するためのリファキシミンを含有する医薬製剤 | |
CN110545820B (zh) | 可利霉素及其药学上可接受的盐在制备治疗和/或预防肿瘤药物方面的应用 | |
EA022324B1 (ru) | Рифаксимин в форме порошка, способ его получения и композиции контролируемого высвобождения, содержащие указанный рифаксимин, полезные для достижения длительного эффекта | |
WO2016057635A1 (en) | Cationic steroidal antimicrobial prodrug compositions and uses thereof | |
CN103462884B (zh) | 一种加米霉素注射液及其制备方法 | |
JPS61210025A (ja) | 安定化された抗生物質複合顆粒製剤 | |
WO2013029297A1 (zh) | 广藿香醇在制备抗幽门螺旋杆菌的药物中的应用 | |
CN102258460B (zh) | 黄芩素脂质体凝胶及其制备方法 | |
CN101633683A (zh) | 抗肝炎药物及其制备和用途 | |
CN102702300A (zh) | 一种预防或治疗自身免疫性糖尿病的化合物及其制备方法和用途 | |
WO2020124088A1 (en) | Lachnospiraceae mitigates against radiation-induced hematopoietic/gastrointestinal injury and death, and promotes cancer control by radiation | |
CN114085237A (zh) | 左氧氟沙星新化合物及其脂质体纳米药物 | |
CN111870591B (zh) | 一种控制乙酰半胱氨酸溶液硫化氢含量的方法 | |
CN101062057A (zh) | 注射用熊胆解热冻干粉制备方法及用途 | |
CN1732934B (zh) | 注射用盐酸倍他司汀冻干粉针剂及其制备方法 | |
CN100569789C (zh) | 硫酸阿奇霉素和其应用及其冻干粉针剂和冻干粉针剂的制备方法 | |
CN103083338B (zh) | 增效复方安乃近注射液及其制备方法 | |
Marlin et al. | Study of serum levels, venous irritation and gastrointestinal side-effects with intravenous erythromycin lactobionate in patients with bronchopulmonary infection | |
CN102973595B (zh) | 一种克林霉素磷酸酯的药物组合物 | |
CN110384802A (zh) | 一种用于预防和/或治疗发热的药物、组合产品及其应用 | |
CN108096198A (zh) | 预防和治疗需氧菌与厌氧菌混合感染时的新型抗菌药物组合物及其制备方法 | |
CN108066338A (zh) | 预防和治疗需氧菌与厌氧菌混合感染时的新型抗生素组合物及其制备方法 | |
CN111939278A (zh) | 一种盐酸去甲乌药碱注射液的灭菌工艺 | |
CN103655460B (zh) | 一种含氨曲南的注射用药物组合物及其制备方法和用途 | |
CN113616620A (zh) | 安罗替尼白蛋白纳米颗粒及其制备方法和用途、及包含其的制剂 |
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 |