CN105193774A - Sevoflurane inhalant - Google Patents
Sevoflurane inhalant Download PDFInfo
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- CN105193774A CN105193774A CN201510604328.9A CN201510604328A CN105193774A CN 105193774 A CN105193774 A CN 105193774A CN 201510604328 A CN201510604328 A CN 201510604328A CN 105193774 A CN105193774 A CN 105193774A
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- sevoflurane
- inhalant
- thioglycerol
- ethanol
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Abstract
The invention belongs to the field of medicine and particularly relates to a sevoflurane inhalant which contains sevoflurane, thioglycerol and ethyl alcohol. The inhalant is prepared through the method which includes the steps that thioglycerol is dissolved in ethyl alcohol, the mixture is added into sevoflurane, and a glass bottle is filled with the inhalant. Compared with the prior art, the technology is simple, and stability is good.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of Sevoflurane inhalant.
Background technology
Compound Sevoflurane (1,1,1,3,3,3-hexafluoro isopropyl fluoromethyl ether or hexafluoro isopropyl fluoromethyl ether or (CF3) 2CHOCH2F) is widely used inhalation anesthetic, is particularly useful for outpatient operation.Therefore, cost-effective method is starved of to prepare stable Sevoflurane.
Described many methods preparing Sevoflurane, wherein many commercial application value are limited.United States Patent (USP) 3,683,092 describes four kinds of preparation methoies, wherein three kinds from 1,1,1,3,3,3-hexafluoro isopropyl methyl ether starts (react with potassium fluoride in sulfolane or react with bromine trifluoride), a kind of from 1,1,1,3,3,3-hexafluoroisopropanol starts (with formaldehyde and hydrogen fluoride reaction).United States Patent (USP) 3,897,502 describe 1,1,1,3,3,3-hexafluoro isopropyl methyl ether in argon with the direct fluorination reaction of element fluorine.United States Patent (USP) 4,874,901 disclose at supercritical conditions the halogen exchange reaction that (i.e. High Temperature High Pressure) adopts sodium fluoride.United States Patent (USP) 4,996, reports the carboxylated synthesis of fluorine adopting bromine trifluoride in 371.United States Patent (USP) 4,874, also uses bromine trifluoride in the another kind of building-up process described by 902.Adopt the another kind of synthetic method of hexafluoro isopropyl, formaldehyde, fluohydric acid gas and sulphuric acid at United States Patent (USP) 4,250, there is detailed description in 334.
United States Patent (USP) 5,969,193 prepare Sevoflurane by the optional method of viable commercial.Which provide 1,1,1,3,3,3-hexafluoro isopropyl methyl ether, this material and chlorinated with chlorine produce 1,1,1,3,3,3-hexafluoro isopropyl chloromethylether, then in the mixture of fluohydric acid gas and sterically hindered amines, fluoridize this intermediate product and obtain Sevoflurane.United States Patent (USP) 5,886,239 describe the similar synthetic method adopting other amine to prepare Sevoflurane.
In the product that the preparation method of current Sevoflurane obtains, usual water content is up to 0.12-0.14 % by weight, or 1200-1400ppm, and this is approximately the water saturation limit of Sevoflurane.
United States Patent (USP) 5,990,176,6,288,127,6,444,859 and 6,677,492 (" Abbott patents ") are pointed out, for making Sevoflurane keep stable between the storage life in standard anesthetis packaging (such as type III Brown Glass Brown glass bottles and jars only), in Sevoflurane, the existence of moisture is necessary.(because unsaturated Sevoflurane has hygroscopicity, solution between the storage life usually water content increase in time, therefore adding moisture is very easily)
Can there is slight degradation in Sevoflurane, produce Fluohydric acid. (a kind of known glass etching agent) and other catabolite between the storage life.Abbott patent is open, and when Sevoflurane is stored in vial, the Fluohydric acid. of generation, by etching glass inner surface, forms the material of such as aluminium oxide, and these materials play Lewis acid, further catalysis Sevoflurane degraded, thus forms more Fluohydric acid..Fluohydric acid. accelerate to produce as a result, produce increasing Lewis acid substance by degrade " cascade reaction " along with vial inner surface.
In order to solve the resolution problem of Sevoflurane between the storage life, think that can there is Lewis acid inhibitor (such as water) in the sevoflurane solution stored prevents the Lewis acid substance catalysis cascade degradation reaction in etching glass.Think that the amount that Lewis acid inhibitor exists must be enough to prevent Sevoflurane from degrading, to obtain in Lewis acid as sevoflurane solution stable under the existence of etching glass.But laws and regulations requirement Sevoflurane manufacturer indicates the storage stability in commercially available back (such as glass, plastics or metal).Therefore, if display is stable under the Sevoflurane moisture condition of dissolving in low-level, then the method retaining a small amount of moisture in Sevoflurane product will become useful Sevoflurane manufacture method.
CN101180250B provides the stable Sevoflurane that water content is less than 150ppm.The low water content sevoflurane solution that water content is about 0.0-0.003 % by weight (i.e. 0-30ppm) has long-time stability when storing in glass container.Solution is made to be exposed to the molecular sieve partly containing aluminium oxide, use salic molecular sieve, although due to salic and introduce known Lewis acid, though solution being dried to low water content, water content can be ignored or anhydrous after, still unexpectedly do not cause Sevoflurane to degrade.
In prior art, generally need containing minor amount of water in Sevoflurane, to improve the stability of medicine.Even but add water, be also only alleviate its degraded, can not avoid degraded completely, for the defect of prior art, inventor intends the Sevoflurane inhalant providing a kind of good stability.
Inventor considers, if Sevoflurane can be avoided to degrade, nature can ensure the stability of Sevoflurane in storage process.But Fluohydric acid. character is special, in infinitely rare solution, its ionization degree only has 15%, and this is the weak solution of HF is weakly acidic main cause.Along with the increase of HF concentration, the HF that F-becomes stability stronger with non-dissociated fluohydric acid gas molecule HF with hydrogen bonded
2 -ion, its hydrogen bond is short and strong symmetrical hydrogen bond, and acidity strengthens.
Inventor considers, water might not be the best solvent of effect, considers to replace water with micro ethanol, and result stability is improved greatly, but still can slowly degraded.Further, inventor considers to add a kind of material again, and to suppress Sevoflurane to be degraded, find unexpectedly, after adding thioglycerol, Sevoflurane is not substantially degraded in storage process.
Through qualification, thioglycerol molecular formula is C
3h
8o
2s, molecular weight 108.16 (CAS96-27-5)
Specifically, the present invention is realized by following technology:
The invention provides a kind of Sevoflurane inhalant, containing Sevoflurane, thioglycerol, ethanol.
Described Sevoflurane inhalant, the weight ratio of Sevoflurane and ethanol is 1:0.001-0.003.
Described Sevoflurane inhalant, the weight ratio of Sevoflurane and ethanol is 1:0.002.
Described Sevoflurane inhalant, the weight ratio of Sevoflurane and thioglycerol is 1:0.002-0.004.
Described Sevoflurane inhalant, the weight ratio of Sevoflurane and thioglycerol is 1:0.003.
The described method preparing Sevoflurane inhalant, is made up of following steps: thioglycerol dissolves in ethanol, and add in Sevoflurane, fill is in vial
Compared with prior art, the present invention is by adding ethanol and thioglycerol in Sevoflurane, reduce the degraded of Sevoflurane in storage process, prepared Sevoflurane inhalant has better stability in the present invention.
Summary of the invention
Detailed description of the invention
Following examples further describe beneficial effect of the present invention, embodiment is only for the object of illustration, do not limit the scope of the invention, the simultaneously apparent change made according to the present invention of those of ordinary skill in the art and modification are also contained within the scope of the invention.
Embodiment 1
Sevoflurane 375g
Ethanol 0.375g
Thioglycerol 0.75g
Preparation technology:
The thioglycerol taking recipe quantity dissolves in ethanol, and add in recipe quantity Sevoflurane, fill is in vial.
Embodiment 2
Sevoflurane 375g
Ethanol 1.125g
Thioglycerol 1.5g
Preparation technology:
The thioglycerol taking recipe quantity dissolves in ethanol, and add in recipe quantity Sevoflurane, fill is in vial.
Embodiment 3
Sevoflurane 375g
Ethanol 0.75g
Thioglycerol 1.125g
Preparation technology:
The thioglycerol taking recipe quantity dissolves in ethanol, and add in recipe quantity Sevoflurane, fill is in vial.
Embodiment 4
Preparation technology:
The thioglycerol taking recipe quantity dissolves in ethanol, and add recipe quantity ferrum oxide, then add in recipe quantity Sevoflurane, fill is in vial.
Embodiment 5
Sevoflurane 375g
Ethanol 0.75g
Preparation technology:
Take the ethanol of recipe quantity, join in recipe quantity Sevoflurane, fill is in vial.
Comparative example 1
Sevoflurane 375g
Water 0.01g
Preparation technology:
Take the water of recipe quantity, add in recipe quantity Sevoflurane, fill is in vial.
Comparative example 2
Sevoflurane is mixed with molecular sieve, then makes these materials keep several hours together.By KarlFischer assay water content.The Sevoflurane sample of drying is placed in new I11 type Brown Glass Brown glass bottles and jars only, this vial at 100 DEG C dry 2 hours.With gathering the black phenol/urea resin lid sealing bottle of sealed liner with polyvinyl resin and shrink wrapped, or with Teflon band parcel and shrink wrapped.Then sample is preserved under room temperature (25-27 DEG C) and envionmental humidity.
Checking embodiment
Gas chromatography determination Sevoflurane content.
As seen from the table, embodiment of the present invention 1-3, through accelerating investigation after 12 months and 24 months, Sevoflurane occurs without signs of degradation; In embodiment 4, add ferrum oxide, after accelerating, Sevoflurane content does not change substantially, illustrates and adds ethanol and thioglycerol can stop Sevoflurane to be degraded by lewis acid effectively; In embodiment 4, although add ethanol as stabilizing agent in Sevoflurane, behind 12 and 24 months Acceleration study, Sevoflurane still has certain degraded.Comparative example 1,2, are prior art, and after acceleration, Sevoflurane all has degraded in various degree.
Claims (6)
1. a Sevoflurane inhalant, is characterized in that, containing Sevoflurane, thioglycerol, ethanol.
2. Sevoflurane inhalant according to claim 1, the weight ratio of Sevoflurane and ethanol is 1:0.001-0.003.
3. Sevoflurane inhalant according to claim 1, the weight ratio of Sevoflurane and ethanol is 1:0.002.
4. Sevoflurane inhalant according to claim 1, the weight ratio of Sevoflurane and thioglycerol is 1:0.002-0.004.
5. Sevoflurane inhalant according to claim 1, the weight ratio of Sevoflurane and thioglycerol is 1:0.003.
6. prepare a method for Sevoflurane inhalant described in claim 1, step comprises:
Dissolved in ethanol by thioglycerol, add in Sevoflurane, fill is in vial.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510604328.9A CN105193774B (en) | 2015-09-21 | 2015-09-21 | A kind of sevoflurane inhalant |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510604328.9A CN105193774B (en) | 2015-09-21 | 2015-09-21 | A kind of sevoflurane inhalant |
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| Publication Number | Publication Date |
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| CN105193774A true CN105193774A (en) | 2015-12-30 |
| CN105193774B CN105193774B (en) | 2018-01-16 |
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| CN201510604328.9A Active CN105193774B (en) | 2015-09-21 | 2015-09-21 | A kind of sevoflurane inhalant |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111053760A (en) * | 2019-12-27 | 2020-04-24 | 江苏恒丰强生物技术有限公司 | Inhalation sevoflurane for pets |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126517A (en) * | 1994-04-08 | 1996-07-10 | 森陶硝子株式会社 | Gas chromatographic analysis of fluoromethyl 1,1,1,3,3,3-hexafluoroisopropylether |
| CN1244797A (en) * | 1997-01-27 | 2000-02-16 | 艾博特公司 | Fluoroether compositions and methods for inhibiting their degradation in the presence of a lewis acid |
| US20030185761A1 (en) * | 1997-10-01 | 2003-10-02 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
| WO2005023175A2 (en) * | 2003-09-10 | 2005-03-17 | Cristália Produtos Químicos Farmacêuticos Ltda. | Stable pharmaceutical composition of fluoroether compound for anesthetic use, method for stabilizing a fluoroether compound, use of stabilizer agent for precluding the degradation of a fluoroether compound |
-
2015
- 2015-09-21 CN CN201510604328.9A patent/CN105193774B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126517A (en) * | 1994-04-08 | 1996-07-10 | 森陶硝子株式会社 | Gas chromatographic analysis of fluoromethyl 1,1,1,3,3,3-hexafluoroisopropylether |
| CN1244797A (en) * | 1997-01-27 | 2000-02-16 | 艾博特公司 | Fluoroether compositions and methods for inhibiting their degradation in the presence of a lewis acid |
| US20030185761A1 (en) * | 1997-10-01 | 2003-10-02 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating pain |
| WO2005023175A2 (en) * | 2003-09-10 | 2005-03-17 | Cristália Produtos Químicos Farmacêuticos Ltda. | Stable pharmaceutical composition of fluoroether compound for anesthetic use, method for stabilizing a fluoroether compound, use of stabilizer agent for precluding the degradation of a fluoroether compound |
Non-Patent Citations (1)
| Title |
|---|
| 蒋玲，等: "二氧化碳吸收剂中水分对七氟醚分解反应的影响", 《临床麻醉学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111053760A (en) * | 2019-12-27 | 2020-04-24 | 江苏恒丰强生物技术有限公司 | Inhalation sevoflurane for pets |
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|---|---|
| CN105193774B (en) | 2018-01-16 |
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