CN108113986A - A kind of raising processing method of dexmedetomidine hydrochloride parenteral solution stability and dexmedetomidine hydrochloride parenteral solution - Google Patents
A kind of raising processing method of dexmedetomidine hydrochloride parenteral solution stability and dexmedetomidine hydrochloride parenteral solution Download PDFInfo
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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Abstract
The invention discloses a kind of raising processing methods of dexmedetomidine hydrochloride parenteral solution stability and dexmedetomidine hydrochloride parenteral solution, the processing method to include the following steps：Under nitrogen protection, prepared dexmedetomidine hydrochloride parenteral solution through micropore filter element is filtered, is cooled to 35 40 DEG C, be fitted into inner surface and be modified in the vial of active group, sterilizing；Wherein, the active group is the one or more in amino, sulfydryl, carboxyl, acid anhydrides.After being handled using this method, its stability can be improved without adding any auxiliary material in dexmedetomidine hydrochloride parenteral solution, auxiliary material is avoided and is adversely affected caused by parenteral solution.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of place for improving dexmedetomidine hydrochloride parenteral solution stability
Reason method and dexmedetomidine hydrochloride parenteral solution.
Background technology
Dexmedetomidine hydrochloride is a highly selective α 2- adrenoceptor agonists, has tranquilizing soporific, anti-coke
Consider, ease pain, the effect of retardance sympathetic nerve, being a kind of effective calmness, ease pain, adjunct anesthetic.Dexmedetomidine hydrochloride
It is succeeded in developing jointly by Abbott Laboratories of the U.S. and Orion company of Finland earliest, at present in more than 30 a countries and regions listing pin of the whole world
It sells, 2012 global marketing volumes are up to 2.56 hundred million dollars, and growth rate is up to 96.8%, and global marketing volume increases very fast.The medicine carries
Unique calm type i.e. " calmness for retaining consciousness " has been supplied, and anesthesia, the dosage of analgesic in art can be reduced, has effectively been inhibited
The stress situation of perianesthesia care improves blood samples of patients dynamics, and without apparent respiration inhibition, while can be disliked with prevention of postoperative
The heart is vomitted and shiver with cold, and has potential benefit to nerve, heart and protection renal.
Dexmedetomidine hydrochloride parenteral solution is formulated by dexmedetomidine hydrochloride and sodium chloride, the parenteral solution easily by
The influence of pH value and metal ion so that property is very unstable, and the prior art is mostly by adding complexing of metal ion agent, resistance
The auxiliary materials such as color composition, pH buffer solutions ensure the stability of drug.Since dexmedetomidine hydrochloride parenteral solution should in clinic
Used time is directly entered in vivo, absorbs fast, effect rapidly, and the drug is mainly used in the patient with operation of general anesthesia, such
Patient body is extremely weak, and harm issuable to auxiliary material is more sensitive, therefore dexmedetomidine hydrochloride parenteral solution is to auxiliary material
The requirement of dosage, security level, species etc. is more stringent, once quality problems occurs in auxiliary material, body will be generated not rapidly
Reversible damage, the extent of injury are very big.Therefore urgent need development is a kind of does not add any auxiliary material i.e. right U.S. of hydrochloric acid with stability
Support miaow determines parenteral solution.
The content of the invention
To solve the above-mentioned problems, dexmedetomidine hydrochloride can be improved by not adding any auxiliary material the present invention provides one kind
The processing method of parenteral solution stability and dexmedetomidine hydrochloride parenteral solution.
The present invention is achieved by the following technical solutions：
A kind of processing method for improving dexmedetomidine hydrochloride parenteral solution stability, which is characterized in that include the following steps：
Under nitrogen protection, prepared dexmedetomidine hydrochloride parenteral solution through micropore filter element is filtered, is cooled to 35-40 DEG C, be packed into
Inner surface is modified in the vial of active group, sterilizing；Wherein, the active group is amino, sulfydryl, carboxyl, acid
One or more in acid anhydride.
The metal ion contained in dexmedetomidine hydrochloride parenteral solution can make it foreign matter, color burn, related substance occur
The problems such as rise, so as to influence the stability of dexmedetomidine hydrochloride parenteral solution.It is easy to the present invention is based on metal ion and ammonia
The characteristics of base, sulfydryl, carboxyl coordination form complex, is handled by the inner surface to vial, is allowed on inner surface band
It can be with the active group of metallic ion coordination, you can the adsorption of metal ions in parenteral solution to glass surface, it is possible thereby to subtract
Metal ion content in few dexmedetomidine hydrochloride parenteral solution ensures the stable quality of product.
The present invention active group can be amino, sulfydryl, carboxyl or acid anhydrides, preferred anhydrides, because acid anhydrides is easily water-soluble
Dicarboxylic acids is hydrolyzed to form in liquid, compared with band is there are one the active group of carboxylic acid, coordination ability is stronger.Moreover, carboxyl with
Amino is compared with sulfydryl, can be with further types of metallic ion coordination.
Since each active group is different from the coordination ability of metal ion, such as sulfydryl and the configurational energy of heavy metal ion
Power is more than amino and carboxyl, therefore the vial of the present invention can use various active base group modification, thus can more thoroughly remove
Metal ion in parenteral solution.
Further, the preparation method of the dexmedetomidine hydrochloride parenteral solution is as follows：
The water for injection of amount of preparation 40% (percent by volume) is taken, the temperature of water for injection is 70-80 DEG C, adds in recipe quantity
Sodium chloride, stirring to dissolve；The dexmedetomidine hydrochloride of recipe quantity is added, stirring adds to the full amount of water for injection to dissolving,
Stir 20-35min.
Further, before the preparation of dexmedetomidine hydrochloride parenteral solution, further include with water for injection to preparing tank and pipe
Road carries out the step of sealing and circulating processing, and circular treatment temperature is 70-80 DEG C, and the circular treatment time is 20-30min.The step
It can ensure the cleannes with container.
Further, the inner surface be modified with active group vial be silanization vial, the silanization
Vial be by being impregnated in vial in the silylating reagent with active group, carry out Silanization reaction and obtain.
Specifically, the present invention is using silylating reagent and vial the inner surface hair with amino, sulfydryl, carboxyl or acid anhydrides
Raw Silanization reaction, so as to above-mentioned active group modification to vial inner surface.Vial is specifically impregnated in silanization
The acetone soln of silylating reagent is added in the acetone soln of reagent or in vial, the volume fraction of silylating reagent is 2-
10%.Active group with metallic ion coordination is to be connected to by chemical bond on vial, stronger with reference to power, it is not easy to de-
It falls in liquid, and the invention avoids metal chelating agent is directly added into liquid.That is, without adding in liquid
Enter the removal that metal ion can be completed in auxiliary material, therefore can be to avoid influence of the auxiliary material to the stability of liquid.It is appreciated that
It is that the signified auxiliary material of the present invention does not include sodium chloride, and sodium chloride is the osmotic pressure regulator being routinely added to when preparing liquid, and
It is not belonging to the scope of auxiliary material of the present invention.
In the present invention, silylating reagent it is specific enumerable go out：3- triethoxies-propylsuccinic anhydride silane (CAS：
93624-68-3), 3- aminopropyl triethoxysilanes (CAS：919-30-2), 3- aminopropyl trimethoxysilanes, 3- mercapto propyl
Trimethoxy silane (CAS:4420-74-0), 3- mercaptopropyltriethoxysilanes (CAS:14814-09-6).
Further, the temperature of the Silanization reaction is 10-40 DEG C, time 0.5-4h.
Be conducive to the progress of Silanization reaction using above-mentioned temperature and time, improve the effect of Silanization reaction, make glass
The Silanization reaction of bottle inner surface is more complete.
Further, before vial carries out Silanization reaction, further including that vial inner surface pre-process makes
Hydroxylated process.
The organic molecule for being adsorbed vial inner surface by preprocessing process removes, and vial inner surface is made to expose hydroxyl
Base, in favor of the Silanization reaction of next step.
Further, the process of the pretreatment is：Vial is impregnated in Piranha solution, room temperature processing
Then 30min is washed, is dry.
H in Piranha solution2SO4∶H2O2Volume ratio=70: 30, room temperature processing 30min, then with a large amount of water wash, then
Drying can obtain the hydroxylated vial of inner surface.
Further, after vial carries out Silanization reaction, further include and the vial of silanization is used into acetone successively
With deionized water cleaning, dry process.
After Silanization reaction, first the silylating reagent of remained on surface is washed with acetone, then is cleaned with deionized water, so
After dry, obtain the vial of silanization.
Further, the water for injection is nitrogen charging treated water for injection.
Water for injection used in the present invention is nitrogen charging treated water for injection so that the oxygen content in water for injection subtracts
It is few, the dexmedetomidine hydrochloride parenteral solution prepared is avoided to be gone bad by oxidation.
Further, described filter is specially：By prepared dexmedetomidine hydrochloride parenteral solution first through 0.45 μm of micropore
Filter core, then filtered through 0.22 μm of micropore filter element.
Further, the micropore filter element is polyether sulfone micropore filter element.
By the aseptic filtration of micropore filter element, the sterility assurance level of liquid is improved.
Further, the vial is middle borosilicate glass bottle.
Due to middle borosilicate glass bottle chemical stability, better heat stability, sodium potassium content is less, water-tolerant, to drug
PH, the various indexs such as acid-base value, clarity, stability it is all very good.
But middle borosilicate glass bottle hardness is larger, in processing, softening point temperature is higher and makes elongation technological temperature higher,
Sodium potassium ion is promoted to generate sodium oxide molybdena and potassium oxide, in high-temperature sterilization, H to surface enrichment+Active apparent increase, makes oxidation
Sodium, potassium oxide generate sodium hydroxide and potassium hydroxide and increase solubility in water, and pH value is caused to increase.
Vulcanizing treatment is processed for neutral boron silica glass surface, by insoluble sodium oxide molybdena and potassium oxide vulcanizing treatment
Generation is dissolved in the sodium sulphate or potassium sulfate of water, and clean, product pH value increase after high-temperature sterilization is rinsed when vial cleans
Scope does not exceed 0.3, and pH value will not go out after ensureing dexmedetomidine hydrochloride parenteral solution before sterilization and in prolonged storage
Existing significant changes keep stablizing.
The middle borosilicate glass bottle that the present invention uses can for vulcanizing treatment after middle borosilicate glass bottle, or without sulphur
Change the middle borosilicate glass bottle of processing.Even if middle borosilicate glass bottle is uncured treated vial, pre-processed in vial
In the process, H is contained in the Piranha solution of use2SO4, can also be with the sodium oxide molybdena in vial and oxidation nak response generation sulphur
Sour sodium and potassium sulfate, sodium sulphate and potassium sulfate are then cleaned up by water, increase interior surfaces of glass water resistance, so that this
PH value significant changes to the dexmedetomidine hydrochloride parenteral solution of invention does not occur afterwards and in prolonged storage before sterilization so that this
The parenteral solution of invention is relatively stablized.
Another aspect of the present invention additionally provides a kind of dexmedetomidine hydrochloride parenteral solution obtained using above-mentioned processing method.
The present invention by vial carry out silanization treatment, make amino on the inner surface band of vial, sulfydryl, carboxyl or
With the metal ion in dexmedetomidine hydrochloride parenteral solution coordination can occur for acid anhydrides isoreactivity group, this active group,
Therefore the metal ion in dexmedetomidine hydrochloride parenteral solution is adsorbed to vial inner surface, adds dexmedetomidine hydrochloride
The stability of parenteral solution.
The middle borosilicate glass bottle of the present invention is vulcanized in hydroxylating preprocessing process, while to vial inner surface
Processing improves the water resistance of vial inner surface so that the liquid contained in vial pH in autoclaving process is not sent out
Raw significant change adds the pH stability of parenteral solution.
The present invention to vial inner surface by carrying out silanization treatment, without adding in dexmedetomidine hydrochloride parenteral solution
Add any auxiliary material that can improve its stability, avoid auxiliary material adverse effect caused by injection liquid energy.
Specific embodiment
Carry out the embodiment that the present invention will be described in detail below with reference to embodiment, illustrated embodiment is served only for explaining this hair
It is bright, it is not intended to limit the scope of the present invention.
All material that the present invention uses, reagent are conventional material, conventional reagent unless otherwise specified, commercially available
It obtains.
Embodiment 1
Prescription：Dexmedetomidine hydrochloride (0.2g based on Dexmedetomidine) 0.236g, sodium chloride 450g, after nitrogen charging is added to handle
Water for injection (pH=5) to 50000mL, be made 1000 bottles.
A kind of processing method for improving dexmedetomidine hydrochloride parenteral solution stability, includes the following steps：
S1：Piranha solution (H is added in middle borosilicate glass bottle2SO4∶H2O2Volume ratio=70: 30), room temperature processing
30min obtains the hydroxylated middle borosilicate glass bottle of inner surface, then ultrasonic wave water washing, and it is standby to be put into drying in 105 DEG C of baking oven
With；
S2：3- triethoxies-propylsuccinic anhydride that volume fraction is 3% is added in hydroxylated middle borosilicate glass bottle
The acetone soln of silane carries out Silanization reaction, and reaction temperature is 25 DEG C, reaction time 1h, obtains the middle borosilicate of silanization
Then vial is rinsed three times with acetone soln, ultrasonic wave water washing three times is put into drying for standby in 105 DEG C of baking oven；
S3：Under nitrogen protection, the water for injection of amount of preparation 40% is taken, the temperature of water for injection is 75 DEG C, adds in prescription
The sodium chloride of amount, stirring to dissolving；The dexmedetomidine hydrochloride of recipe quantity is added, stirring injects water to complete to dissolving
Amount stirs 30min；Remaining oxygen is not more than 3% wherein in preparing tank；
S4：By solution made from step S3 first through 0.45 μm of micropore filter element, then through 0.22 μm of micropore filter element filtering, it is cooled to
It 35 DEG C, is fitted into the middle borosilicate glass bottle of the silanization obtained by step S2, comes into full contact with, connect with the middle borosilicate glass bottle of silanization
The time is touched not less than 0.5h, sterilizing；
Wherein, the water for injection is nitrogen charging treated water for injection.
Embodiment 2
Prescription：Dexmedetomidine hydrochloride (0.2g based on Dexmedetomidine) 0.236g, sodium chloride 450g, after nitrogen charging is added to handle
Water for injection (pH=6) to 50000mL, be made 1000 bottles.
A kind of processing method for improving dexmedetomidine hydrochloride parenteral solution stability, includes the following steps：
S1：Piranha solution (H is added in middle borosilicate glass bottle2SO4∶H2O2Volume ratio=70: 30), room temperature processing
30min obtains the hydroxylated middle borosilicate glass bottle of inner surface, then ultrasonic wave water washing, and it is standby to be put into drying in 105 DEG C of baking oven
With；
S2：The 3- aminopropyl triethoxysilanes that volume fraction is 5% are added in hydroxylated middle borosilicate glass bottle
Acetone soln carries out Silanization reaction, and reaction temperature is 15 DEG C, reaction time 0.5h, obtains the middle Pyrex of silanization
Then bottle is rinsed three times with acetone soln, ultrasonic wave water washing three times is put into drying for standby in 105 DEG C of baking oven；
S3：Under nitrogen protection, the water for injection of amount of preparation 40% is taken, the temperature of water for injection is 70 DEG C, adds in prescription
The sodium chloride of amount, stirring to dissolving；The dexmedetomidine hydrochloride of recipe quantity is added, stirring injects water to complete to dissolving
Amount stirs 30min；Remaining oxygen is not more than 2% wherein in preparing tank；
S4：By solution made from step S3 first through 0.45 μm of micropore filter element, then through 0.22 μm of micropore filter element filtering, it is cooled to
It 38 DEG C, is fitted into the middle borosilicate glass bottle of the silanization obtained by step S2, comes into full contact with, connect with the middle borosilicate glass bottle of silanization
The time is touched not less than 0.5h, sterilizing；
Wherein, the water for injection is nitrogen charging treated water for injection.
Embodiment 3
Prescription：Dexmedetomidine hydrochloride (0.2g based on Dexmedetomidine) 0.236g, sodium chloride 450g, after nitrogen charging is added to handle
Water for injection (pH=7) to 50000mL, be made 1000 bottles.
A kind of processing method for improving dexmedetomidine hydrochloride parenteral solution stability, includes the following steps：
S1：Piranha solution (H is added in middle borosilicate glass bottle2SO4∶H2O2Volume ratio=70: 30), room temperature processing
30min obtains the hydroxylated middle borosilicate glass bottle of inner surface, then ultrasonic wave water washing, and it is standby to be put into drying in 105 DEG C of baking oven
With；
S2：The 3- mercaptopropyltriethoxysilanes that volume fraction is 8% are added in hydroxylated middle borosilicate glass bottle
Acetone soln carries out Silanization reaction, and reaction temperature is 30 DEG C, reaction time 1.5h, obtains the middle Pyrex of silanization
Then bottle is rinsed three times with acetone soln, ultrasonic wave water washing three times is put into drying for standby in 105 DEG C of baking oven；
S3：Under nitrogen protection, the water for injection of amount of preparation 40% is taken, the temperature of water for injection is 80 DEG C, adds in prescription
The sodium chloride of amount, stirring to dissolving；The dexmedetomidine hydrochloride of recipe quantity is added, stirring injects water to complete to dissolving
Amount stirs 30min；Remaining oxygen is not more than 1% wherein in preparing tank；
S4：By solution made from step S3 first through 0.45 μm of micropore filter element, then through 0.22 μm of micropore filter element filtering, it is cooled to
It 40 DEG C, is fitted into the middle borosilicate glass bottle of the silanization obtained by step S2, comes into full contact with, connect with the middle borosilicate glass bottle of silanization
The time is touched not less than 0.5h, sterilizing；
Wherein, the water for injection is nitrogen charging treated water for injection.
Comparative example 1
Prescription：Dexmedetomidine hydrochloride (0.2g based on Dexmedetomidine) 0.236g, sodium chloride 450g, after nitrogen charging is added to handle
Water for injection (pH=5) to 50000mL, be made 1000 bottles.
A kind of processing method for improving dexmedetomidine hydrochloride parenteral solution stability, includes the following steps：
S1：Under nitrogen protection, the water for injection of amount of preparation 40% is taken, the temperature of water for injection is 75 DEG C, adds in prescription
The sodium chloride of amount, stirring to dissolving；The dexmedetomidine hydrochloride of recipe quantity is added, stirring injects water to complete to dissolving
Amount stirs 30min；Remaining oxygen is not more than 3% wherein in preparing tank；
S2：By solution made from step S1 first through 0.45 μm of micropore filter element, then through 0.22 μm of micropore filter element filtering, it is cooled to
It 35 DEG C, is fitted into the middle borosilicate glass bottle of unvulcanized processing, sterilizing；
Wherein, the water for injection is nitrogen charging treated water for injection.
Comparative example 2
Prescription：Dexmedetomidine hydrochloride (0.2g based on Dexmedetomidine) 0.236g, sodium chloride 450g, after nitrogen charging is added to handle
Water for injection (pH=6) to 50000mL, be made 1000 bottles.
A kind of processing method for improving dexmedetomidine hydrochloride parenteral solution stability, includes the following steps：
S1：Under nitrogen protection, the water for injection of amount of preparation 40% is taken, the temperature of water for injection is 70 DEG C, adds in prescription
The sodium chloride of amount, stirring to dissolving；The dexmedetomidine hydrochloride of recipe quantity is added, stirring injects water to complete to dissolving
Amount stirs 30min；Remaining oxygen is not more than 2% wherein in preparing tank；
S2：By solution made from step S1 first through 0.45 μm of micropore filter element, then through 0.22 μm of micropore filter element filtering, it is cooled to
It 38 DEG C, is fitted into the middle borosilicate glass bottle of unvulcanized processing, sterilizing；
Wherein, the water for injection is nitrogen charging treated water for injection.
Comparative example 3
Prescription：Dexmedetomidine hydrochloride (0.2g based on Dexmedetomidine) 0.236g, sodium chloride 450g, after nitrogen charging is added to handle
Water for injection (pH=7) to 50000mL, be made 1000 bottles.
A kind of processing method for improving dexmedetomidine hydrochloride parenteral solution stability, includes the following steps：
S1：Under nitrogen protection, the water for injection of amount of preparation 40% is taken, the temperature of water for injection is 80 DEG C, adds in prescription
The sodium chloride of amount, stirring to dissolving；The dexmedetomidine hydrochloride of recipe quantity is added, stirring injects water to complete to dissolving
Amount stirs 30min；Remaining oxygen is not more than 1% wherein in preparing tank；
S2：By solution made from step S1 first through 0.45 μm of micropore filter element, then through 0.22 μm of micropore filter element filtering, it is cooled to
It 40 DEG C, is fitted into the middle borosilicate glass bottle of unvulcanized processing, sterilizing；
Wherein, the water for injection is nitrogen charging treated water for injection.
Stability test
The present invention is by the character of naked-eye observation parenteral solution, visible foreign matters and measures the right U.S. support of pH, enantiomter, hydrochloric acid
Miaow is fixed, the content in relation to substance judges the stability of dexmedetomidine hydrochloride parenteral solution.Visual results show：Embodiment 1-
3 without visible foreign matters, no color burn phenomenon；And the solution colour of comparative example 1-3 is deep compared with embodiment 1-3, it is seen that foreign matter increases.
After illustrating the present invention by carrying out silanization treatment to vial inner surface, the metal ion in dexmedetomidine hydrochloride parenteral solution
Content is reduced, and substantially increases the stability of dexmedetomidine hydrochloride parenteral solution.
Related substances assay method and result are as follows：
1st, the measure of dexmedetomidine hydrochloride
It is filler with octadecylsilane chemically bonded silica, using the phosphate buffer of pH7.0 and methanol as mobile phase, inspection
Survey wavelength is 220nm, and column temperature is 30 DEG C, flow velocity 1.0mL/min.
Example and reference examples sample are appropriate, as test solution；Separately take dexmedetomidine hydrochloride reference substance appropriate,
As reference substance solution.Precision measures reference substance solution and test solution is each appropriate, is injected separately into high performance liquid chromatograph, remembers
Chromatogram is recorded, by external standard method with calculated by peak area, as a result as shown in table 1 and table 2.
2nd, the measure of enantiomter
With cellulose iii (3,5- dimethylphenylcarbamate) coating silica gel for stationary phase, with acetonitrile -0.1mol/L
Hexafluorophosphoric acid potassium solution is mobile phase；Flow velocity is 0.5mL/min, Detection wavelength 220nm, takes 100 μ L of system suitability solution
High performance liquid chromatograph is injected, adjusts detection sensitivity, the peak height for making dexmedetomidine hydrochloride peak is the 10-20% of full scale,
Record chromatogram；Peak sequence is followed successively by the left Medetomidine of dexmedetomidine hydrochloride, hydrochloric acid, and separating degree therebetween should meet
It is required that.
Example and reference examples sample are appropriate, as test solution；Separately take the left Medetomidine reference substance of hydrochloric acid appropriate,
As the left Medetomidine reference substance solution of hydrochloric acid.It takes dexmedetomidine hydrochloride reference substance appropriate, adds in the left Medetomidine pair of hydrochloric acid
It is appropriate according to product solution, as system suitability solution.Precision measurement test solution is appropriate, is injected separately into liquid chromatograph, remembers
Chromatogram is recorded, by external standard method with calculated by peak area, as a result as shown in Table 1 and Table 2.
3rd, the measure in relation to substance
It is filler with octadecylsilane chemically bonded silica；Using acetonitrile-phosphate buffer as mobile phase A, acetonitrile is
Mobile phase B carries out gradient elution.Detection wavelength is 220nm；Column temperature is 35 DEG C；Flow velocity is 1.0mL/min.
Example and reference examples sample are appropriate, as test solution；Precision measures dexmedetomidine hydrochloride reference substance
In right amount, as contrast solution.It takes dexmedetomidine hydrochloride and impurity C appropriate, Dexmedetomidine and miscellaneous is made with aqueous dissolution
The mixed solution of matter C, as system suitability solution.Precision measures system suitability solution, contrast solution and test solution
It is each appropriate, high performance liquid chromatograph is injected separately into, records chromatogram.Dexmedetomidine peak and impurity C in system suitability solution
The separating degree at peak should be greater than 1.5, and control is not greater than if any impurity peaks, single impurity peak area in the chromatogram of test solution
The sum of solution main peak area (0.5%), each impurity peak area are not greater than 2 times (1.0%) of contrast solution main peak area, as a result
As shown in Table 1 and Table 2.
Table 1
Remarks：The acceptability limit of pH is 4.5-7.0；The acceptability limit of dexmedetomidine hydrochloride content is 95.0-
105.0%；The content acceptability limit of enantiomter is≤0.5%；In relation to maximum single miscellaneous acceptability limit in substance for≤
0.5%, total miscellaneous acceptability limit is≤1.0%
Table 1 has investigated illumination (total illumination 3.24 × 106Lux 〃 hr) 30 days, the survey of (60 DEG C ± 2 DEG C) processing 30 days of high temperature
Test result finds out that under the conditions of two kinds are investigated, significant change, the right U.S. support of hydrochloric acid do not occur embodiment 1-3 for pH from the result of table 1
The fixed content of miaow is qualified, and enantiomter and related substance do not detect, illustrate the salt that processing method using the present invention obtains
The high stability of sour Dexmedetomidine parenteral solution；And pH is changed greatly in comparative example 1-3, super acceptance line, the right U.S. support of hydrochloric acid
Miaow is determined content and is also declined, and maximum single miscellaneous and total miscellaneous content rise, more than acceptance line, illustrates the processing without the present invention
Treated that dexmedetomidine hydrochloride parenteral solution stability is poor for method.
Table 2
Remarks：The acceptability limit of pH is 4.5-7.0；The acceptability limit of dexmedetomidine hydrochloride content is 95.0-
105.0%；The content acceptability limit of enantiomter is≤0.5%；In relation to maximum single miscellaneous acceptability limit in substance for≤
0.5%, total miscellaneous acceptability limit is≤1.0%
Table 2 has investigated accelerated test and 25 DEG C ± 2 DEG C of the sample under the conditions of 40 DEG C ± 2 DEG C, humidity 75% ± 5%, wet
Long term test under the conditions of degree 60% ± 5% the results show that in embodiment 1-3, accelerates 6 months and after long-term 24 months, pH
Significant change, the content qualification of dexmedetomidine hydrochloride do not occur, enantiomter and related substance do not detect, illustrate to use
The high stability for the dexmedetomidine hydrochloride parenteral solution that the processing method of the present invention obtains；And in comparative example 1-3 pH variation compared with
Greatly, super acceptance line, the content of dexmedetomidine hydrochloride are slightly decreased sample segment, and maximum single miscellaneous and total miscellaneous content liter
Height, part super acceptance line illustrate without processing method of the invention treated dexmedetomidine hydrochloride parenteral solution stability
Difference.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all the present invention spirit and
Within principle, any modifications, equivalent replacements and improvements are made should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of processing method for improving dexmedetomidine hydrochloride parenteral solution stability, which is characterized in that include the following steps：
Under nitrogen protection, prepared dexmedetomidine hydrochloride parenteral solution through micropore filter element is filtered, is cooled to 35-40 DEG C, in loading
In the vial of the active group of surface modification, sterilizing；Wherein, the active group is amino, sulfydryl, carboxyl, acid anhydrides
In one or more.
2. processing method according to claim 1, which is characterized in that the preparation side of the dexmedetomidine hydrochloride parenteral solution
Method is as follows：
The water for injection of amount of preparation 40% is taken, the temperature of water for injection is 70-80 DEG C, adds in the sodium chloride of recipe quantity, stirring is extremely
Dissolving；The dexmedetomidine hydrochloride of recipe quantity is added, stirring adds to the full amount of water for injection to dissolving, and stirs 20-35min.
3. processing method according to claim 1, which is characterized in that the inner surface is modified with the vial of active group
For the vial of silanization, the vial of the silanization is tried by the way that vial to be impregnated in the silanization with active group
In agent, carry out Silanization reaction and obtain.
4. processing method according to claim 3, which is characterized in that the temperature of the Silanization reaction is 10-40 DEG C, when
Between be 0.5-4h.
5. processing method according to claim 3, which is characterized in that before vial carries out Silanization reaction, also wrap
It includes that vial inner surface pre-process and is allowed to hydroxylated process.
6. processing method according to claim 5, which is characterized in that the process of the pretreatment is：Vial is impregnated
In Piranha solution, then room temperature processing 30min is washed, is dry.
7. processing method according to claim 3, which is characterized in that after vial carries out Silanization reaction, also wrap
Include the process that the vial of silanization is cleaned and dried with acetone and deionized water successively.
8. processing method according to claim 2, which is characterized in that the water for injection is nitrogen charging treated injection
Water.
9. according to claim 1-8 any one of them processing methods, which is characterized in that the vial is middle Pyrex
Bottle.
10. a kind of dexmedetomidine hydrochloride parenteral solution obtained using claim 2-9 any one of them processing methods.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109580854A (en) * | 2018-12-03 | 2019-04-05 | 石药银湖制药有限公司 | Detection method in relation to substance in a kind of dexmedetomidine hydrochloride raw material or preparation |
| CN111249230A (en) * | 2020-03-18 | 2020-06-09 | 遂成药业股份有限公司 | Preparation process of dexmedetomidine hydrochloride injection |
| CN113797092A (en) * | 2020-06-16 | 2021-12-17 | 四川远大蜀阳药业有限责任公司 | Method for stabilizing pH value and/or conductivity of small-volume glass container-contained liquid preparation |
| CN113827590A (en) * | 2020-06-08 | 2021-12-24 | 四川普锐特药业有限公司 | Application of dexmedetomidine in preparation of sleep-aiding medicine |
| CN114983934A (en) * | 2022-06-16 | 2022-09-02 | 南京正科医药股份有限公司 | Dexmedetomidine hydrochloride injection |
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| CN109580854A (en) * | 2018-12-03 | 2019-04-05 | 石药银湖制药有限公司 | Detection method in relation to substance in a kind of dexmedetomidine hydrochloride raw material or preparation |
| CN111249230A (en) * | 2020-03-18 | 2020-06-09 | 遂成药业股份有限公司 | Preparation process of dexmedetomidine hydrochloride injection |
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