CN108743551A - A kind of dexmedetomidine hydrochloride freezing-dried powder injection and preparation method - Google Patents
A kind of dexmedetomidine hydrochloride freezing-dried powder injection and preparation method Download PDFInfo
- Publication number
- CN108743551A CN108743551A CN201810840977.2A CN201810840977A CN108743551A CN 108743551 A CN108743551 A CN 108743551A CN 201810840977 A CN201810840977 A CN 201810840977A CN 108743551 A CN108743551 A CN 108743551A
- Authority
- CN
- China
- Prior art keywords
- dexmedetomidine hydrochloride
- acid
- injection
- dried powder
- freezing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—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
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Anesthesiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of dexmedetomidine hydrochloride freezing-dried powder injection and preparation methods, belong to Western medicine preparation field.Dexmedetomidine hydrochloride freezing-dried powder injection provided by the invention contains the dexmedetomidine hydrochloride of 1 parts by weight and the middle-molecular-weihydroxyethyl dextran of 2-20 parts by weight.Method is that dextran is now added partial syringe water dissolution, then stirs, filters；Dexmedetomidine hydrochloride is taken to be added in the solution after taking off charcoal, benefit adds to the full amount of water for injection after citric acid-sodium citrate buffer dissolving of addition again；PH value is adjusted to 5.0-6.0, micro-filtration is freeze-dried to obtain the final product.The dexmedetomidine hydrochloride freezing-dried powder injection solubility of the present invention is good, stability is good, safe.
Description
Technical field：
The present invention relates to a kind of dexmedetomidine hydrochloride freezing-dried powder injection and preparation methods, belong to Western medicine preparation neck
Domain.
Background technology：
Dexmedetomidine hydrochloride (DexmedetomidineHydrochloride) by OrionPharma (Finland) companies and
The α 2- adrenoceptor agonists of Abott (U.S.) company cooperation research and development exploitation, are used for the patient with operation gas of row general anesthesia
Calmness when cannula and mechanical ventilation.Entitled (+) -4- (S)-of dexmedetomidine hydrochloride chemistry [1- (2,3- 3,5-dimethylphenyls)
Ethyl] -1H- imidazole hydrochlorides.Structural formula is as follows：
This product shows that dexmedetomidine hydrochloride can generate stable calm and feel in the U.S. using the clinical experience more than 5 years
It wakes up and acts on, the demand of physiology and psychological aspects to critically ill patient has unique synergistic effect, can obviously reduce induced anesthesia institute
The anesthetic dosage needed；The preoperative dosage given this product and can reduce preoperative and postoperative opium or non-opium analgesic, this
Characteristic has important meaning for anesthesia and Intensive Care Therapy；It can also promote the stability of catecholamine haemodynamics, have
Effect mitigates trachea cannula, Fundamental Operations and anesthesia and restores early stage haemodynamics response.
Dexmedetomidine is a kind of relative selectivity 2- adrenoceptor agonists, has sedation.Animal is slow
The visible selectively acting to 2- adrenocepters when venoclysis 10~300g/kg of Dexmedetomidine, but in higher dosage
Under (1000g/kg) when slowly venoclysis or rapid intravenous injection are administered a pair 1 and 2- receptors have effect.
The Vdss (Vss) of Dexmedetomidine is about 118 liters.In normal healthy male and female volunteers
The protein binding of Dexmedetomidine is evaluated in blood plasma.Its average protein Percentage bound is in different concentration tests
94%；The protein binding rate of male and female is similar.Compared with health volunteer, hepatic injury subject Dexmedetomidine and blood plasma
It is protein bound
Function is decreased obviously.It is right that in vitro study observes fentanyl, ketorolac, theophylline, digoxin and lidocaine substitution
The protein-bonded possibility of Medetomidine, does not as a result observe the change of Dexmedetomidine plasma protein binding rate.It is external to study again
Dilantin sodium, warfarin, brufen, Propranolol, theophylline and digoxin protein binding by Dexmedetomidine replace can
It can, the results showed that the protein binding of drug does not seem obviously to be replaced by Dexmedetomidine.Dexmedetomidine is almost given birth to
Object converts, and is seldom discharged from urine and excrement with original shape.Bioconversion includes that direct glucuronidation and Cytochrome P450 are situated between
The metabolism led.
The main metabolic pathway of Dexmedetomidine is：Direct N- glucuronides are melted into nonactive metabolite；Fat hydroxyl
Change acts on (mainly being mediated by CYP2A6) and generates 3- hydroxyls Dexmedetomidine, 3- hydroxyl Dexmedetomidine glucosiduronic acids and 3- carboxyls
Dexmedetomidine；Dexmedetomidine N-, which methylates, generates the right U.S. support miaow of 3- Hydroxy N-Methyls Dexmedetomidine, 3- carboxyl N- methyl
Fixed and N- methyl O- glucosiduronic acid Dexmedetomidines.The removing of end eventually half-life period (t1/2) of Dexmedetomidine is about 2 hours, clearly
Except rate is about 39L/h.Mass balance research confirms the radiolabeled Dexmedetomidine of venoclysis average 95% after 9 days
Radioactive materials are recycled from urine, and 4% in excrement.Dexmedetomidine original shape can be detected in urine.24 after infusion this product
About 85% radioactive materials are discharged from urine in hour.The radioactive materials segmentation separation being discharged in urine turns out to be N-
Glucuronidation product accounts for 34%.In addition, fat hydroxylization effect product 3- hydroxyls Dexmedetomidine, 3- hydroxyl Dexmedetomidines
Glucosiduronic acid and 3- carboxylic acid Dexmedetomidines account about 14%.Dexmedetomidine N- methylates right U.S. of 3- Hydroxy N-Methyls of generation
Support miaow is determined, 3- carboxyls N- methyl Dexmedetomidine and N- methyl O- glucosiduronic acid Dexmedetomidines account about 18%.N- methyl generations
It is secondary circulating component to thank to product itself, is not detected in urine.About 28% urine metabolin is unrecognized.
Dexmedetomidine hydrochloride is white to off-white color crystalline powder；This product easily dissolves, in water in methanol, ethyl alcohol
It is readily soluble, it is almost insoluble in the hydrochloric acid solution, toluene of 0.1mol/L.Salt containing 1 molecule in dexmedetomidine hydrochloride molecular formula
Acid, in the process for preparation of injection easily with the equipment reactions such as Agitation Tank, filter, the iron ion on dissolving part thereof surface,
Increase in the related substance of placement process to form injection, the phenomenon that color and luster is deepened.Color and luster is also dexmedetomidine hydrochloride drop
A kind of reaction of solution, the liquid phase of current UV detector still cannot effectively detect such impurity, need to carry out area by coloration
Point.
CN105168122A discloses a kind of dexmedetomidine hydrochloride injection and its preparation process, uses the right U.S. of hydrochloric acid
The injection for holding in the palm the preparations such as fixed miaow, osmotic pressure regulator and complexing of metal ion agent solves related substance and increases, it is seen that foreign matter
Increased trend, but fail to solve the phenomenon that excessively middle color and luster of long term storage is deepened.
CN103284945A discloses a kind of pre-filled dexmedetomidine hydrochloride injection, solves dexmedetomidine hydrochloride
The case where injection ease of use, but in failing to solve long term storage excessively related substance increase, color and luster intensification the phenomenon that.
CN105534891A discloses a kind of dexmedetomidine hydrochloride injection, and in particular to dexmedetomidine hydrochloride is injected
Liquid and its a kind of preparation method, the injection are using dexmedetomidine hydrochloride as main component：By dexmedetomidine hydrochloride, resistance
Color composition, sodium hydroxide and water for injection dissolving embedding sterilize；The fastness composition is prepared as follows
It forms：Mosatil, sodium pyrosulfite are uniformly mixed, the weight ratio of mosatil and sodium pyrosulfite is 1:1~3.
The dexmedetomidine hydrochloride injection of the present invention solves the disadvantage that color and luster intensification and the increase of related substance during storage, improves
Drug safety has more preferably therapeutic effect.
Invention content：
Therefore, first purpose of the invention is to overcome the deficiencies of the prior art and provide that a kind of solubility is good, stability
Good, safe dexmedetomidine hydrochloride freezing-dried powder injection.
Freeze drying powder injection is subsequently used for intramuscular injection or intravenous injection, after redissolution using preceding needing to be redissolved with appropriate solvent
Solution in should clarify, without visible foreign matters, and particulate matter inspection should also meet States Pharmacopoeia specifications, to ensure clinical patients medication
Safety.
A kind of macromolecule glucose polymerisation that dextran system sucrose generates after leuconostoc mesenteroide -1226 is fermented
Object is obtained through handling refined.Since the glucose molecule number of polymerization is different, and generate the product of different molecular weight.There is high score
Sub- dextran (average molecular weight 100,000-20 ten thousand), medium molecular dextran (average molecular weight 60,000-8 ten thousand), low molecule dextrorotation
Sugared acid anhydride (average molecular weight 20,000-4 ten thousand) and Dextran 10 (average molecular weight 10,000-2 ten thousand).Dextrose of the present invention
Acid anhydride includes high molecular dextran, medium molecular dextran, D-40 and Dextran 10.
It is found surprisingly that, dextran, especially average molecular weight 6 is added in the present invention during preparing freeze-dried powder
The property of ten thousand -8 ten thousand dextran, dexmedetomidine hydrochloride is more stable, and redissolution effect is more preferable, and safety is also more preferable.Then, it sends out
A person of good sense screens its dosage, and inventor is had found by lot of experiments, the weight of dextran and dexmedetomidine hydrochloride
Amount ratio is measured in 2-20：When in the range of 1, sample indices meet the requirements, can preferably solve sample redissolve after can
See foreign matter problem.When dosage is less than 2, the content of dexmedetomidine hydrochloride reduces, and is not inconsistent standardization requirement, and is more than 20 times of amounts
Afterwards, sample solubility is deteriorated again after freeze-drying, and indices cannot meet the requirements, these illustrate that the dosage of dextran is also shadow
Ring the factor of dexmedetomidine hydrochloride freezing-dried powder injection stability and solubility, i.e., the tribute that the present invention makes the prior art
Offer the amount ratio for being that and having filtered out dextran and dexmedetomidine hydrochloride.
Further, dexmedetomidine hydrochloride freezing-dried powder injection provided by the invention, contains the hydrochloric acid of 1 parts by weight
The dextran of Dexmedetomidine and 10 parts by weight, and the pH value of its solution before freeze-drying is 5.0-6.0.
It is highly preferred that dexmedetomidine hydrochloride freezing-dried powder injection described above, the PH of the solution before freeze-drying
Value is 5.5.
It is a further object of the present invention to provide a kind of preparation methods of dexmedetomidine hydrochloride freezing-dried powder injection.System
Preparation Method is first that dexmedetomidine hydrochloride is added after citric acid-sodium citrate buffer dissolving and is added to containing dextran
Water for injection in, then degerming, filtering, drying and obtain.
Further, a kind of method preparing dexmedetomidine hydrochloride freezing-dried powder injection provided by the invention, it is wrapped
Include following steps：
1) 2-20 parts of dextran is taken, the dissolving of 30% water for injection is added, the needle that 0.05~0.5% (g/v) is added is lived
Property charcoal, 25~80 DEG C stir 5~60 minutes, filtering decarbonization；
2) 1 part of dexmedetomidine hydrochloride is weighed, citric acid-sodium citrate buffer dissolving that pH value is 3.0-4.0 is added
Afterwards, it is added in the solution after step 1) takes off charcoal, stirs evenly, benefit adds to the full amount of water for injection；
3) it is 5.0-6.0 with pharmaceutically acceptable sour regulating liquid medicine pH value, it is fixed with 0.22 μm of miillpore filter aseptic filtration
Measure it is filling in aseptic cillin bottle, half plus rubber plug, be freeze-dried to obtain the final product.
Preferably, the method for preparing dexmedetomidine hydrochloride freezing-dried powder injection described above, wherein dextran
Dosage be 10 parts.
It is highly preferred that the method for preparing dexmedetomidine hydrochloride freezing-dried powder injection described above, with pharmaceutically may be used
The sour regulating liquid medicine pH value of receiving is 5.5.
The method for preparing dexmedetomidine hydrochloride freezing-dried powder injection described above, in the PH of regulating liquid medicine, institute
It is one kind in phosphoric acid, citric acid, hydrochloric acid, boric acid, acetic acid or amino acid to state pharmaceutically acceptable acid；Preferably, the pharmacy
Acceptable acid is citric acid.
Compared with the prior art, the advantages of the present invention are as follows：
(1) currently preferred dextran does the injection of the dexmedetomidine hydrochloride freeze-dried powder prepared by frozen-dried supporting agent
Agent, all indicators are better than the auxiliary materials samples such as other lactose.
(2) product solubility and stability are good, and dexmedetomidine hydrochloride freezing-dried powder injection of the invention can answer rapidly
Molten, solution visible foreign matters, clarity and particulate matter inspection after redissolution meet 2015 editions requirements of Chinese Pharmacopoeia；Product matter
Amount is more stablized compared with injection, and related substance is stablized in the term of validity, it is seen that the inspections such as foreign matter meet the requirements, and freeze-drying sample compared with
Injection facilitates storage and transport, better than other products of prior art report.
Specific implementation mode：
With reference to specific embodiment, the present invention is further illustrated：
Embodiment 1：
Prescription
Specifically preparation process is：
(1) it takes dextran that the dissolving of 300ml waters for injection is added, the needle-use activated carbon of 0.30% (g/v) is added, 55 DEG C are stirred
30 minutes are mixed, filtering decarbonization；
(2) dexmedetomidine hydrochloride is weighed, after citric acid-sodium citrate buffer dissolving that pH value is 3.5 is added, is added
In solution after the de- charcoal of step 1), stir evenly, benefit adds to the full amount of water for injection；
(3) it is 5.5 to use citric acid regulating liquid medicine pH value, and with 0.22 μm of miillpore filter aseptic filtration, quantitative filling is in sterile
In clean cillin bottle, half adds rubber plug, is freeze-dried to obtain the final product.
Embodiment 2：
Prescription
Specifically preparation process is：
(1) it takes dextran that 30% water for injection is added to dissolve, the needle-use activated carbon of 0.05% (g/v) of addition, 25 DEG C
Stirring 60 minutes, filtering decarbonization；
(2) dexmedetomidine hydrochloride is weighed, after citric acid-sodium citrate buffer dissolving that pH value is 3.0 is added, is added
In solution after the de- charcoal of step 1), stir evenly, benefit adds to the full amount of water for injection；
(3) it is 5.0 with pharmaceutically acceptable sour regulating liquid medicine pH value, it is quantitative with 0.22 μm of miillpore filter aseptic filtration
It is filling in aseptic cillin bottle, half plus rubber plug, be freeze-dried to obtain the final product.
Embodiment 3：
Prescription
Specifically preparation process is：
(1) it takes dextran that the dissolving of 30% water for injection is added, the needle-use activated carbon of 0.5% (g/v), 80 DEG C of stirrings is added
15 minutes, filtering decarbonization；
(2) dexmedetomidine hydrochloride is weighed, after citric acid-sodium citrate buffer dissolving that pH value is 4.0 is added, is added
In solution after the de- charcoal of step 1), stir evenly, benefit adds to the full amount of water for injection；
(3) it is 6.0 with pharmaceutically acceptable sour regulating liquid medicine pH value, it is quantitative with 0.22 μm of miillpore filter aseptic filtration
It is filling in aseptic cillin bottle, half plus rubber plug, be freeze-dried to obtain the final product.
Embodiment 4：
Prescription
Using hydrochloric acid as pH adjusting agent, with the preparation method of embodiment 1.
Comparative Examples 1：
Prescription
With the preparation method of embodiment 1.
Comparative Examples 2：
Prescription
With the preparation method of embodiment 1.
Comparative Examples 3：
Prescription
3.5 are adjusted to using pH value, other preparation methods with embodiment 1
Comparative Examples 4：
Prescription
Using sulfuric acid as pH adjusting agent, other preparation methods with embodiment 1
Comparative Examples 5：
Prescription：
Preparation method：The mosatil of recipe quantity, burnt sulfurous is added in the water for injection (50 DEG C~60 DEG C) for taking recipe quantity 75%
Sour sodium, dexmedetomidine hydrochloride, are stirred to dissolve；Be cooled to 35 DEG C hereinafter, with 1mol/L sodium hydroxide solutions adjust pH value to
7.5, then water for injection is mended to recipe quantity, activated carbon stirring and adsorbing is added, through at the beginning of 1 μm of stud, 0.45 μm of polyether sulfone filter core in stirring
Filter；It is filling after 0.22 μm of polyether sulfone filter core refined filtration, it sterilizes to get finished product.
Comparative Examples 6
Preparation method：
Include the following steps：
(1) the disodium ethylene diamine tetraacetate aqueous solution for injection of use quality a concentration of 2.5 ‰ matches stainless steel before preparing
Tank and pipeline processed carry out sealing and circulating processing, and sealing and circulating temperature is 40 DEG C, and the sealing and circulating time is 30min；
(2) it takes 60 DEG C of water for injection of recipe quantity 90% in stainless steel preparing tank, right U.S. of hydrochloric acid of recipe quantity is added
It asks miaow to determine, disodium ethylene diamine tetraacetate, sodium chloride, polyethylene glycol 400, is stirred to dissolve；It is cooled to 35 DEG C, it is molten with sodium hydroxide
Liquid adjusts pH value to 7, is supplemented water for injection to recipe quantity, the ethylenediamine tetrem of water for injection total amount 0.07% is added in stirring
Acid disodium modified activated carbon stirring and adsorbing, after filtering out disodium ethylene diamine tetraacetate modified activated carbon, successively with 0.5 μm of stud and
0.22 μm of millipore filter aseptic filtration, then filling then sterilized, lamp inspection, packaging are to get finished product.
The preparation method of above-mentioned disodium ethylene diamine tetraacetate modified activated carbon is：At 100 DEG C, 0.18MPa, concentration is utilized
Processing, solid-to-liquid ratio 1 are modified to activated carbon for 0.04mol/L disodium ethylene diamine tetra-acetic acid solutions：9, react 40min, mistake
Filter, is dried in vacuo to obtain the final product.
Stability comparison is carried out to the various embodiments described above sample：
Detection method：
Assay：It is measured according to high performance liquid chromatography (Chinese Pharmacopoeia version annex V D in 2015).
Chromatographic condition and system suitability test are using octyl silane group silica gel as filler, 0.02M sodium dihydrogen phosphates
Solution (sodium hydroxide tune PH to 5.5)-acetonitrile (75：25) it is mobile phase, 1.5ml/min, Detection wavelength 227nm, theoretical tower
Plate number is calculated by dexmedetomidine hydrochloride peak should be not less than 2000.
It is appropriate that measuring method precision weighs this product, adds flowing phased soln and quantifies dilution about hydrochloric right U.S. is made in every 1ml
Support miaow determines the solution of 125 μ g, and as test solution, precision measures 20 μ L and injects liquid chromatograph, records chromatogram；Separately take salt
Sour Dexmedetomidine reference substance is appropriate, is measured in the same method, by external standard method with calculated by peak area to get.
Related substance：It takes this product appropriate, add flowing phased soln and quantifies dilution hydrochloric Dexmedetomidine in every 1ml is made
The contrast solution of the test solution of 250 μ g and 2.5 μ g.Precision measures test solution and each 20 μ L of contrast solution, notes respectively
Enter liquid chromatograph, 3 times of record chromatogram to principal component retention time, the peak of each impurity peaks in the chromatogram of test solution
The sum of area is not greater than contrast solution main peak area (1.0%).
Visible foreign matters：According to Chinese Pharmacopoeia two annex IX H method inspections of version in 2015.States Pharmacopoeia specifications freeze-dried powder redissolves
The external visible foreign matters such as chips of glass, cilium should not be detected in solution afterwards, other foreign matters (such as white point, block) are if any detection quantity
Answer≤4.Such as only have 1 it is against regulation, separately take 10 with method retrial.
Particulate matter：According to Chinese Pharmacopoeia two annex IX C method inspections of version in 2015.
Clarity：This product 1 is taken, after being dissolved in water, solution should be clarified；Such as aobvious muddiness, with No. 1 turbidity standard (China
Two annex IX B of pharmacopeia version in 2015) compare, it must not be denseer.
Test method：
1) accelerated test：Test specimen is taken, 40 DEG C is placed in, investigates in the climatic chamber of RH75%, respectively at the 0th
These parameters are investigated in the end of month sampling of the moon, 1 month, 2 months, 3 months, 6 months.(being shown in Table 1)
Influence of 1 accelerated test of table to dexmedetomidine hydrochloride freezing-dried powder injection
By the above accelerated test data as it can be seen that the dexmedetomidine hydrochloride freezing-dried powder injection of the present invention was at 6 months
Very stable always in accelerated test, clarity, visible foreign matters, particulate matter show qualification, and the content in relation to substance is small
In 0.15%；Especially the content of the related substance of embodiment 1 is 0.09%.Comparative Examples 1-6 is in accelerated test process the 6th
At a month, it is seen that foreign matter is apparent, has particulate matter, clarity poor.These explanations, dexmedetomidine hydrochloride of the invention
Freezing-dried powder injection is more stable.
2) long term test：Test specimen is taken, is placed in and investigates under room temperature, in 3rd month, 6 months, 12 months the end of month
These parameters are investigated in sampling.(being shown in Table 2)
Influence of 2 long term test of table to dexmedetomidine hydrochloride freezing-dried powder injection
By the above long term test data as it can be seen that the dexmedetomidine hydrochloride freezing-dried powder injection of the present invention was at 6 months
Very stable always in accelerated test, clarity, visible foreign matters, particulate matter show qualification, and the content in relation to substance is small
In 0.15%；Especially the content of the related substance of 1 embodiment 3 of embodiment is 0.09%.Comparative Examples 1-6 is in accelerated test
When process 6th month, it is seen that foreign matter is apparent, has particulate matter, clarity poor.These explanations, hydrochloric acid of the invention are right
Medetomidine freezing-dried powder injection is more stable.
Claims (10)
1. a kind of dexmedetomidine hydrochloride freezing-dried powder injection, which is characterized in that the injection contains the right U.S. support of hydrochloric acid
Miaow determines freeze-dried powder and dextran, and the preparation method of injection is that citric acid-citric acid first is added in dexmedetomidine hydrochloride
Be added after sodium buffer solution in the water for injection containing dextran, then degerming, filtering, drying and obtain.
2. dexmedetomidine hydrochloride freezing-dried powder injection according to claim 1, it is characterised in that the dextran
Weight part ratio with dexmedetomidine hydrochloride freeze-dried powder is 1:2-20.
3. according to any dexmedetomidine hydrochloride freezing-dried powder injections of claim 1-2, it is characterised in that the right side
The sugared acid anhydride of rotation includes medium molecular dextran.
4. a kind of method preparing dexmedetomidine hydrochloride freezing-dried powder injection, it is characterised in that include the following steps：
1) take dextran that partial syringe water dissolution, the needle-use activated carbon of addition is added to stir, filtering；
2) dexmedetomidine hydrochloride is weighed, after citric acid-sodium citrate buffer dissolving is added, is added molten after the de- charcoal of step 1)
It in liquid, stirs evenly, benefit adds to the full amount of water for injection；
3) with pharmaceutically acceptable sour regulating liquid medicine pH value, with 0.22 μm of miillpore filter aseptic filtration, quantitative filling is in sterile
In clean cillin bottle, half adds rubber plug, is freeze-dried to obtain the final product.
5. according to the method described in claim 4, it is characterized in that the dosage of the dextran is 10 parts.
6. according to the method described in claim 4, it is characterized in that the pH value in the step 3) is 5.0-6.0.
7. according to the method described in claim 4, it is characterized in that the pH value in the step 3) is 5.5.
8. according to the method described in claim 4, it is characterized in that the pH value in the step 2) is 3.0-4.0.
9. according to the method described in claim 4, it is characterized in that the pharmaceutically acceptable acid be phosphoric acid, the sour acid of rafter, hydrochloric acid,
One kind in boric acid, acetic acid or amino acid.
10. according to the method described in claim 9, it is characterized in that the pharmaceutically acceptable acid is citric acid acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810840977.2A CN108743551A (en) | 2018-07-27 | 2018-07-27 | A kind of dexmedetomidine hydrochloride freezing-dried powder injection and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810840977.2A CN108743551A (en) | 2018-07-27 | 2018-07-27 | A kind of dexmedetomidine hydrochloride freezing-dried powder injection and preparation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108743551A true CN108743551A (en) | 2018-11-06 |
Family
ID=63972016
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810840977.2A Withdrawn CN108743551A (en) | 2018-07-27 | 2018-07-27 | A kind of dexmedetomidine hydrochloride freezing-dried powder injection and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108743551A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113521250A (en) * | 2021-08-02 | 2021-10-22 | 山西锦波生物医药股份有限公司 | Protein freeze-dried powder and solution for injection thereof |
-
2018
- 2018-07-27 CN CN201810840977.2A patent/CN108743551A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113521250A (en) * | 2021-08-02 | 2021-10-22 | 山西锦波生物医药股份有限公司 | Protein freeze-dried powder and solution for injection thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110638751A (en) | Stable sugammadex sodium injection and preparation method thereof | |
| CN108992400B (en) | Pharmaceutical composition containing irinotecan hydrochloride and preparation method thereof | |
| CN106668830A (en) | Octreotide acetate injection and preparation process thereof | |
| CN101756915B (en) | Tirofiban hydrochloride lyophilized powder injection and preparation method thereof | |
| CN108498469A (en) | Dexmedetomidine hydrochloride freeze-dried powder and preparation method thereof | |
| CN108743551A (en) | A kind of dexmedetomidine hydrochloride freezing-dried powder injection and preparation method | |
| CN105663127B (en) | Injection is freeze-dried famotidine composition | |
| CN110227063A (en) | A kind of preparation method of Linezolid Injection | |
| CN113876697A (en) | Dopamine hydrochloride injection and preparation process thereof | |
| CN108159026A (en) | A kind of sucking ambroxol hydrochloride solution of stabilization and preparation method thereof | |
| CN110507605B (en) | Stable ornidazole injection and S-ornidazole injection and preparation method thereof | |
| CN104706655B (en) | Meglumine cyclic adenosine for injecta powder-injection pharmaceutical composition and preparation method | |
| CN111494311A (en) | Dopamine hydrochloride injection and preparation method thereof | |
| CN109908077A (en) | A kind of preparation method of Irinotecan hydrochloride injection | |
| CN100430417C (en) | Transferin (Tf)- nerve growth factor (NGF) conjugate preparation method | |
| CN110123742A (en) | A kind of preparation method of high-quality Plerixafor injection | |
| CN105193712B (en) | Ambroxol hydrochloride injection and preparation method | |
| CN103071145B (en) | N(2)-L-alanyl-L-glutamine/compound amino acid injection (18AA-V) pharmaceutical composite preparation | |
| CN111568860B (en) | Ornidazole injection and preparation method thereof | |
| CN107823130A (en) | A kind of preparation method of tetrandrine injection agent medicine composition | |
| CN111529485B (en) | Preparation method of levetiracetam concentrated solution for injection | |
| CN106943342A (en) | A kind of pharmaceutical composition containing argatroban | |
| CN114767627B (en) | Preparation method of ciprofloxacin lactate sodium chloride injection | |
| CN103637983B (en) | A kind of pharmaceutical composition containing nalmefene hydrochloride and preparation method thereof | |
| CN103877015B (en) | A kind of preparation method of Bisolvon glucose injection |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20181106 |