CN106619541A - Isavuconazonium sulfate freeze-dried powder injection and preparation method - Google Patents
Isavuconazonium sulfate freeze-dried powder injection and preparation method Download PDFInfo
- Publication number
- CN106619541A CN106619541A CN201610950606.0A CN201610950606A CN106619541A CN 106619541 A CN106619541 A CN 106619541A CN 201610950606 A CN201610950606 A CN 201610950606A CN 106619541 A CN106619541 A CN 106619541A
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- CN
- China
- Prior art keywords
- chinese mugwort
- injection
- dried powder
- mugwort saperconazole
- sulfuric acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
The invention discloses isavuconazonium sulfate freeze-dried powder injection and a preparation method and belongs to the technical field of antifungal freeze-dried powder injections. The powder injection contains an effective treating ingredient isavuconazonium sulfate, an excipient mannitol and a pH regulator dilute sulfuric acid. In the preparation process, the mannitol is dissolved with 70-80% water for injection firstly, heat preservation is performed to 0-15 DEG C after all the mannitol is dissolved, the isavuconazonium sulfate is added, pH is regulated to be 1.2-1.8 with the dilute sulfuric acid after stirring and dissolution, the volume is fixed with the water for injection to make the concentration of the isavuconazonium sulfate be 90-130 mg/mL, and then pyrogen removal, aseptic filtration, split charging (the volume is 3-4 mL) and freeze drying are performed to obtain the injection. The prepared isavuconazonium sulfate freeze-dried powder injection is quick to redissolve, complete, good in stability and convenient to store and transport, and the application of the isavuconazonium sulfate in the field of preparations is enriched.
Description
Technical field
The invention belongs to antimycotic freeze drying powder injection technical field, more particularly, it relates to the Saperconazole sulfate jelly that ends
Dry powder injection and preparation method.
Background technology
The Chinese chemical name of Chinese mugwort Saperconazole sulfuric ester：
Glycine, N- methyl -, [2- [[[1- [1- [(2R, 3R) -3- [4- (4- cyano-phenyls) -2- thiazolyls] -2- (2,
5- difluorophenyls) -2- hydroxyl butyl] interior -4- bases of -4H-1,2,4- triazoles] ethyoxyl] carbonyl] methylamino] -3- pyridine radicals] first
Ester, sulfate；
English language Chemical title：
Glycine,N-methyl-,[2-[[[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-
thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl]
ethoxy]carbonyl]methylamino]-3-pyridinyl]methylester,sulfate；
Molecular weight:814.853；
CAS registration numbers:946075-13-4；
Molecular formula：C35H36F2N8O5S·SO4；
Its structural formula is (shown in accompanying drawing 1)：
Chinese mugwort Saperconazole sulfuric ester (isavuconazonium sulfate) is by Ba Sai Leahs pharmaceutcal corporation, Ltd of Switzerland
With Japanese Astellas (Astellas) company jointly research and development for treatment adult's invasive aspergillosis and aggressive Mucor
The new drug of bacterium disease, U.S. FDA approval listing is obtained on March 6th, 2015, and trade name Cresemba, the formulation this time ratified has
Oral formulations and intravenous injection.On October 15th, 2015, EU Committee authorizes Chinese mugwort Saperconazole listing license, suffers from for treating
The adult patients of invasive aspergillosis, and for treating the adult patients of the unaccommodated mucormycosis of amphotericin B.
Chinese mugwort Saperconazole sulfuric ester belong to antifungal drug in triazole class, be end Saperconazole water-soluble prodrug form, vein
After injection or oral administration, Chinese mugwort Saperconazole can be quickly and completely converted in the presence of esterase.Chinese mugwort Saperconazole can suppress fungi
The demethylation of 14 α of cytochrome P 450 mediated-sterol, so as to suppress the biosynthesis of fungal cell membrane ergosterol,
So that ergosterol lacks, and toxicity intermediate product lanosterol is accumulated, and causes permeability of cell membrane to strengthen and growth inhibition, enters
And play antifungic action.Compared with other antifungal drugs, he has following advantage：
(1) patent medicine composition is water-soluble prodrug, cyclodextrin is not contained in intravenous formulations, without the potential renal toxicity wind of auxiliary material
Danger.
(2) bioavilability is high, the excellent pharmacokinetic characteristics with treatment system fungi medicine：Clearance rate
Low, long half time, volume of distribution are big；Drug interaction is less.
(3) In vitro Bactericidal Experiments show to end Saperconazole to the saccharomycetic work such as candida albicans, Aspergillus, mucor, cryptococcus
Property be better than or be not inferior to other most of antifungals.
With regard to the patent of formulation, Chinese Patent Application No. is 200880103639.5, and publication date is on July 21st, 2010
Patent application document discloses a kind of combination of oral medication, self-emulsifying when itself and water phase, particularly gastro-intestinal Fluid are contacted, comprising
The carrier of Isavuconazole and solubilizer, HLB value less than 20；It is protected to be used to treating systemic mycosis and (send out simultaneously
Property aspergillosis or candidiasis) purposes.The liquid preparation is only capable of the dispenser in the way of being administered orally, in the severe for being difficult to swallow
Application on patient is restricted, in addition, the composition of self-emulsifying microemulsion system is complicated, process for preparation is loaded down with trivial details, the medicine on market
There is only a few to be self-emulsifying microemulsion system by successful formulation, and said composition contains surfactant, there is potential renal toxicity
Risk.
So how to enrich the application form of Chinese mugwort Saperconazole, a kind of suitable injection, content height, good stability are obtained, just
In transport and the Chinese mugwort Saperconazole dosage form for storing, become assistant officer's technical problem to be solved.
The content of the invention
1. the problem to be solved
For the problem that existing Chinese mugwort Saperconazole sulfate can only be administered orally, an object of the present invention is to provide one
Plant Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection, the Chinese mugwort Saperconazole sulfate containing therapeutically effective amount, excipient and pH regulations
Agent dilute sulfuric acid, can be administered by venous transfusion.
It is a further object of the present invention to provide a kind of preparation method of Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection, solves
The problem that stability is poor, bioavilability is low that Chinese mugwort Saperconazole causes because insoluble.
2. technical scheme
In order to solve the above problems, the technical solution adopted in the present invention is as follows：
One kind Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection, including following components：The Chinese mugwort Saperconazole sulfate of survival dose,
Excipient and pH adjusting agent.
Further, described Chinese mugwort Saperconazole sulfate and the mass ratio of excipient are 1:2～5:1.
Further, described Chinese mugwort Saperconazole sulfate and the mass ratio of excipient are 4:1～5:1.
Further, described excipient is one or more mixture in mannitol, lactose, sodium chloride, sorbierite.
Further, described excipient is mannitol.
The preparation method of above-mentioned Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection, its step is：
(1) injection water excipient dissolving is used, is incubated to preference temperature；
(2) Chinese mugwort Saperconazole sulfate, stirring and dissolving is added to adjust pH value；
(3) injection water constant volume is added, the concentration for making Chinese mugwort Saperconazole sulfate is 60～190mg/mL；
(4) it is sterile filtered, dispenses, freeze-drying obtains final product described Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection.
Further, holding temperature is 0～15 DEG C after excipient dissolving in step (1).
Further, pH value is adjusted in step (2) to 1.0～3.0；Preferred pH value is 1.2～1.8.
Further, injection water constant volume is added in step (3), the concentration for making Chinese mugwort Saperconazole sulfate is 90～130mg/
mL。
Further, packing volume is 2～6mL in step (4)；Preferred packing volume is 3～4mL.
According to Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection prepared by above proportioning and method, can be given by venous transfusion
Medicine, the venoclysis time is no less than 1 hour after 250mL diluent compatibilities.It is sure not as disposable vein inject administration.Dispenser model
Enclose for intravenously administrable 1mg to 30mg per kg body weight per day per kg body weight per day, preferred intravenously administrable is per kg body weight per day
5mg to 30mg per kg body weight per day, each accurate dosage is true according to patient age, sex and symptomatic condition and diagnosis
Bacterium gradient of infection it is different and different.
3. beneficial effect
Compared to prior art, beneficial effects of the present invention are：
(1) Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection prepared by the present invention, solves Chinese mugwort Saperconazole and causes because insoluble
The problem that stability is poor, bioavilability is low；Products obtained therefrom outward appearance is plentiful, fine and smooth, quality is loose, rapid after adding water to dissolve simultaneously
Recover the original characteristic of liquid；
(2) Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection prepared by the present invention, with stable performance, it is convenient to transport and store
Etc. characteristic；Clinically, used in the form of venoclysis, both improve the curative effect of medicine, the scope of formulation is expanded again, it is full
The needs of foot treatment.
Description of the drawings
Fig. 1 is the structural representation of Chinese mugwort Saperconazole sulfuric ester.
Specific embodiment
The present invention is further described below with reference to specific embodiment.
Embodiment 1-7
The consumption of the excipient of table 1. and fill volume are screened
| Project | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 |
| Chinese mugwort Saperconazole/g | 4 | 4 | 4 | 4 | 4 | 4 | 4 |
| Mannitol/g | / | 1 | 2 | 1 | 4 | / | / |
| Lactose/g | / | / | / | / | 2 | / | / |
| Sodium chloride/g | / | / | / | / | / | 3 | / |
| Sorbierite/g | / | / | / | 2 | / | / | 3 |
| Water for injection/ml | 40 | 40 | 40 | 40 | 40 | 40 | 30 |
| Amount of preparation/bottle | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
Preparation method：Take 70～80% water for injection excipient dissolving (herein the amount of water for injection is not strict with,
As long as less than last constant volume, excipient can be completely dissolved), after all dissolvings, temperature is reduced to 0～15
DEG C (temperature control within this range can with), adds Chinese mugwort Saperconazole sulfate, and stirring and dissolving is after settled solution, to use dilute sulphur
Acid adjusts pH to 1.2～1.8, plus water for injection constant volume, then aseptic filtration, packing, freeze-drying.The compound method of dilute sulfuric acid
For：It is by volume 2 with water for injection and the concentrated sulfuric acid (95%～98%):1 prepares.
The outward appearance of the Chinese mugwort Saperconazole father-in-law's sulfate freeze-dried powder of table 2.
Above-mentioned sample is carried out into stability setting-out experiment, it is as a result as follows：
The Chinese mugwort Saperconazole sulfate freeze-dried powder stability test result of table 3.
The Chinese mugwort Saperconazole sulfate freeze-dried powder stability test result of table 4.
As a result understand：
1. one or more mixture such as mannitol, lactose, sodium chloride, sorbierite selected by can make Chinese mugwort Saperconazole
The excipient of sulfate freeze-dried powder, preferred mannitol；
2. different mannitol concentrations can function well as the effect of excipient, preferred Chinese mugwort Saperconazole sulfate and figuration
Agent ratio is 4:1～5:1；
3. the canned volumes of 3～4mL are obtained the Chinese mugwort Saperconazole sulfate freeze-dried powder of high-quality；
4. end Saperconazole sulfate freeze-dried powder non-refractory, and temperature is higher, and feed degradation is faster, and impurity increases to be got over
Hurry up, particulate matter is also more, redissolution speed is slower, in appearance, substantially unchanged；
5. 8 DEG C of setting-outs 10 days, Chinese mugwort Saperconazole sulfate freeze-dried powder active constituent content is essentially unchanged；
6. illumination also has a certain impact to the Saperconazole sulfate freeze-dried powder stability that ends, and makes feed degradation, impurity
Increase；
7. the Saperconazole sulfate freeze-dried powder that ends should be stored in sealing, lucifuge, under 0～10 DEG C of environment.
Claims (10)
1. a kind of Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection, it is characterised in that：Including following components：The Chinese mugwort Saperconazole of survival dose
Sulfate, excipient and pH adjusting agent.
2. a kind of Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection according to claim 1, it is characterised in that：Described Ai Sha
Health azoles sulfate is 1 with the mass ratio of excipient:2～5:1.
3. a kind of Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection according to claim 1 and 2, it is characterised in that：Described
Chinese mugwort Saperconazole sulfate is 4 with the mass ratio of excipient:1～5:1.
4. a kind of Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection according to claim 1, it is characterised in that：Described figuration
Agent is one or more mixture in mannitol, lactose, sodium chloride, sorbierite.
5. a kind of Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection according to claim 1 or 4, it is characterised in that：Described
Excipient is mannitol.
6. the preparation method of the Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection described in claim 1, its step is：
(1) injection water excipient dissolving is used, is incubated to preference temperature；
(2) Chinese mugwort Saperconazole sulfate, stirring and dissolving is added to adjust pH value；
(3) injection water constant volume is added, the concentration for making Chinese mugwort Saperconazole sulfate is 60～190mg/mL；
(4) it is sterile filtered, dispenses, freeze-drying obtains final product described Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection, packing volume is 2
～6mL.
7. it is according to claim 6 it is a kind of Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection preparation method, it is characterised in that：
Holding temperature is 0～15 DEG C after excipient dissolving in step (1).
8. a kind of preparation method of the Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection according to claim 6 or 7, its feature exists
In：PH value is adjusted in step (2) to 1.0～3.0.
9. it is according to claim 8 it is a kind of Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection preparation method, it is characterised in that：
PH value is adjusted in step (2) to 1.2～1.8.
10. the preparation method of a kind of Chinese mugwort Saperconazole sulfuric acid salt freeze-dried powder-injection according to claim 6, its feature exists
In：Add injection water constant volume in step (3), the concentration for making Chinese mugwort Saperconazole sulfate is 90～130mg/mL；Packing in step (4)
Volume is 3～4mL.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610950606.0A CN106619541A (en) | 2016-10-27 | 2016-10-27 | Isavuconazonium sulfate freeze-dried powder injection and preparation method |
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| CN201610950606.0A CN106619541A (en) | 2016-10-27 | 2016-10-27 | Isavuconazonium sulfate freeze-dried powder injection and preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107661298A (en) * | 2017-10-17 | 2018-02-06 | 上海键合医药科技有限公司 | A kind of injection sulfuric acid Chinese mugwort Saperconazole and its lyophilized technique |
| CN115300467A (en) * | 2022-08-26 | 2022-11-08 | 开封明仁药业有限公司 | Isaconazole sulfate freeze-dried powder injection for injection and preparation process thereof |
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| CN102225063A (en) * | 2011-05-10 | 2011-10-26 | 江苏奥赛康药业有限公司 | Pantoprazole sodium composition for injection |
| WO2016055918A1 (en) * | 2014-10-08 | 2016-04-14 | Wockhardt Limited | Novel stable polymorphs of isavuconazole or its salt thereof |
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2016
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102225063A (en) * | 2011-05-10 | 2011-10-26 | 江苏奥赛康药业有限公司 | Pantoprazole sodium composition for injection |
| WO2016055918A1 (en) * | 2014-10-08 | 2016-04-14 | Wockhardt Limited | Novel stable polymorphs of isavuconazole or its salt thereof |
Non-Patent Citations (3)
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| DRUGS@FDA: "APPLICATION NUMBER:207500Orig1s000/207501Orig1s000 LABELING", 《CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 207500ORIG1S000 / 207501ORIG1S000 LABELING,WWW.ACCESSDATA.FDA.GOV/DRUGSATFDA_DOCS/NDA/2015/207500ORIG1207501ORIG1S000LBL.PDF》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107661298A (en) * | 2017-10-17 | 2018-02-06 | 上海键合医药科技有限公司 | A kind of injection sulfuric acid Chinese mugwort Saperconazole and its lyophilized technique |
| CN107661298B (en) * | 2017-10-17 | 2022-05-27 | 上海键合医药科技有限公司 | Isaconazole sulfate for injection and freeze-drying process thereof |
| CN115300467A (en) * | 2022-08-26 | 2022-11-08 | 开封明仁药业有限公司 | Isaconazole sulfate freeze-dried powder injection for injection and preparation process thereof |
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Application publication date: 20170510 |