CN1997360B - 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 com - Google Patents
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 com Download PDFInfo
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- CN1997360B CN1997360B CN2004800211331A CN200480021133A CN1997360B CN 1997360 B CN1997360 B CN 1997360B CN 2004800211331 A CN2004800211331 A CN 2004800211331A CN 200480021133 A CN200480021133 A CN 200480021133A CN 1997360 B CN1997360 B CN 1997360B
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Abstract
The present invention has as objective the stabilization of a fluoroether compound against degradation by acid substances. The stabilizers proposed are selected among appropriate pharmaceutical compounds selected from the group constituted of propylene glycol, polyethylene glycol, hexylene glycol and 1,3-butileneglicol, or a saturated cyclic alcohol preferably menthol, and are used for preparing stable pharmaceutical compositions of a fluoroether compound. Method for stabilizing a fluoroether compound and use of stabilizers agents for precluding the degradation of a fluoroether are also described.
Description
Invention field
The objective of the invention is to stablize the degraded that fluoroether compound acid-resisting material causes.
Especially, the present invention relates to the stable stable pharmaceutical composition that has the fluoroether compound of anesthesia characteristic and be used for the fluoroether compound of anesthetic use.The stabilizing agent that uses is selected from suitable medical compounds, and is used to prepare stable pharmaceutical composition.The present invention has also described, and a kind ofly is used to stop the method for fluoroether compound degraded and the purposes that stabilizing agent is used to stop the fluoroether compound degraded, and described degraded is caused by acidic materials.
The fluoroether compound with anesthesia characteristic that the present invention relates to comprises sevoflurane, desflurane, isoflurane, enflurane and methoxiflurane.In these fluoroether compound, the present invention is particularly useful for sevoflurane.
According to scope of the present invention, acidic materials refer to present the material of acidic nature, especially refer to the metal impurities of acidic nature, and it can contact with fluoroether compound such as sevoflurane in various situations.
Background technology
The decomposition of fluoroether compound is a kind of rare phenomenon, generally originates from conjunction with the material that presents pattern of reactivity or the characteristic relevant with these chemical compounds.
In the decomposition type, known by CO
2The degraded of the fluoroether compound sevoflurane that (carbon dioxide) absorbent causes is generally used for the vaporization circulation of this product.These CO
2Absorbent be strong relatively alkali as " sodium calcium Calx " (by calcium hydroxide, sodium hydroxide and potassium hydroxide are formed), the example of " barium calcium Calx (baralime) " (forming) by calcium hydroxide and barium hydroxide, the water content of two kinds of adsorbents is 14% to 19%, to provide effectively and CO efficiently
2Absorb.Degradation mechanism comprises by these alkali removes acid proton from sevoflurane, formation is called the alkene (2-(fluoro methoxyl group)-1 of compd A, 1,3,3,3-five fluoro-propylene), it is the theme of strong arguement, because its possible downright bad toxicity [Royal College OfAnesthetics Newsletter-January 2000, Issue no.50pg.287-289] in the mankind.
For fear of this by common CO
2The degraded that adsorbent causes is used sevoflurane and is used small throughput steam to become expert and anesthetist are used this narcotic common suggestion in open loop.
In addition, the degraded of sevoflurane, and may form a large amount of compd As, stimulated the CO that can avoid this degraded
2The exploitation of adsorbent, its example is
[J.M.Murrayet al, " Amsorb-a new carbon dioxide absorbent for use inanesthetic breathing systems "-Anesthesiology 1999].
Except there being CO
2The degradation mechanism of sevoflurane during adsorbent, only with the anesthesia process in outside the high-probability event of vaporization circular correlation of this product, determined second kind of degradation mechanism, it is the result when existing with lewis acid that this material contacts.Present-any fluoroether compound of C-O-C-F group although this mechanism has covered, the sevoflurane proof is especially responsive to this degraded.
Fig. 1 has presented the degradation mechanism of the sevoflurane by Louis acid catalysis (S) of suggestion in the document WO 98/32430.In the mechanism of this suggestion, the degraded of sevoflurane is by lewis acid (LA) the institute catalysis in the compositions that is present in the vial of packing as sevoflurane.
Analyze from chemistry, glass is made up of silicate, and except other material, comprises a spot of aluminium oxide.Glass is handled with its surface of passivation glass after making, and its meaning refers to not expose the free hydroxyl group that is incorporated into Silicon stone.Yet the exposure of this hydroxyl can cause that it can cause by seam or the loss that glass surface exists in any manufacturing step or during the preservative treatment of this material.These are incorporated into the hydroxyl of Silicon stone, if expose, just contact with sevoflurane and cause the degraded of sevoflurane.
The complex mechanism of the sevoflurane that confirms among Fig. 1 degraded causes the formation of toxicity volatile substance, other chemical compound of Fluohydric acid. or it and glass reaction generation wherein, and SiF4 (Silicon fluoride .), two all is the material that extremely corrodes respiratory tract.
Further according to mechanism illustrated in fig. 1, infer that it is that a chain mechanism is possible, catabolite wherein, especially Fluohydric acid., the integrity (G) of etching glass by reaction illustrated in fig. 2, make more the multichannel Lewis acid be exposed to the surface and go up (LA), its will with one that restarts degradation mechanism new sevoflurane molecular reaction.
In the present available suction anesthetis, sevoflurane has presented preferably by the index of medical expert and their patient acceptance.Since it in nineteen ninety since Japan puts on market, this anesthetis presents the application that increases gradually always, because being better than other, its quality sucks anesthetis, mainly due to its pleasant and non-stimulated abnormal smells from the patient and in adult and child, induce faster and recover and anaesthetize.
Since it was put on market, this product was sold with glass packaging, and glass packaging is the narcotic selection packings of several suctions.Because exist catalytic amount be incorporated into the lewis acid on surface the time, the quality of glass almost is impossible control, so exploitation is used for stablizing the stable composition of sevoflurane or method for being very important with the promising sale of this packing.
It is very extensive and broad having the material classification of serving as lewis acidic characteristic.According to Lewis, acid is equivalent to a kind of material that can accept electron pair and form the unoccupied orbital of covalent bond that has.In a word, acid is the receptor of electron pair, and alkali is the donor [John B.Russel-Quimica Geral-1982 pg.395] of electron pair.Because can be included into the coverage of the material of Louis's classification such as acids, glass has not only been represented the potential risk to sevoflurane stability, and several other packing, container or the materials of having represented sevoflurane to contact.
Once there were some to discuss the list of references that is degraded to the final degraded that lewis acid causes of solution that sevofluranes produce.For example, document WO 98/32430 has been described and has been utilized Lewis acid inhibitor to avoid the sevoflurane degraded.This patent has been described, and utilizes water to avoid the degraded of sevoflurane, and water is preferably with 150ppm to 1, and the concentration of 400ppm is used, and also, with respect to the weight of sevoflurane, the percentage by weight of water is 0.0150% to 0.1400%.A large amount of lewis acids is used in the experiment of carrying out, with the inhibition of proof by water is degraded to sevoflurane.
Although document WO 98/32430 shows the inhibition of water to the sevoflurane degraded according to supposition, in fact this reagent does not prove efficiently, even when being used to suppress the sevoflurane degraded with recommended amounts, because the solution that produces causes HFIP (1,1,1,3,3, the 3-hexafluoroisopropanol) form, it causes further degraded, forms acetal (methylene glycol two-hexafluoro diisopropyl ether) and Fluohydric acid..
Other list of references for fear of sevoflurane degraded purpose is patent US 6.074.668, and it has advised that is used for the container that sevoflurane is stored.This container is made by the material that is different from glass, to avoid owing to the lewis acid that finally has catalytic amount causes degrading according to the sevoflurane of above-mentioned mechanism.The material of container is polyethylene naftalate (PEN), and the author advises that it is except that glass, avoids sevoflurane degraded and because the only material of the container fragmentation that possible accident causes in surgicenter's (surgical operation).Polyethylene naftalate is the material with the more impermeable plastics outward appearance of anesthetis, and can be used as glass subsitute and be used for narcotic storage.This material is its high price and lacks its method of recycling at present as the major defect of packing.
Since in the document seldom list of references propose to solve the method for the degradation problem of the fluoroether compound, the especially sevoflurane that are used for anesthetic use, therefore need the enough high-efficiency method of exploitation stablizing this chemical compound, and control the degraded that it is caused by acidic materials.
The packing of other material is used in other list of references suggestion, because there are some inconvenience in plastic material, for example, it is to the permeability of volatile matter.The selection in this field is those materials of describing among special plastics or polymeric material such as the patent US 6.074.688, it is except the price of costliness, they can not reuse and the refuse that causes polluting, opposite with the packing of being made by glass, it can easily reuse is the ecological suitable selection of.Other shortcoming of these materials is the probability of acetaldehyde migration, and acetaldehyde is because material heats and owing to contain some degradation mechanism of the packing of polyethylene polymer, the material that produces during the packing extrusion process.
Except those inconvenience, these materials can also be categorized as lewis acid, or can be polluted by lewis acid in any fabrication stage or operating period, and when lewis acid contacted with sevoflurane, it can start the sevoflurane degradation mechanism.
The method of describing in the document WO 98/32430, its suggestion water is as the inhibitor of sevoflurane degraded, do not confirm to guarantee suitably to suppress the degraded of this chemical compound, because observed HFIP (1,1,1,3,3,3-hexafluoroisopropanol) formation is can not fully suppress this mechanism to guarantee not form other degradation by-products, also is the credible evidence of Fluohydric acid..Except the evidence that obtains document support, Wallin et al.[R.F.Wallin, B.M.Regan, M.D.Napoli, I.J.Stern Anesthesia and Analgesia 1975,54 (6), 758] the sevoflurane degraded of report also is known, it has been described in water, and this chemical compound has carried out slight still measurable hydrolysis.HFIP forms and shows in the sevoflurane degradation mechanism about the information of sevoflurane hydrolysis and also may relate to water, and this makes it become inappropriate material as the reliable inhibitor of this anesthetis degraded.
Summary of the invention
In order to overcome all inconvenience of prior art, the invention describes a kind of stable anesthetis compositions, it contains fluoroether compound such as sevoflurane and a kind of effective dose at least a stabilizing agent that is selected from polyhydric alcohol and saturated cyclic alcohol.Wherein the suitable polyhydric alcohol with used as stabilizers is propylene glycol, Polyethylene Glycol, methyl pentanediol and 1,3 butylene glycol among the present invention.The example that is used for suitable saturated cyclic alcohol of the present invention is a menthol.
Chemical name through authenticating compound sevoflurane (CAS 28523-86-6) is a methyl fluoride 2,2,2-three fluoro-1-(trifluoromethyl) ether, and its molecular weight is 200.06, molecular formula is C
4H
3F
7O, the structural formula of representing by alphabetical S among structural formula such as Fig. 1.
Chemical name through identifying propylene glycol is 1,2-propylene glycol (CAS 57-55-6).
Polyethylene Glycol (CAS 25322-68-3) is corresponding to general formula H (OCH
2CH
2)
nThe polymer of OH, wherein n is equal to or greater than 4.Generally, there is the numeral corresponding to its mean molecule quantity each Polyethylene Glycol back.
Chemical name through identifying methyl pentanediol is a 2-methyl-2,4-pentanediol (CAS107-41-5).
Chemical name through identifying 1,3 butylene glycol is 1,3 butylene glycol (CAS 107-88-0).
Chemical name through identifying menthol is (1 α, 2 β, 5 α)-5-methyl-2-(1-Methylethyl) Hexalin (CAS 89-78-1).
Can pass through to add effective amount of stabilizer in fluoroether compound such as sevoflurane, or, be degraded by acidic materials, prepare pharmaceutical composition of the present invention to prevent fluoroether compound such as sevoflurane by adding fluoroether compound such as sevoflurane in stabilizing agent.Acidic materials of the present invention refer to the material of acidic nature, especially refer to the metal impurities of acidic nature, and it can contact with fluoroether compound such as sevoflurane in various situations.
The present invention has also described a kind of fluoroether compound that is used to make, fluoroether compound such as the stable method of sevoflurane in particular for anesthetic use, it comprises that the interpolation effective amount of stabilizer is in fluoroether compound such as sevoflurane, or effective amount of stabilizer is contacted with fluoroether compound such as sevoflurane, to stop the degraded of fluoroether compound.In the suitable stabilizers of the antihunt means that are used for the present invention's suggestion, polyhydric alcohol and saturated cyclic alcohol are specified.Be used for the inventive method, especially be proposed to be used in the suitable polyhydric alcohol of stablizing sevoflurane, propylene glycol, Polyethylene Glycol, methyl pentanediol, 1,3 butylene glycol or its mixture are specified.Be used for suitable saturated cyclic alcohol of the present invention, menthol is specified.
According to the present invention, can use as the polyhydric alcohol that is selected from propylene glycol, Polyethylene Glycol, 1,3 butylene glycol, methyl pentanediol or its mixture and saturated cyclic alcohol and stablize fluoroether compound such as sevoflurane as materials such as menthol wherein.These materials prevent HFIP fully, and the formation of other catabolite of HF and sevoflurane can protect sevoflurane to avoid the effect of the reactive materials of acidic nature very efficiently.
The present invention has further described the anesthetis compositions that contains sevoflurane, owing to added stabilizing agent material such as polyhydric alcohol and saturated cyclic alcohol, sevoflurane is not degraded when having acidic materials.The present invention has also described the stable anesthetis method for compositions of preparation sevoflurane.
Pharmaceutical composition of the present invention comprises by the sevoflurane with respect to the weight any amount of stabilizing agent.For as sucking anesthetis, it is 95% to 99.999% sevoflurane that pharmaceutical composition preferably contains by the final composition weight concentration.The stabilizing agent that adds in the pharmaceutical composition of the present invention is when existence has the reactive materials of acidic nature, can prevent the material of sevoflurane degraded.This stabilizing agent is selected from polyhydric alcohol and saturated cyclic alcohol.In being used as the suitable polyhydric alcohol of stabilizing agent of the present invention, propylene glycol, Polyethylene Glycol, methyl pentanediol, 1,3 butylene glycol or its mixture are specified.Be used for suitable saturated cyclic alcohol of the present invention, menthol is specified.
Be used for fluoroether compound, in particular for the stabilizing agent of sevoflurane, with the weight with respect to sevoflurane, 0.001% until its level that reaches capacity in sevoflurane by weight, also is that it keeps dissolved Cmax to use in sevoflurane.The amount of the stabilizing agent that reaches capacity depends on stabilizing agent and temperature, and can be higher according to its dissolution mode in these materials.This is the situation of PEG400 for example, and it easily is dissolved in sevoflurane.Usually, the preferred use amount of stabilizing agent of the present invention is, with respect to the weight of sevoflurane, and by weight 0.001% to 5%.But, the stabilizing agent of higher amount also within the scope of the invention because the stabilizing agent of any content all promotes the stable of material target.
In stablizing the suitable polyhydric alcohol of fluoroether compound sevoflurane, select propylene glycol, Polyethylene Glycol, methyl pentanediol and 1,3 butylene glycol.These materials are the suitable drug excipients that are used for pharmaceutical composition, and their toxicology data is known.Quote as the front, the content range of stabilizing agent is by weight 0.001% level that reaches capacity up to it in sevoflurane.In the particular case of propylene glycol, the level that it reaches capacity in sevoflurane is about 2.5%, and PEG400 is soluble in sevoflurane.Therefore, in general, the preferred use amount of polyhydric alcohol is the weight with respect to sevoflurane, by weight 0.001% to 5.0%.
In stablizing the suitable saturated cyclic alcohol of sevoflurane, menthol preferably.This material is the suitable drug excipient that is used for pharmaceutical composition, and its toxicology data is known.Quote as the front, the content range of this stabilizing agent is by weight 0.001% level that reaches capacity up to it in sevoflurane, also is about 6.8%, and preferred use amount scope is the weight with respect to sevoflurane, and by weight 0.001% to 5.0%.
Be used for stabilizing agent proof of the present invention and can stop the sevoflurane degraded very efficiently with any use amount.In sucking anesthetis, narcotic purity is even more important, because the existence of a large amount of different materials can cause being used for vaporization and use the undesirable effect of narcotic machine,, or even need the special purpose machinery in the product vaporization situation to calibrate as the deposition of residue in the circulation.
Therefore, in the most preferred variant of the present invention, being used to stop the amount of the stabilizing agent that sevoflurane degraded by acidic materials is 10ppm to 2,000ppm (with respect to sevoflurane, stabilizing agent is 0.001% to 0.200% by weight).
A key factor of emphasizing is, with respect to its concentration, the characteristic of stabilizing agent material is because according to the concentration of inactivation type and the degraded in medium, its concentration in end-product can reduce during final product storage.Stabilizing agent works by elimination or deactivation harmful substance and reaches the stability that is stabilized reagent, and in situation of the present invention, being stabilized reagent is fluoroether compound such as sevoflurane.Stabilizing agent efficient is directly related with its affinity to degraded, and this affinity must surpass treats that stable material is to several times of the affinity of identical degraded.
The method that is used for stablizing sevoflurane of the present invention comprises adds effective amount of stabilizer to sevoflurane, or effective amount of stabilizer is contacted with sevoflurane, to prevent the formation of HFIP and HF fully.Several method can be used for the antihunt means of suggestion, but is favourable, and preferably practical approach is to cause forming homogeneous mixture, and quantitatively sets up between stabilizing agent and sevoflurane.In the suitable stabilizers of the antihunt means that are used for the present invention's suggestion, it is fixed that polyhydric alcohol and saturated cyclic alcohol are meant.Be used for the suitable polyhydric alcohol of antihunt means of the present invention, propylene glycol, Polyethylene Glycol, methyl pentanediol, 1,3 butylene glycol or its mixture are specified.Be used for suitable saturated cyclic alcohol of the present invention, menthol is specified.
In general, stabilizing agent can add in the sevoflurane in any stage of its preparation, for example, in the industrial packaging that product is stored in large quantities and transported, bin at the machine that is used for filling the drug products of making, in filling the bottle of final pharmaceutical composition, last, in any stage of sevoflurane operation.
Preferably, before the packing of product,, stabilizing agent is added in the sevoflurane,, add the stabilizing agent of appropriate amount, and form homogeneous mixture to guarantee with respect to the content for the treatment of stable sevoflurane by the quantitative measurement instrument.
Selectively, the method according to the suggestion that is used for stablizing sevoflurane is full of between the sevoflurane at hold-up vessel, and stabilizing agent is added in the hold-up vessel.
For fear of unstabilized fluoroether compound such as sevoflurane are exposed to the surface that may have acidic materials the preceding, antihunt means suggestion of the present invention is handled non-stabilized fluoroether compound with stabilizing agent by the whole bag of tricks, with the acidic materials of elimination or the final trace of deactivation.In a variant of this method, by with stabilizing agent rinsing container or accepter, make for example glass of stabilizing agent and container or accepter, plastics, the bottle contact of steel or other material.According to the physical characteristic of stabilizing agent, it can be sprayed, and vaporizes or is spread across on the inner surface of the bottle of storing sevoflurane or accepter, and the surface is gone up and formed film within it.
Most of packaging material are made up of the mixture of the material with acidic nature or these materials.When packaging material did not contain this material, fluoroether compound can contact them in any stage of operation.Because the degraded of sevoflurane is a chain mechanism that is only started by the acidic materials that have catalytic amount,, sevoflurane can impair its stability so being exposed to this material.Therefore, the invention provides the method that stops fluoroether compound such as sevoflurane to be degraded by acidic materials, it is enough to be used in storing in the packing of any kind of of sevoflurane.
Because the existence of the acid impurities material of catalytic amount can be unfavorable for sevoflurane, so a safety measure is only to use the sevoflurane that contains stabilizing agent.Therefore, in other variant, the present invention be used for stabilising packaging be not only glass and also be plastic material, steel, resin, polymer, at last, in the packing container of any material that may have an acid impurities, perhaps in processing, store, transhipment, preservative treatment, operation, or the like during the sevoflurane that may contact with material with acidic nature.
The present invention has confirmed, has important performance as materials such as polyhydric alcohol and saturated cyclic alcohol, and can bring into play the effect that stops sevoflurane to be degraded by acidic materials, wherein with respect to the prior art of suggestion water as stabilizing agent, when improvement is to have acidic materials, stop the formation of other catabolite of HFIP and HF and sevoflurane.
A class novel substance has been introduced in the development that the present invention obtains, and it presents the stability to chemical compound, described chemical compound such as sevoflurane, and other can suffer the similar fluoroether compound of identical illeffects when contacting with the material with acidic nature.
The comparative study that shows among the embodiment of this document has proved the ability of the chemical compound described in the present invention in preventing fluoroether compound sevoflurane degraded, and the chemical compound described in the present invention provides prevents to act on such as what the water described in the document WO 98/32430 provided and prevent that effect is more effective.
And according to the research shown in the embodiment, preferred pin has confirmed that to the research of fluoroether compound sevoflurane the present invention is not limited to the stable of anhydrous sevoflurane.
The sample that " contains the sevoflurane of water as stabilizing agent " is exposed to material with acidic nature such as the analysis result of aluminium oxide confirms, stable is not effective, because HFIP forms with the content of fluoride increase and confirmed the sample degraded, this shows the low potentiality that water is stable.
Contain the not degraded of wet sample of stabilizing agent of the present invention, show the high potentiality that these materials are stable.
Quote as the front, studies confirm that shown in the embodiment, water-soluble sevoflurane has carried out slight still measurable hydrolysis.Chemical compound of the present invention has prevented degraded fully, because HFIP and content of fluoride do not increase.
According to the present invention, being proposed to be used in the chemical compound of stablizing sevoflurane, to surpass in the sevoflurane of 20ppm in stable aqueous amount also be efficiently, when being used for water content for the time, be stabilizing agent efficiently up to its wet sevoflurane of about 1400ppm (0.14%) of saturated level.
Scope of the present invention without limits so that the effectively stable of a kind of sevoflurane and the fluoroether compound with similar chemical characteristic is provided, it is not only applicable to compositions, and is applicable to preparation or stores in the different solutions of sevoflurane or fluoroether compound.
Description of drawings
Then, the accompanying drawing of quoting in this document is briefly described:
Fig. 1: when having the lewis acid (LA) be incorporated into the surface, the degraded diagram of sevoflurane (S) forms derivant 1,2 simultaneously, and 3 and acetal;
Fig. 2: the reaction scheme of Fluohydric acid. (HF) and intact glass surface (V), more lewis acid is exposed to the surface and goes up (LA);
Fig. 3: when lacking aluminium oxide, after 60 ℃ of heating 22 hours, the anhydrous sevoflurane (chromatogram of water content=20ppm);
Fig. 4: when having every milliliter of sevoflurane 1mg aluminium oxide, after 60 ℃ of heating 22 hours, the anhydrous sevoflurane (chromatogram of water content=20ppm);
Fig. 5: when having aluminium oxide, the degraded diagram of sevoflurane;
Fig. 6: sample is after 60 ℃ of heating 72 hours, and when degrading about the oxidized aluminum of sevoflurane (every milliliter of sevoflurane 1mg aluminium oxide), water is to the influence of sevoflurane stability;
Fig. 7: when having every milliliter of sevoflurane 1mg aluminium oxide, after 60 ℃ of heating 22 hours, contain the chromatogram of the anhydrous sevoflurane of 50ppm propylene glycol;
Fig. 8: sample is after 60 ℃ of heating 22 hours, and when degrading about the oxidized aluminum of sevoflurane (every milliliter of sevoflurane 1mg aluminium oxide), propylene glycol is to the influence of sevoflurane stability;
Fig. 9: sample is after 60 ℃ of heating 22 hours, and when degrading about the oxidized aluminum of sevoflurane (every milliliter of sevoflurane 1mg aluminium oxide), propylene glycol is to the influence of the stability of HFIP impurity content;
Figure 10: sample is after 60 ℃ of heating 22 hours, and when degrading about the oxidized aluminum of sevoflurane (every milliliter of sevoflurane 1mg aluminium oxide), menthol is to the influence of the stability of HFIP impurity content;
Figure 11: when lacking or having every milliliter of sevoflurane 1mg aluminium oxide, sample relatively contains the average total impurities value of the anhydrous sevoflurane (approximately 20ppm water) of 50ppm propylene glycol or 50ppm PEG 400 after 60 ℃ of heating 22 hours.
Figure 12: with respect to " 0 ", it is when lacking aluminium oxide, 60 ℃ the heating 22 hours after, contain the result that the sevoflurane sample of 50ppm water is obtained, when having every milliliter of sevoflurane 1mg aluminium oxide, sample relatively contains the catabolite of the sevoflurane of 50ppm water, propylene glycol, PEG 400 or menthol after 60 ℃ of heating 22 hours.
The present invention will comprise or be described in detail by the exemplary embodiment of deutero-several application of the present invention and probability by following, yet and non exhaustive.Though the compositions of the following examples and method are the descriptions for its preferred variants, it will be apparent to one skilled in the art that and to carry out some changes and do not deviate from scope of the present invention.
The specific embodiment
In the following example, add 2 μ L toluene (internal standard) in the sevoflurane sample that 10mL studied, carry out all analyses by gas chromatography.Each is analyzed and all to carry out double, and to the ratio of every kind of impurity area/toluene area of each chromatographic computation of obtaining.Value representation shown in the table is available from the average ratio of double chromatography.
The purpose of this guided bone research is to select to be used for the following stress condition that uses the research of stabilizing agent material.
For example, when making anhydrous sevoflurane sample and aluminium oxide (Al
2O
3) when contacting, and, can observe the degraded of acidic materials to sevoflurane in 60 ℃ of heating 22 hours.
The sevoflurane that is used for this test carries out drying with molecular sieve in advance, and reaching water content is 20ppm.Adding the anhydrous sevoflurane of 20mL is in two III type vials of 100mL to capacity, adds the 20mg aluminium oxide in 1 bottle wherein, finally reaches every milliliter of sevoflurane 1.0mgAl
2O
3Two bottles are all used plug and screw cap sealing, and heat 22 hours in 60 ℃ in baking oven.After this stage, use internal standard additive process (toluene), sample is carried out the double analysis by gas chromatography.Fig. 3 has shown the chromatograph of the anhydrous sevoflurane sample that does not have the aluminium oxide heating, does not observe degraded in this case.By the catabolite of gas chromatography monitoring sevoflurane, as shown in Figure 4, in containing the sevoflurane sample of aluminium oxide, there is a large amount of HFIP in heating, acetal, 2,5,7 and 8 later.
Fig. 5 has shown under the effect of aluminium oxide, the degraded diagram of sevoflurane, and showing has the impurity of observing and monitoring.
Because the use amount of activated alumina is enough to cause the remarkable degraded of sevoflurane, so in this research, use this amount to select to be used for the stabilizing agent of sevoflurane.
This embodiment has shown about the research of water to the sevoflurane stability influence.According to document WO 98/32430, the 150ppm that is present in the sevoflurane will guarantee that to the water content of 1400ppm it suppresses the stability that catabolite forms.
Use sevoflurane to carry out this research, to reach the initial water content of 20ppm with molecular sieve drying.When having water, contact with aluminium oxide, from containing different moisture content, with or without the protection or the palliating degradation degree of the sevoflurane sample evaluating sevoflurane of alumina treatment, wherein this processing is carried out in the ratio of every milliliter of sevoflurane 1mg aluminium oxide.The preparation sample, and place III type vial, and also bottle seals with plug and screw cap.
Sample is placed under two kinds of stress conditions, promptly in baking oven, carry out 22 hours circulation and carry out another circulation of 72 hours in 60 ℃ of heating.
Following table 1 has shown the chromatography result of sample:
Table 1
1The average summation of every kind of impurity area/toluene (internal standard) area ratio;
2The meansigma methods of HFIP area/toluene area ratio.
Consistent with the result in have water and the aluminium oxide time table, total impurity quite big with HFIP value with the different variations of studying.Though this result has shown that only the water of 600ppm has just started the degraded of inhibited oxidation aluminum to sevoflurane, this result also shows the relative value that remaining HFIP obtains of having assessed.
Fig. 6 has shown under higher stress condition, the development of the average product of sevoflurane degraded.Consistent with the result, observed sevoflurane degraded is higher than the sevoflurane degraded in the sample that contains 20ppm water in the sample that contains 100ppm water, it shows that water may be important to the sevoflurane degraded takes place, water participates in the degradation mechanism of sevoflurane under acid condition, and is not only as the stabilizing agent described in the patent WO 98/32430.As taking place in many organic reactions usually, the water of higher concentration obviously suppresses the decomposition of sevoflurane.Simultaneously, as Wallin et al.[R.F.Wallin, B.M.Regan, M.D.Napoli, I.J.Stern Anethesia andAnalgesia 1975,54 (6), 758] described, but the sevoflurane in the water has stood slowly measurable hydrolysis, and this is an evidence, supported in some mechanism that promote the sevoflurane degraded, may relate to the hypothesis of water, and the result who obtains has observed this phenomenon in this research.
In this embodiment, use polyhydric alcohol and saturated cyclic alcohol to prevent the degraded of aluminium oxide to sevoflurane.The material of selecting in every group is respectively propylene glycol and menthol.
Preparation contains 0,50,200,600,1000 and the sample of 1400ppm stabilizing agent.The sevoflurane that is used to prepare these samples carries out drying with molecular sieve in advance, is the water of 20ppm to obtain content.This research comprises makes sevoflurane contact with acidic materials, sample is in the stress in 22 hours by 60 ℃ of heating, and passes through the chromatographic purity of comparative assessment sevoflurane after stress.Use activated alumina as acidic materials, with the constant consumption of every milliliter of sevoflurane 1mg activated alumina.
The test sevoflurane and the 20mg aluminium oxide that 20mL are contained true quantitative stabilizing agent (0,50,200,600,1000 and 1400ppm) are transferred in the III type vial that capacity is 100mL.Bottle is immediately with plug and screw cap sealing.These bottles heated 22 hours in 60 ℃ in baking oven.After this stress, use internal standard additive process (toluene), sample is carried out the double analysis by gas chromatography.Do not having under the situation of aluminium oxide to carry out parallel study with true quantitative stabilizing agent (0,50,200,600,1000 and 1400ppm).
Table 2 has been summarized with being intended for use in stablize the reagent propylene glycol of sevoflurane antioxidation aluminium degraded and the test that menthol carries out, and after 60 ℃ of stress of 22 hours, with and the total impurities that obtains without aluminium oxide and the result of single impurity HFIP.Total impurities is the summation of the ratio between the area (toluene) of the area of every kind of impurity obtaining in chromatograph and internal standard, and HFIP is the ratio between the area of the area of the HFIP that obtains in chromatograph and toluene.
Table 2
1The average summation of the ratio of the area of the area/toluene of every kind of impurity (internal standard);
2The meansigma methods of the ratio of the area of area/toluene of HFIP.
The result of table 2 shows do not having under the situation of aluminium oxide, and the value of average total impurities of sample that contains the variable concentrations stabilizing agent is very near the value that do not have stabilizing agent to obtain.When having aluminium oxide, the high average total impurities value of the observed sevoflurane that does not have a stabilizing agent significantly reduces in as the sample of stabilizing agent comprising propylene glycol or menthol.Fig. 7 shows, compares with embodiment 2, when having aluminium oxide, is in after 60 ℃ of stress of 22 hours, contains the not degraded of sevoflurane of 50ppm propylene glycol, proves that propylene glycol is the stabilizing agent that is better than water.
Embodiment 3.1. is along with the total impurities development of the different sevofluranes of stabilizer concentration.
The bar diagram of Fig. 8 shown, after 60 ℃ of stress of 22 hours, the comparison of the average total impurities of sevoflurane with the difference of propylene glycol concentration, arranged or when not having every milliliter of 1mg aluminium oxide.This chart understands that propylene glycol with the low concentration of 50ppm and the propylene glycol concentration of all researchs, can effectively be stablized the degraded of sevoflurane antioxidation aluminium to it.
Have or do not have aluminium oxide, the average total impurities that contains the sample of propylene glycol does not change, and this shows that it can effectively stable sevoflurane.
Menthol also can effectively be stablized the degraded of sevoflurane antioxidation aluminium to it, and in fact Stabilization does not rely on its concentration, table 2.Although the average total impurities of sevoflurane that contains menthol is just over value that does not have aluminium oxide to obtain and the value that contains the sample of propylene glycol, and may notice that the Stabilization that menthol provides is the same or more effective with the observed Stabilization of water, table 1.
Embodiment 3.2. is along with the development of the different impurities HFIP of stabilizer concentration.
Fig. 9 has shown, the propylene glycol of 50ppm is enough to prevent the degraded of sevoflurane, and the formation of follow-up HFIP to be different from water observed, when having aluminium oxide, even with the concentration of 260ppm, water can not suppress the degraded of sevoflurane fully, and this sample that contains aluminium oxide shows that the value of HFIP is higher than the observed HFIP value of sample (table 1) of oxygen-free aluminum.
The obvious suppression effect that water provides is relative, because for the sample that does not have aluminium oxide, impurity HFIP value has increased about 10 times, and this has proved the degraded of sevoflurane.This does not observe with propylene glycol, and when existence or shortage aluminium oxide, the HFIP value of propylene glycol remains unchanged.
Contain at sevoflurane under the situation of menthol, Figure 10 shows that impurity HFIP reduces along with menthol concentration increases.
The result total and single impurity (respectively as embodiment 3.1 and 3.2) of propylene glycol shows, when having aluminium oxide, and the result when not having aluminium oxide, the impurity result that enough Stabilization of propylene glycol antioxidation aluminium degraded remain unchanged substantially.
This result shows that propylene glycol can be considered to than the better stabilizing agent of water, therefore can prevent the degraded of acidic materials to sevoflurane fully, and the formation that can prevent HFIP substantially, and HFIP is first product of sevoflurane degraded.
Proportionate water has been compared in this research, and propylene glycol and Polyethylene Glycol are all used with the concentration of 50ppm the Stabilization of sevoflurane.
Table 3 has shown, after 60 ℃ of stress of 12 hours, contains 50ppm stabilizing agent water, and propylene glycol and Polyethylene Glycol have and do not have the total impurities of sevoflurane sample of aluminium oxide and the result of single impurity (HFIP).
Table 3
1The average summation of the ratio of the area of the area/toluene of every kind of impurity (internal standard);
2The meansigma methods of the ratio of the area of area/toluene of HFIP.
The bar diagram that Figure 11 shows has compared the effect of the total impurities that the result of stabilizing agent his-and-hers watches 3 represents.With polyhydric alcohol such as propylene glycol and PEG 400, observed the prevention fully to the degraded of sevoflurane of alumina catalyzation.PEG 400, as propylene glycol, stoped the formation of HFIP fully, and different with water, water can not suppress the formation of HFIP, even with the concentration of 260ppm.
The bar chart that Figure 12 shows is understood the difference with stabilizing agent, and with the fixed amount of 50ppm, the primary product of the sevoflurane of generation degraded is shown in the result of table 2 (menthol) and table 3 (water, propylene glycol or PEG 400).In the sample that contains 50ppm water, follow HFIP, acetal, degraded has been observed in 2 and 5 formation, and in the sample that contains propylene glycol or PEG 400, the degraded of alumina catalyzation is prevented from fully.The water sevoflurane degraded that causes of inhibited oxidation aluminum fully detects in all analyses, has caused the increase of impurity HFIP and acetal, and it improves average total impurities result on a large scale.
Embodiment 5. stablizes the degraded of sevoflurane antioxidation aluminium.Impurity is analyzed and the fluoride limit.
In this research, aluminium oxide uses with the final concentration of every milliliter of sevoflurane 1mg aluminium oxide.Preparation sevoflurane sample is existing the water of 260ppm or the propylene glycol of 260ppm in III type Brown Glass Brown glass bottles and jars only, and this Brown Glass Brown glass bottles and jars only is under 60 ℃ of stress of 22 hours then with plastic plug and screw cap sealing.
Table 4 shown after the stress, contains the gas chromatographic analysis result of the sample of the water of 260ppm or propylene glycol.Observe the degraded that has prevented sevoflurane fully with propylene glycol, and the product that contains propylene glycol has reached single and specification total impurities.Yet the water of 260ppm does not have the degraded of inhibited oxidation aluminum to sevoflurane, and after the stress, aqueous product does not reach single and specification total impurities.
Table 4
1Pharmacopeial Forum USP Vol.27n ° 3;
2Be used to prepare the first analysis result of the anhydrous sevoflurane of the sample that contains stabilizing agent;
3The PG=propylene glycol.
When having aluminium oxide, containing the observed degraded of the sample of 260ppm water increases, and sample do not reach Pharmacopeial Forum USP, about chromatographic purity analysis and mensuration.
The amount that observed another key factor is a fluoride in the sample that is under the stress in this research.Table 5 has shown the result of the anhydrous sevoflurane that is used for this test, and the result who is in the sample under this stress condition:
Table 5
1Pharmacopeial Forum USP Vol.27n ° 3;
2Be used to prepare the first analysis result of the anhydrous sevoflurane of the sample that contains stabilizing agent;
3The PG=propylene glycol.
Consistent with table 5, the quantitative analysis of fluoride has shown that water is higher as the result of the sample of stabilizing agent.In this sample that is subjected to stress, the primary sample of analyzing before the amount specific stress of fluoride is high 339 times, and is higher 8 times than the maximum that obtains by this method, the degraded of its proof fluoride danger, and water is invalid as the inhibitor of sevoflurane degraded.Differently, when having aluminium oxide, the sevoflurane sample that contains the 260ppm propylene glycol does not show any degraded, and reached the specification described in the Pharmacopeial Forum vol 27n ° 3, the content that comprises fluoride is compared with primary sample, does not present variation.
Embodiment 6. uses polyhydric alcohol stablizing wet sevoflurane.
The stabilizing power of polyhydric alcohol in stoping wet sevoflurane degraded for example understood in this research.
The degraded of having verified sevoflurane when water is as stabilizing agent among the embodiment 5 increases the weight of.The purpose of this research is, proves polyhydric alcohol, and for example, propylene glycol is stable to moist sevoflurane, to stop the degraded of acidic materials to sevoflurane.
Aluminium oxide uses with the final concentration of every milliliter of sevoflurane 1mg aluminium oxide.Preparation sevoflurane sample is with the water of the water that has 260ppm in III type Brown Glass Brown glass bottles and jars only or 260ppm and the mixture of the propylene glycol of 260ppm, and this Brown Glass Brown glass bottles and jars only seals with plastic plug and screw cap, is in then under 60 ℃ of stress of 22 hours.
Carry out this research with check degradation-resistant stabilizing power of observed propylene glycol in the wet sample of sevoflurane.
The result who has shown the qualification of the gas chromatographic analysis of sample and fluoride in the table 6:
Table 6
1Pharmacopeial Forum USP Vol.27n ° 3;
2Be used to prepare the first analysis result of the anhydrous sevoflurane of the sample that contains stabilizing agent;
3The PG=propylene glycol.
According to former research, when water used with 260ppm, the antioxidation aluminium that water provides was inadequate to the protective effect of sevoflurane degraded.
In this research, we can approve that the effectiveness of propylene glycol not only provides the effective protective effect of antagonism by the catalytic anhydrous sevoflurane degraded of acidic materials, and have effectively protected wet sevoflurane, and it has shown that water does not disturb the stabilizing power of propylene glycol.
Here showing the research be used to prove effect of the present invention, is exemplary, rather than in order to limit the scope of the invention, it is applicable to as narcotic various fluoroether compound, as sketching previously in description.
Claims (9)
1. stable pharmaceutical composition, it is characterized in that comprising a certain amount of sevoflurane that is selected from, Desflurane, isoflurane, the fluoro-ether anesthetis chemical compound of enflurane and methoxiflurane, with at least a stabilizing agent, this stabilizing agent uses with 0.001% to 0.200% concentration of final composition weight, and this stabilizing agent is to be selected from propylene glycol, Polyethylene Glycol, 2-methyl-2,4-pentanediol and 1, the polyhydric alcohol of 3-butanediol, or menthol, or its mixture.
2. stable anesthetic agents compositions, it is characterized in that comprising a certain amount of sevoflurane, with at least a stabilizing agent, this stabilizing agent uses with 0.001% to 5% concentration of final composition weight, this stabilizing agent is to be selected from propylene glycol, Polyethylene Glycol, 2-methyl-2, the polyhydric alcohol of 4-pentanediol and 1,3 butylene glycol, or menthol, or its mixture.
3. the stable anesthetic agents compositions of claim 2, wherein this stabilizing agent is the propylene glycol that uses with 0.001% to 0.200% concentration of final composition weight.
4. the stable anesthetic agents compositions of claim 2, wherein this stabilizing agent is a PEG400, its concentration of 0.001% to 0.200% with final composition weight is used.
5. the stable anesthetic agents compositions of claim 2, wherein this menthol uses with 0.001% to 0.200% concentration of final composition weight.
6. stablize the method for sevoflurane, it is characterized in that using weight with respect to sevoflurane, concentration is 0.001% to 5% at least a stabilizing agent by weight, this stabilizing agent is to be selected from propylene glycol, Polyethylene Glycol, 2-methyl-2,4-pentanediol and 1, the polyhydric alcohol of 3-butanediol, or menthol, or its mixture.
7. the method for claim 6, wherein this stabilizing agent is with the weight with respect to sevoflurane, by weight the propylene glycol that uses of 0.001% to 0.200% concentration.
8. the method for claim 6, wherein this stabilizing agent is a PEG400, and it is with the weight with respect to sevoflurane, and 0.001% to 0.200% concentration is used by weight.
9. the method for claim 6, wherein this menthol is with the weight with respect to sevoflurane, and 0.001% to 0.200% concentration is used by weight.
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| BRPI0303489-5 | 2003-09-10 | ||
| BR0303489A BR0303489A (en) | 2003-09-10 | 2003-09-10 | Stabilized pharmaceutical composition of fluorine ether compound and method for inhibiting the degradation of fluorine ether compound. use of stabilizing agent to inhibit the degradation of fluorine ether compound |
| BRPI03034895 | 2003-09-10 | ||
| BRPI0405842A BRPI0405842B8 (en) | 2004-07-29 | 2004-07-29 | stabilized pharmaceutical composition of a fluor-ether compound for anesthetic use. method for stabilizing a fluorine-ether compound. use of stabilizing agent to prevent the degradation of fluor ether compound. |
| BR007698 | 2004-07-29 | ||
| PCT/BR2004/000156 WO2005023175A2 (en) | 2003-09-10 | 2004-08-20 | 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998032430A1 (en) * | 1997-01-27 | 1998-07-30 | Abbott Laboratories | Fluoroether compositions and methods for inhibiting their degradation in the presence of a lewis acid |
| WO2003018102A2 (en) * | 2001-08-29 | 2003-03-06 | Vectura Limited | Topical administration device |
| WO2003030862A2 (en) * | 2001-10-08 | 2003-04-17 | Maelor Pharmaceuticals Limited | Anaesthetic compositions and method for their administration |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998032430A1 (en) * | 1997-01-27 | 1998-07-30 | Abbott Laboratories | Fluoroether compositions and methods for inhibiting their degradation in the presence of a lewis acid |
| WO2003018102A2 (en) * | 2001-08-29 | 2003-03-06 | Vectura Limited | Topical administration device |
| WO2003030862A2 (en) * | 2001-10-08 | 2003-04-17 | Maelor Pharmaceuticals Limited | Anaesthetic compositions and method for their administration |
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