CN1565446A - Freeze-drying fluconazole injection and its preparation method - Google Patents
Freeze-drying fluconazole injection and its preparation method Download PDFInfo
- Publication number
- CN1565446A CN1565446A CNA031431550A CN03143155A CN1565446A CN 1565446 A CN1565446 A CN 1565446A CN A031431550 A CNA031431550 A CN A031431550A CN 03143155 A CN03143155 A CN 03143155A CN 1565446 A CN1565446 A CN 1565446A
- Authority
- CN
- China
- Prior art keywords
- injection
- bottle
- acid
- fluconazole
- lyophilized formulations
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000004108 freeze drying Methods 0.000 title claims abstract description 7
- 229940091713 fluconazole injection Drugs 0.000 title abstract 2
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000000243 solution Substances 0.000 claims abstract description 25
- 229960004884 fluconazole Drugs 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 30
- 238000009472 formulation Methods 0.000 claims description 25
- 238000002347 injection Methods 0.000 claims description 25
- 239000007924 injection Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000008215 water for injection Substances 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 9
- 229920000053 polysorbate 80 Polymers 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 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 description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 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 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000012856 packing Methods 0.000 claims description 7
- 108010010803 Gelatin Proteins 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 6
- 230000003115 biocidal effect Effects 0.000 claims description 6
- 239000008273 gelatin Substances 0.000 claims description 6
- 229920000159 gelatin Polymers 0.000 claims description 6
- 235000019322 gelatine Nutrition 0.000 claims description 6
- 235000011852 gelatine desserts Nutrition 0.000 claims description 6
- 239000004310 lactic acid Substances 0.000 claims description 6
- 235000014655 lactic acid Nutrition 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- 229920002307 Dextran Polymers 0.000 claims description 4
- 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 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- 239000004411 aluminium Substances 0.000 claims description 4
- 235000001014 amino acid Nutrition 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 229920005549 butyl rubber Polymers 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 108010009736 Protein Hydrolysates Proteins 0.000 claims description 3
- 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 3
- 239000000945 filler Substances 0.000 claims description 3
- 238000007710 freezing Methods 0.000 claims description 3
- 230000008014 freezing Effects 0.000 claims description 3
- 239000000413 hydrolysate Substances 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 235000010338 boric acid Nutrition 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 239000012528 membrane Substances 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- YRWWOAFMPXPHEJ-OFBPEYICSA-K sodium L-ascorbic acid 2-phosphate Chemical compound [Na+].[Na+].[Na+].OC[C@H](O)[C@H]1OC(=O)C(OP([O-])([O-])=O)=C1[O-] YRWWOAFMPXPHEJ-OFBPEYICSA-K 0.000 claims description 2
- 229940048058 sodium ascorbyl phosphate Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 238000000859 sublimation Methods 0.000 claims description 2
- 230000008022 sublimation Effects 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000013505 freshwater Substances 0.000 claims 3
- 238000009835 boiling Methods 0.000 claims 1
- 238000001514 detection method Methods 0.000 claims 1
- 239000001509 sodium citrate Substances 0.000 claims 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 abstract 1
- 206010017533 Fungal infection Diseases 0.000 description 4
- 208000031888 Mycoses Diseases 0.000 description 4
- 229940119744 dextran 40 Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 4
- 235000019799 monosodium phosphate Nutrition 0.000 description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 241000335423 Blastomyces Species 0.000 description 1
- 241000228405 Blastomyces dermatitidis Species 0.000 description 1
- 240000004307 Citrus medica Species 0.000 description 1
- 241000223203 Coccidioides Species 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 208000036649 Dysbacteriosis Diseases 0.000 description 1
- 208000027244 Dysbiosis Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000228404 Histoplasma capsulatum Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940091771 aspergillus fumigatus Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000007140 dysbiosis Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- -1 ll Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a freeze-drying fluconazole injection and its preparation method which comprises, charging a definite quantity of supporting agent into reactive medicinal Fluconazole (50-200mg per bottle), adding pH modifier, solubilizing agent so as to prepare solution of a finite concentration, and loading for freeze drying.
Description
Technical field
What the present invention relates to is pharmaceutical preparation in the field of medicaments, especially relates to a kind of fluconazole for injection lyophilized formulations and preparation method with broad-spectrum antifungal effect.
Background technology
Fluconazol (C
13H
12F
2N
6O, molecular weight: 306.28) be a kind of white crystalline powder, easily molten in methanol, in ethanol, dissolve, slightly soluble in water, it is novel antifungal drug in triazole class, and the broad-spectrum antifungal effect is arranged, the sterol that can optionally suppress fungus is synthetic, and the inhibitory action that fungal cell's pigment P-450 is relied on enzyme has high selectivity.It in vivo and in vitro to Cryptococcus, read Coccus, yellow aspergillosis, aspergillus fumigatus, Blastomyces dermatitidis, Blastomyces coccidioides, Histoplasma capsulatum and all show good antibacterial action.It and protein binding rate are lower, and the bioavailability height, and have the characteristics of the maincenter of penetrating, and are the choice drugs of clinical anti-fungal infection, can also be used for the treatment of or prevent the fungal infection patient after abuse of antibiotics causes dysbacteriosis.Because the HIV sufferers immunity is sunken, mucosa is fungal infection especially easily, so this medicine also can be used for the anti-treatment of fungal infections of HIV sufferers.
The intravenous drip administration is rapid-action, often some patients with severe symptoms or oral inconvenient patient is implemented the intravenous drip administration clinically.Have for the fluconazol preparation of intravenous drip clinically: regulate among the high-capacity injection (infusion solutions) that contains the 200mg fluconazol among the isoosmotic 100ml and the 10ml with sodium chloride or glucose and contain the injection with small volume (small-volume injection) that contains the 200mg fluconazol among 100mg fluconazol and the 5ml.Because the poorly water-soluble of fluconazol, usually adopt the method that adds organic solvent when preparing injection with small volume, increase the dissolubility of fluconazol in solution, the general propylene glycol solvent that adds, and the viscosity of this solvent is big, the injection of preparation is very thick, causes dilution dosage inaccurate in use easily, also can bring certain untoward reaction to the patient.The active medicine fluconazol is in solution state for a long time besides, is subject to the influence of natural cause and variations such as oxidation, hydrolysis take place, and is unfavorable for the stable of medicine.The injection of solution-type also causes breakage easily in transportation, be unfavorable for carrying and transporting of medicine.For overcoming above-mentioned various unfavorable factor, we develop the fluconazole for injection lyophilized formulations, adopt control antibiotic cillin bottle packing, and butyl rubber plug and aluminium lid seal, and it can effectively overcome the deficiency that solution type injection agent exists.This lyophilized formulations is white block, and quality is loose, and adding low amounts of water (3-10ml) can dissolve rapidly, solution adding sodium chloride after will dissolve again or glucose etc. ooze be used in the injection clinical.This lyophilized formulations medicine stability is good, uses the effect duration limit for length, clinically uses and carries, transports all very convenient.For fluconazol provides another new preparation in clinical use.
Summary of the invention
The object of the present invention is to provide a kind of the stable of medicine that help, be easy to carry about with one and transport clinical fluconazole for injection lyophilized formulations and preparation method easy to use.
Fluconazole for injection lyophilized formulations advantage of the present invention is: avoid active medicine to decompose rotten because of heating or being in solution state for a long time, increased stability of drug, the lyophilized formulations quality is loose, adding low amounts of water is solubilized, but the storage period of prolong drug, untoward reaction clinical easy to use, that no preparation formulation causes.
Fluconazole for injection lyophilized preparation system of the present invention is achieved in that prescription of the present invention forms (every bottle of content) by following composition:
Fluconazol 50-200mg
Caffolding agent (filler) 2-200mg
PH value regulator 0.1-100mg
Solubilizing agent 0.1-50mg
Water for injection adds to 2-10ml
Active medicine fluconazol content is in the prescription of lyophilized formulations of the present invention: every bottle is 50mg or 100mg or 200mg.
Lyophilized formulations medium-height trestle of the present invention agent (filler) is: the mixture of one or more in lactose, mannitol, dextran, glucose, gelatin hydrolysate, sorbitol, aminoacid, sodium chloride, calcium chloride, sucrose, polyvidone, citron sodium, the sodium ascorbyl phosphate etc., and preferred: lactose, mannitol, dextran, gelatin hydrolysate.
The pH value regulator is in the lyophilized formulations of the present invention: in hydrochloric acid, acetic acid, lactic acid, methanesulfonic acid, phosphoric acid, citric acid, boric acid, tartaric acid, malic acid, aminoacid, sodium carbonate, sodium bicarbonate, the sodium hydroxide etc. one or more mixing and, preferred lactic acid, methanesulfonic acid, acetic acid, citric acid, sodium bicarbonate, sodium hydroxide.
Solubilizing agent is in the lyophilized formulations of the present invention: a kind of in tween 80, poloxamer, Polyethylene Glycol, the polyvidone etc.
Preparation method of the present invention is:
1. fluconazol, caffolding agent, the solubilizing agent with recipe quantity mixes, add a certain amount of water for injection, after reuse pH value regulator is made into certain density solution or directly adds by recipe quantity, stirring makes whole dissolvings (can be heated to 60-80C or boil), the adjusting pH value is 3-6, and reuse water for injection adds to the amount of preparation of prescription regulation.
2. after the active carbon that the solution for preparing is added every bottle of 3-10mg boils, stirring and adsorbing 15 minutes, remove by filter active carbon with core filter stick or No. 3 sintered filter funnels, filtrate is again through Φ 0.22um microporous filter membrane fine straining, detect through intermediate and can be sub-packed in by recipe quantity in the 15ml control antibiotic cillin bottle after qualified, packing solution 2-10ml in every bottle.
3. the control antibiotic cillin bottle that branch is installed solution is put in the vacuum freezing drying oven, carries out vacuum lyophilization by cryodesiccated operation sequence, after sublimation drying 40-48 hour, open drying baker, bottleneck adds the butyl rubber gag, and rolls the envelope aluminium lid, gets product.
The specific embodiment
Below in conjunction with embodiment the present invention is described in further detail, but should understands this bright non-scope that only limits to these embodiment of scope.
Embodiment 1
Prescription 1: every bottle of lyophilized formulations contains fluconazol 50mg
Fluconazol 500mg
Mannitol 500mg
Dextran 40 100mg
1mol/L HCl solution 5ml
1mol/L NaOH solution is transferred PH in right amount
Tween 80 25mg
Water for injection adds to 30ml
10 bottles of packing, every bottle of 3ml
Preparation method: get fluconazol adding tween 80,1mol/L HCl solution in the prescription, in 60-80 ℃ of water-bath, heat, stirring is all dissolved fluconazol, the water for injection that adds about total amount 80%, transfer pH value to 3-5 with 1mol/L NaOH solution, the mannitol, Dextran 40, the stirring that add recipe quantity make whole dissolvings, add the active carbon of 30mg, and add the injection water to the full dose of writing out a prescription, boil the back and stirred 15 minutes.Remove by filter active carbon with No. 3 sintered filter funnels, No. 5 sintered filter funnel fine straining of filtrate reuse.After testing, be sub-packed in after filtrate is up to specification in the control antibiotic cillin bottle, carried out lyophilization 48 hours in the uncovered placement vacuum freezing drying oven,, and roll the envelope aluminium lid and get product with butyl rubber gag tight bottleneck.
Embodiment 2
Prescription 2: every bottle of lyophilized formulations contains fluconazol 100mg
Fluconazol 1000mg
Lactose 1000mg
50% lactic acid 7ml
0.2mol/L sodium dihydrogen phosphate 10ml
1mol/L NaOH solution is transferred PH in right amount
Tween 80 40mg
Water for injection adds to 40ml
10 bottles of packing, every bottle of 4ml
Preparation method: get fluconazol adding tween 80,50% lactic acid, 0.2mol/L sodium dihydrogen phosphate heated and stirred in the prescription, fluconazol is all dissolved, transfer solution PH 2-5 with 1mol/L NaOH, the lactose that adds recipe quantity, stirring makes whole dissolvings, add the active carbon of 40mg, and add the injection water, boil the back and stirred 15 minutes to the full dose of writing out a prescription.Other method is with embodiment 1.
Embodiment 3
Prescription 3: every bottle of lyophilized formulations contains fluconazol 150mg
Prescription 1: every bottle of lyophilized formulations contains fluconazol 50mg
Fluconazol 500mg
Dextran 40 750mg
Citric acid (anhydrous) 75mg
0.2mol/L sodium dihydrogen phosphate 10ml
1mol/L NaOH solution is transferred PH in right amount
Tween 80 40mg
Water for injection adds to 50ml
10 bottles of packing, every bottle of 5ml
Preparation method: get fluconazol in the prescription, Dextran 40, citric acid, 0.2mol/L sodium dihydrogen phosphate, the about 40ml of tween 80 adding water for injection, heating and stirring make whole dissolvings in 80 ℃ of water-baths, transfer solution PH 2-4 with 0.5mol/L NaOH, the active carbon that adds 40mg, and add the injection water to the full dose of writing out a prescription, boil the back and stirred 15 minutes.Other method is with embodiment 1.
Embodiment 4
Prescription 4: every bottle of lyophilized formulations contains fluconazol 200mg
Fluconazol 2000mg
Mannitol 400mg
Gelatin hydrolysate 400mg
Methanesulfonic acid 2g
0.5mol/L NaOH solution is transferred PH in right amount
Tween 80 50mg
Water for injection adds to 50ml
10 bottles of packing, every bottle of 5ml
Preparation method: get fluconazol in the prescription, mannitol, gelatin hydrolysate, methanesulfonic acid, the about 40ml of tween 80 adding water for injection, heating and stirring make whole dissolvings in 80 ℃ of water-baths, transfer solution PH 2-5 with 0.5mol/LNaOH, the active carbon that adds 50mg, and add the injection water to the full dose of writing out a prescription, boil the back and stirred 15 minutes.Other method is with embodiment 1.
Claims (7)
1. fluconazole for injection lyophilized formulations is characterized in that: every bottle contains fluconazol 50-200mg and other composition is formed:
Fluconazol 50-200mg
Caffolding agent (filler) 2-200mg
PH value regulator 0.1-100mg
Solubilizing agent 0.1-50mg
Fresh water for injection adds to 2-10ml
2. prepare the preparation method of fluconazole for injection lyophilized formulations as claimed in claim 1, it is characterized in that:
(1) fluconazol, caffolding agent, the solubilizing agent with recipe quantity mixes, add certain quantity of fresh water for injection, after reuse pH value regulator is made into certain density solution or adds by recipe quantity, stirring makes whole dissolvings (can be heated to 60-80 ℃ or boil), the adjusting pH value is 2-5, and the reuse fresh water for injection adds to the amount of preparation of prescription regulation.
(2) solution for preparing is added the active carbon of every bottle of 3-10mg, after boiling, stirring and adsorbing 15 minutes, remove by filter active carbon with core filter stick or No. 3 sintered filter funnels, filtrate is again through Φ 0.22um microporous filter membrane fine straining, filtrate can be sub-packed in the 10-15ml control antibiotic cillin bottle every bottle of packing solution 2-10ml by recipe quantity after the intermediate detection is qualified.
(3) cillin bottle that branch is installed solution is put in the vacuum freezing drying oven, carries out vacuum lyophilization by cryodesiccated operation sequence, after sublimation drying 40-48 hour, opens drying baker, adds the butyl rubber gag, rolls the envelope aluminium lid, gets product.
3. the described fluconazole for injection lyophilized formulations of claim 1, the active medicine fluconazol content in its prescription is: every bottle of 50mg or every bottle of 100mg or every bottle of 150mg or every bottle of 200mg.
4. the described fluconazole for injection lyophilized formulations of claim 1, support in its prescription is: the mixture of one or more in lactose, mannitol, dextran, glucose, gelatin hydrolysate, sorbitol, aminoacid, sodium chloride, calcium chloride, sucrose, polyvidone, sodium citrate, the sodium ascorbyl phosphate etc., and preferred: lactose, mannitol, dextran, gelatin hydrolysate.
5. the described fluconazole for injection lyophilized formulations of claim 1, the pH value regulator in its prescription: the mixture of one or more in hydrochloric acid, acetic acid, lactic acid, methanesulfonic acid, phosphoric acid, citric acid, boric acid, tartaric acid, malic acid, aminoacid, sodium carbonate, sodium bicarbonate, the sodium hydroxide etc.Preferably: lactic acid, methanesulfonic acid, acetic acid, citric acid, sodium bicarbonate, sodium hydroxide.
6. the described fluconazole for injection lyophilized formulations of claim 1, the solubilizing agent in its prescription is: a kind of in tween 80, poloxamer, Polyethylene Glycol, the polyvidone etc., the most suitable solubilizing agent is a tween 80.
7. the described fluconazole for injection lyophilized formulations of claim 1, its optimal volume that adds that water for injection is made into certain concentration solution is: every bottle is 3ml or 5ml, and fill is carried out lyophilization in 10ml or 15ml control antibiotic cillin bottle.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031431550A CN1565446A (en) | 2003-06-17 | 2003-06-17 | Freeze-drying fluconazole injection and its preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031431550A CN1565446A (en) | 2003-06-17 | 2003-06-17 | Freeze-drying fluconazole injection and its preparation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1565446A true CN1565446A (en) | 2005-01-19 |
Family
ID=34471278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031431550A Pending CN1565446A (en) | 2003-06-17 | 2003-06-17 | Freeze-drying fluconazole injection and its preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1565446A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103877031A (en) * | 2014-02-21 | 2014-06-25 | 安徽省先锋制药有限公司 | Fosfluconazole lyophilized preparation composition stable at normal temperature and preparation method thereof |
| CN104873468A (en) * | 2014-02-27 | 2015-09-02 | 陕西合成药业股份有限公司 | Fosfluconazole for injection, a preparing method thereof and uses of the fosfluconazole |
| CN104940133A (en) * | 2015-06-11 | 2015-09-30 | 山东新时代药业有限公司 | Fluconazole injection and preparation method thereof |
| CN104940135A (en) * | 2015-07-11 | 2015-09-30 | 鲁南贝特制药有限公司 | Fluconazole injection and preparation method thereof |
| CN106265540A (en) * | 2016-08-31 | 2017-01-04 | 安徽省润生医药股份有限公司 | A kind of good fortune department fluconazol lyophilized formulations compositions and preparation method thereof |
-
2003
- 2003-06-17 CN CNA031431550A patent/CN1565446A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103877031A (en) * | 2014-02-21 | 2014-06-25 | 安徽省先锋制药有限公司 | Fosfluconazole lyophilized preparation composition stable at normal temperature and preparation method thereof |
| CN104873468A (en) * | 2014-02-27 | 2015-09-02 | 陕西合成药业股份有限公司 | Fosfluconazole for injection, a preparing method thereof and uses of the fosfluconazole |
| CN104940133A (en) * | 2015-06-11 | 2015-09-30 | 山东新时代药业有限公司 | Fluconazole injection and preparation method thereof |
| CN104940135A (en) * | 2015-07-11 | 2015-09-30 | 鲁南贝特制药有限公司 | Fluconazole injection and preparation method thereof |
| CN106265540A (en) * | 2016-08-31 | 2017-01-04 | 安徽省润生医药股份有限公司 | A kind of good fortune department fluconazol lyophilized formulations compositions and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1138541C (en) | Pharmaceutically stable oxaliplatinum prepn. | |
| KR101113084B1 (en) | Liquid pharmaceutical formulations of palonosetron | |
| US20110178470A1 (en) | Pharmaceutical compositions comprising boronic acid compounds | |
| CN1371366A (en) | Benzamide formulation with histone deacetylase inhibitor activity | |
| CN1668332A (en) | Liquid formulation containing high concentration of human growth hormone containing phenol | |
| WO2016098009A1 (en) | Lyophilized injectable compositions of daptomycin | |
| CN101584668A (en) | Bendamustine hydrochloride freeze-dried powder injection | |
| CN1823768A (en) | Cimetidine freeze dried composition | |
| CN1565446A (en) | Freeze-drying fluconazole injection and its preparation method | |
| CN1245987C (en) | Stability enhanced erigeron breviscapus injection and its preparation method | |
| CN112402371B (en) | Rudesiwei injection and preparation method thereof | |
| EP2887953A2 (en) | Improved daptomycin injectable formulation | |
| CN1897940A (en) | Pharmaceutical composition of vinflunine which is intended for parenteral administration preparation method thereof and use of same | |
| CN1259041C (en) | Bromhexine Hydrochloride aseptic freeze-drying formulation for injection and its preparation method | |
| WO2015025000A1 (en) | Pharmaceutical compositions comprising bortezomib | |
| CN102657624B (en) | High optical purity trans-dextro oxaliplatin lyophilized powder injection and preparation method thereof | |
| CN101912361A (en) | Cefotiam hydrochloride/anhydrous sodium carbonate medicinal composition suspension injection and new use thereof | |
| US11957758B2 (en) | Pharmaceutical composition of docetaxel conjugate and preparation method | |
| CN111603439A (en) | A kind of long-acting epipiprazole in situ phase change gel injection and preparation method thereof | |
| CN101125125A (en) | Methylergometrine Maleate powder injection and preparation method thereof | |
| CN1186094C (en) | Piracetam medicine composition with function of promoting thinking and memory and its prepn | |
| CN1442138A (en) | Fukangzuo injection fluid and its preparation method | |
| CN102626411A (en) | Pharmaceutical composition containing propofol and opioid analgesics and use thereof | |
| CN1839842A (en) | Pharmaceutical composition containing levosimendan or its pharmaceutically acceptable salt as active ingredient | |
| CN1820748A (en) | Levo-ornidazole freeze-dried powder injection |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |