CN109620804A - A kind of ceftriaxone sodium for injection powder injection formulation and preparation method thereof - Google Patents
A kind of ceftriaxone sodium for injection powder injection formulation and preparation method thereof Download PDFInfo
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- CN109620804A CN109620804A CN201811606492.3A CN201811606492A CN109620804A CN 109620804 A CN109620804 A CN 109620804A CN 201811606492 A CN201811606492 A CN 201811606492A CN 109620804 A CN109620804 A CN 109620804A
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- sodium hyaluronate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The present invention relates to a kind of ceftriaxone sodium for injection powder injection formulations and preparation method thereof, belong to pharmaceutical technology field.Said preparation is made of Ceftriaxone Sodium and sodium hyaluronate, and wherein sodium hyaluronate is the sodium hyaluronate solution obtained by ultrasonic vibration specially treated.Ceftriaxone sodium for injection aseptic powder of the present invention is in floccule, and dissolubility is fine when powder-injection matches liquid；Product quality is substantially improved, and the indices such as content, single miscellaneous, total miscellaneous, polymer are significantly larger than standards of pharmacopoeia, is better than prior art products；Stability significantly improves, and product was through 6 months accelerated tests, and content only reduces 0.1%-0.2%, and list is miscellaneous only to reduce 0.05%-0.06%, and always miscellaneous only to reduce 0.10%-0.11%, polymer only reduces by 0.02%, and stability is substantially better than prior art products.
Description
Technical field
The present invention relates to a kind of injection powder injection formulation more particularly to a kind of ceftriaxone sodium for injection powder injection formulation and its
Preparation method belongs to pharmaceutical technology field.
Background technique
Ceftriaxone Sodium is also known as Ceftriaxone or ceftriaxone, is cephalosporanic olefinic derivative.Yuan Yan producer is Switzerland
Roche, nineteen eighty-two first Switzerland list, trade name " Rocephin ".In the U.S. after being examined by FDA in December, 1984
Listing lists for 1986 in Japan, and it is cephalosporins that early 1990s are registered in 28 countries and regions in the whole world
" milestone " drug in the development history of antibiotic.Nineteen ninety-five CFDA ratifies the Ceftriaxone Sodium of Shanghai Roche Holding Ag production, quotient
The name of an article is " Ceftriaxone ", and specification is respectively 0.25g, 0.5g, 1.0g.
Ceftriaxone Sodium is Third generation Cephalosporins antibiotic, has powerful activity to enterobacteriaceae lactobacteriaceae；To large intestine angstrom
Uncommon bacterium, Klebsiella Pneumoniae, clostridium perfringen, fluorine labor citrobacter, indole-positive proteus, Pu Luweideng Pseudomonas and
The MIC90 of Serratia is between 0.12~0.25mg/L；Enterobacter cloacae, acinetobacter and pseudomonas aeruginosa are to it
Sensibility is poor；There is stronger antibacterial action to haemophilus influenzae, NEISSERIA GONORRHOEAE and Neisseria meningitidis, to hemolytic streptococcus
Also there is good action with pneumococcus；MIC to staphylococcus aureus is 2~4mg/L；Methicillin-resistant Staphylococcus and intestines
Coccus is to its drug resistance；Most bacteroides fragilis are to its drug resistance.Clinically for lower respiratory tract infection caused by sensitive pathogenic bacteria, urine
Road, infection of biliary tract and abdominal cavity infection, pelvic infection, skin soft-tissue infection, bone and the infection of joint, septicemia, meningitis etc.
And average of operation periods infection mitigation.
The stability of Ceftriaxone Sodium is poor, unstable to heat, meta-acid environment, meta-alkali environment, it may appear that content reduction,
The problems such as impurity increases.Patent CN201510104263.1 discloses a kind of ceftriaxone sodium for injection powder-injection and its preparation side
Method crystallizes crucial production technology using novel coupling, and ceftriaxone sodium for injection powder obtained reaches excellent hydrodynamics
Performance, crystalline form is perfect, and even particle size distribution, color grade, clarity, purity and stability increase, but ideal not enough, and
Injection product is being configured to solution in use, solution rate is slow, is unfavorable for clinical application.It would therefore be desirable to develop one kind
The ceftriaxone sodium for injection of better quality provides better choice for doctors and patients.
Sodium hyaluronate also known as Sodium Hyaluronate are a kind of macromolecules alternately and repeatedly formed by N- acetyl glucosamine aldehydic acid
Polysaccharide body biomaterial.Sodium hyaluronate is the main component of knuckle synovia, is one of ingredient of cartilage matrix.It is risen in articular cavity
Lubricating action can cover and protect articular cartilage, improve the contracture of joint, inhibit cartilage degeneration surface variations, improve pathologic and close
Liquid is saved, increases and drips sliding function.Sodium hyaluronate can be used in intramuscular injection, intra-articular injection and vitreum as injection auxiliary material
Injection etc., primary efficacy are moisturizer, lubricant and sustained release agent etc..
Summary of the invention
The purpose of the invention is to further increase the product quality of ceftriaxone sodium for injection, by adjusting prescription,
The specially treated sodium hyaluronate of special ratios is added, and by specified conditions several times by ceftriaxone sodium water solution and glass
Glass acid sodium solution is uniformly mixed, and the organic solvent for adding optimum ratio carries out Precipitation, is finally obtained a kind of injection
Ceftriaxone Sodium, said preparation have excellent stability, at the same preparation match liquid when its dissolubility also obtains well improve, thus
It ensure that the convenience of the validity of medication, safety and clinical use.
Purpose to realize the present invention, using following technical scheme:
The present invention provides a kind of ceftriaxone sodium for injection, and said preparation is made of Ceftriaxone Sodium and sodium hyaluronate, wherein
Sodium hyaluronate need to obtain sodium hyaluronate solution by the specially treated of ultrasonic vibration.
Above-mentioned ceftriaxone sodium for injection, the sodium hyaluronate need to be to take prescription by the special treatment method of ultrasonic vibration
Sodium hyaluronate is measured, is slowly stirred and is dissolved in 6L distilled water, carried out ultrasonic vibration 30 minutes under the conditions of 20 kHz, 30,000
It is carried out ultrasonic vibration 1 hour under the conditions of hertz, is cooled to room temperature, obtains sodium hyaluronate solution.
Above-mentioned ceftriaxone sodium for injection, be recipe quantity crude product of ceftriaxone sodium is dissolved in 2L distilled water be made into it is water-soluble
Liquid adds active carbon to handle, and filters to get filtrate, and specially treated sodium hyaluronate solution is added in filtrate several times, and is delayed
Slow stirring is stood, at the uniform velocity addition organic solvent, is slowly stirred, is stood, filters, and dry, weighing, packing obtains.
Above-mentioned ceftriaxone sodium for injection, it is described to be added to sodium hyaluronate solution in filtrate several times, specially to filter
20% sodium hyaluronate solution is added in liquid, after 30 revs/min are slowly stirred 15 minutes, adds 38% sodium hyaluronate solution, 40 turns/
After minute is slowly stirred 35 minutes, 26% sodium hyaluronate solution is added, 36 revs/min are slowly stirred after forty minutes, add
Remaining sodium hyaluronate solution, 30 revs/min are slowly stirred 60 minutes, stand 1 hour at room temperature.
Further, above-mentioned ceftriaxone sodium for injection, the organic solvent that is at the uniform velocity added is with 200mL/ minutes speed
Degree is at the uniform velocity added.
It is furthermore preferred that the weight ratio of above-mentioned ceftriaxone sodium for injection, the Ceftriaxone Sodium and sodium hyaluronate is 1:
0.035-0.045。
It is furthermore preferred that above-mentioned ceftriaxone sodium for injection, the volume of the distilled water and the volume ratio of organic solvent are 8:
42。
It is furthermore preferred that above-mentioned ceftriaxone sodium for injection, the organic solvent is the mixed solvent of glycerine and ethyl alcohol, two
Person's volume ratio is 1.5:2.2.
The present invention also provides the preparation methods of above-mentioned ceftriaxone sodium for injection, include the following steps:
Step 1: taking recipe quantity sodium hyaluronate, be slowly stirred and be dissolved in 6L distilled water, ultrasonic vibration processing is cooled to room
Temperature obtains sodium hyaluronate solution, spare；
Step 2: weighing crude product of ceftriaxone sodium raw material 1000g, distilled water 2L is added, 4-6% activity is added in stirring and dissolving
Charcoal desuperheating original and impurity, are stirred 30 minutes, filtering with microporous membrane obtains filtrate；
Step 3: sodium hyaluronate solution prepared by 20% step 1 is added to gained filtrate in step 2,30 revs/min slow
After slow stirring 15 minutes, sodium hyaluronate solution prepared by 38% step 1 is added, after 40 revs/min are slowly stirred 35 minutes,
Sodium hyaluronate solution prepared by 26% step 1 is added, 36 revs/min are slowly stirred after forty minutes, add remaining step
Sodium hyaluronate solution prepared by rapid 1,30 revs/min are slowly stirred 60 minutes, stand 1 hour at room temperature；
Step 4: into step 3 gained reaction solution, it is 1.5:2.2's that volume ratio is at the uniform velocity added with 200mL/ minutes speed
The mixed solvent 42L of glycerine and ethyl alcohol, while be slowly stirred 240 minutes with 25 revs/min of speed, it is small to stand 12
When；
Step 5: filtering, wash filter cake in three times with 6L dehydrated alcohol, filter cake is put into vacuum oven, in 30-40
It is dried in vacuo at DEG C, obtains aseptic powder；
Step 6: the content of 10g aseptic powder measurement Ceftriaxone Sodium is taken, then needed for the powder injection formulation of conversion different size
Aseptic powder dosage, weighing is aseptic subpackaged, and control ambient temperature and humidity is 18~24 DEG C, and humidity obtains injection cephalo less than 30%
Qusong sodium powder-needle preparation.
Above-mentioned preparation method, in the step 1, the ultrasonic vibration processing is that ultrasonic shake is carried out under the conditions of 20 kHz
It swings 30 minutes, is carried out ultrasonic vibration 1 hour under the conditions of 30 kHz.
The macromolecular network structure of sodium hyaluronate can be filled in combination with a large amount of drug molecule, ceftriaxone sodium molecule
Wherein, the present invention is by specially treated, so that sodium hyaluronate forms good mesh system, and can be with the cephalo inside being wrapped in
Qusong sodium mutually balances, this plays a significant role the stability for improving ceftriaxone sodium for injection.In addition, in Ceftriaxone Sodium
When solution mixes dispersion with sodium hyaluronate solution, reasonable additional amount, mixing speed and time control, to the formation equilibrium system
With vital meaning.
The technical effect of scheme specific implementation through the invention: 1. Ceftriaxone Sodium aseptic powders are in floccule, and powder-injection matches
Dissolubility is fine when liquid；2. product quality is substantially improved, the indices such as content, single miscellaneous, total miscellaneous, polymer are significantly larger than medicine
Allusion quotation standard is better than prior art products；3. stability significantly improves, product of the present invention is only reduced through 6 months accelerated tests, content
0.1%-0.2%, list is miscellaneous only to reduce 0.05%-0.06%, and always miscellaneous only to reduce 0.10%-0.11%, polymer only reduces
0.02%, stability is substantially better than prior art products.
Specific embodiment
Below by specific embodiment, invention is further described in detail, but is merely used to help understand this hair
It is bright, it enables those skilled in the art to implement or use the present invention, does not form any restrictions to the present invention.
Test 1 prescription screening
Prepare the ceftriaxone sodium for injection sample of different Ceftriaxone Sodiums Yu sodium hyaluronate consumption proportion, prescription dosage
Ratio and the preparation method is as follows:
The prescription usage ratio of 1 test example 1-7 of table
Preparation method:
Step 1: taking recipe quantity sodium hyaluronate, be slowly stirred and be dissolved in 6L distilled water, carried out under the conditions of 20 kHz
It ultrasonic vibration 30 minutes, is carried out ultrasonic vibration 1 hour under the conditions of 30 kHz, is cooled to room temperature, obtains sodium hyaluronate solution,
It is spare；
Step 2: weighing recipe quantity crude product of ceftriaxone sodium raw material, 2L distilled water is added, it is living that 4-6% is added in stirring and dissolving
Property charcoal desuperheating is former and impurity, stir 30 minutes, filtering with microporous membrane obtains filtrate；
Step 3: sodium hyaluronate solution prepared by 20% step 1 is added to gained filtrate in step 2,30 revs/min slow
After slow stirring 15 minutes, sodium hyaluronate solution prepared by 38% step 1 is added, after 40 revs/min are slowly stirred 35 minutes,
Sodium hyaluronate solution prepared by 26% step 1 is added, 36 revs/min are slowly stirred after forty minutes, add remaining step
Sodium hyaluronate solution prepared by rapid 1,30 revs/min are slowly stirred 60 minutes, stand 1 hour at room temperature；
Step 4: into step 3 gained reaction solution, it is 1.5:2.2's that volume ratio is at the uniform velocity added with 200mL/ minutes speed
The mixed solvent 42L of glycerine and ethyl alcohol, while be slowly stirred 240 minutes with 25 revs/min of speed, it is small to stand 12
When；
Step 5: filtering, wash filter cake in three times with 6L dehydrated alcohol, filter cake is put into vacuum oven, in 30-40
It is dried in vacuo at DEG C, obtains aseptic powder；
Step 6: taking the content of 10g aseptic powder measurement Ceftriaxone Sodium, then convert the powder injection formulation of 0.25g/ bottles of specifications
Required aseptic powder dosage, weighing is aseptic subpackaged, and control ambient temperature and humidity is 18~24 DEG C, and humidity obtains injection less than 30%
Ceftriaxone sodium powder-needle preparation.
To test example 1-7 carry out accelerated test investigation, accelerated test condition be 40 ± 2 DEG C of temperature, relative humidity 75 ±
Under conditions of 5%, place 6 months.Clarity of solution, content, the inspection in relation to object and ceftriaxone polymer (abbreviation polymer)
Survey method is official method (Chinese Pharmacopoeia version two in 2015), the results are shown in Table 2.
2 test example 1-7 accelerated test of table investigates data
It is learnt by 2 result of table, after undergoing 6 months accelerated tests, ceftriaxone sodium for injection sample prepared by test example 3-5
The reduction of product content is slower, and impurity growth is slower, and stability is more preferable.And injection head prepared by test example 1-2 and test example 6-7
Spore Qusong sodium sample stability is poor, and quality accelerates decline.
The analysis showed that be not enough to form Ceftriaxone Sodium and wrap up since test example 1-2 sodium hyaluronate dosage is very little,
And test example 6-7 sodium hyaluronate dosage is too big, sodium hyaluronate solution viscosity is excessively high, so that Ceftriaxone Sodium is also difficult uniform score
It is dispersed in its reticular structure, so final optimization test example 3-5 Ceftriaxone Sodium and sodium hyaluronate amount ratio are 1:0.035-
0.045, gained ceftriaxone sodium for injection product stability is higher.
Test the proportion screening of 2 organic solvents
Organic solvent is added in the step 4 of 4 preparation method of test example promotes Ceftriaxone Sodium to be precipitated, and needs to select and distill
Water can be miscible organic solvent, and may be implemented to crude product Ceftriaxone Sodium purify effect, have finally chosen glycerine
With the mixed solvent of ethyl alcohol.Further the ratio of both solvents is carried out preferably, by the preparation method of test example 4, wherein walking
Organic solvent is added in rapid 4 and presses the glycerine of different proportion and ethyl alcohol addition in table 3 respectively, to prepare injection ceftriaxone
Sodium, to investigate different solvents with the influence for comparing final products.
Influence of the 3 different ratio organic solvent of table to ceftriaxone sodium for injection product
It is shown through test data, in selected organic solvent, glycerine is too many, and sediment is precipitated in bulk, thus prepares
Aseptic powder is distributed into powder-injection, not readily dissolves when using with liquid；Ethyl alcohol is too many, can reduce the yield of preparation aseptic powder, therefore
Final preferably glycerine and ethyl alcohol volume ratio are 1.5:2.2.
Embodiment 1 prepares ceftriaxone sodium for injection powder injection formulation of the present invention (0.25g/ bottles)
Preparation method:
Step 1: taking 40g sodium hyaluronate, be slowly stirred and be dissolved in 6L distilled water, ultrasound is carried out under the conditions of 20 kHz
Concussion 30 minutes, carries out ultrasonic vibration 1 hour under the conditions of 30 kHz, is cooled to room temperature, obtains sodium hyaluronate solution, standby
With；
Step 2: weighing crude product of ceftriaxone sodium raw material 1000g, distilled water 2L is added, 4-6% activity is added in stirring and dissolving
Charcoal desuperheating original and impurity, are stirred 30 minutes, filtering with microporous membrane obtains filtrate；
Step 3: sodium hyaluronate solution prepared by 20% step 1 is added to gained filtrate in step 2,30 revs/min slow
After slow stirring 15 minutes, sodium hyaluronate solution prepared by 38% step 1 is added, after 40 revs/min are slowly stirred 35 minutes,
Sodium hyaluronate solution prepared by 26% step 1 is added, 36 revs/min are slowly stirred after forty minutes, add remaining step
Sodium hyaluronate solution prepared by rapid 1,30 revs/min are slowly stirred 60 minutes, stand 1 hour at room temperature；
Step 4: into step 3 gained reaction solution, it is 1.5:2.2's that volume ratio is at the uniform velocity added with 200mL/ minutes speed
The mixed solvent 42L of glycerine and ethyl alcohol, while be slowly stirred 240 minutes with 25 revs/min of speed, it is small to stand 12
When；
Step 5: filtering, wash filter cake in three times with 6L dehydrated alcohol, filter cake is put into vacuum oven, in 30-40
It is dried in vacuo at DEG C, obtains aseptic powder；
Step 6: taking the content of 10g aseptic powder measurement Ceftriaxone Sodium, then convert the powder injection formulation of 0.25g/ bottles of specifications
Required aseptic powder dosage, weighing is aseptic subpackaged, and control ambient temperature and humidity is 18~24 DEG C, and humidity obtains injection less than 30%
Ceftriaxone sodium powder-needle preparation.
Embodiment 2 prepares ceftriaxone sodium for injection powder injection formulation of the present invention (0.5g/ bottles)
Preparation method:
Step 1: taking 35g sodium hyaluronate, be slowly stirred and be dissolved in 6L distilled water, ultrasound is carried out under the conditions of 20 kHz
Concussion 30 minutes, carries out ultrasonic vibration 1 hour under the conditions of 30 kHz, is cooled to room temperature, obtains sodium hyaluronate solution, standby
With；
Step 2: weighing crude product of ceftriaxone sodium raw material 1000g, distilled water 2L is added, 4-6% activity is added in stirring and dissolving
Charcoal desuperheating original and impurity, are stirred 30 minutes, filtering with microporous membrane obtains filtrate；
Step 3: sodium hyaluronate solution prepared by 20% step 1 is added to gained filtrate in step 2,30 revs/min slow
After slow stirring 15 minutes, sodium hyaluronate solution prepared by 38% step 1 is added, after 40 revs/min are slowly stirred 35 minutes,
Sodium hyaluronate solution prepared by 26% step 1 is added, 36 revs/min are slowly stirred after forty minutes, add remaining step
Sodium hyaluronate solution prepared by rapid 1,30 revs/min are slowly stirred 60 minutes, stand 1 hour at room temperature；
Step 4: into step 3 gained reaction solution, it is 1.5:2.2's that volume ratio is at the uniform velocity added with 200mL/ minutes speed
The mixed solvent 42L of glycerine and ethyl alcohol, while be slowly stirred 240 minutes with 25 revs/min of speed, it is small to stand 12
When；
Step 5: filtering, wash filter cake in three times with 6L dehydrated alcohol, filter cake is put into vacuum oven, in 30-40
It is dried in vacuo at DEG C, obtains aseptic powder；
Step 6: taking the content of 10g aseptic powder measurement Ceftriaxone Sodium, then convert the powder injection formulation institute of 0.5g/ bottles of specifications
Aseptic powder dosage is needed, is weighed, aseptic subpackaged, control ambient temperature and humidity is 18~24 DEG C, and humidity obtains injection head less than 30%
Spore Qusong sodium powder-needle preparation.
Embodiment 3 prepares ceftriaxone sodium for injection powder injection formulation of the present invention (1.0g/ bottles)
Preparation method:
Step 1: taking 45g sodium hyaluronate, be slowly stirred and be dissolved in 6L distilled water, ultrasound is carried out under the conditions of 20 kHz
Concussion 30 minutes, carries out ultrasonic vibration 1 hour under the conditions of 30 kHz, is cooled to room temperature, obtains sodium hyaluronate solution, standby
With；
Step 2: weighing crude product of ceftriaxone sodium raw material 1000g, distilled water 2L is added, 4-6% activity is added in stirring and dissolving
Charcoal desuperheating original and impurity, are stirred 30 minutes, filtering with microporous membrane obtains filtrate；
Step 3: sodium hyaluronate solution prepared by 20% step 1 is added to gained filtrate in step 2,30 revs/min slow
After slow stirring 15 minutes, sodium hyaluronate solution prepared by 38% step 1 is added, after 40 revs/min are slowly stirred 35 minutes,
Sodium hyaluronate solution prepared by 26% step 1 is added, 36 revs/min are slowly stirred after forty minutes, add remaining step
Sodium hyaluronate solution prepared by rapid 1,30 revs/min are slowly stirred 60 minutes, stand 1 hour at room temperature；
Step 4: into step 3 gained reaction solution, it is 1.5:2.2's that volume ratio is at the uniform velocity added with 200mL/ minutes speed
The mixed solvent 42L of glycerine and ethyl alcohol, while be slowly stirred 240 minutes with 25 revs/min of speed, it is small to stand 12
When；
Step 5: filtering, wash filter cake in three times with 6L dehydrated alcohol, filter cake is put into vacuum oven, in 30-40
It is dried in vacuo at DEG C, obtains aseptic powder；
Step 6: taking the content of 10g aseptic powder measurement Ceftriaxone Sodium, then convert the powder injection formulation institute of 1.0g/ bottles of specifications
Aseptic powder dosage is needed, is weighed, aseptic subpackaged, control ambient temperature and humidity is 18~24 DEG C, and humidity obtains injection head less than 30%
Spore Qusong sodium powder-needle preparation.
The untreated sodium hyaluronate of comparative example 1 prepares ceftriaxone sodium for injection
Preparation method:
Step 1: 40g sodium hyaluronate is taken, is slowly stirred and is dissolved in 6L distilled water, obtains sodium hyaluronate solution, it is spare；
Step 2: weighing crude product of ceftriaxone sodium raw material 1000g, distilled water 2L is added, 4-6% activity is added in stirring and dissolving
Charcoal desuperheating original and impurity, are stirred 30 minutes, filtering with microporous membrane obtains filtrate；
Step 3: sodium hyaluronate solution prepared by 20% step 1 is added to gained filtrate in step 2,30 revs/min slow
After slow stirring 15 minutes, sodium hyaluronate solution prepared by 38% step 1 is added, after 40 revs/min are slowly stirred 35 minutes,
Sodium hyaluronate solution prepared by 26% step 1 is added, 36 revs/min are slowly stirred after forty minutes, add remaining step
Sodium hyaluronate solution prepared by rapid 1,30 revs/min are slowly stirred 60 minutes, stand 1 hour at room temperature；
Step 4: into step 3 gained reaction solution, it is 1.5:2.2's that volume ratio is at the uniform velocity added with 200mL/ minutes speed
The mixed solvent 42L of glycerine and ethyl alcohol, while be slowly stirred 240 minutes with 25 revs/min of speed, it is small to stand 12
When；
Step 5: filtering, wash filter cake in three times with 6L dehydrated alcohol, filter cake is put into vacuum oven, in 30-40
It is dried in vacuo at DEG C, obtains aseptic powder；
Step 6: taking the content of 10g aseptic powder measurement Ceftriaxone Sodium, then convert the powder injection formulation of 0.25g/ bottles of specifications
Required aseptic powder dosage, weighing is aseptic subpackaged, and control ambient temperature and humidity is 18~24 DEG C, and humidity obtains injection less than 30%
Ceftriaxone sodium powder-needle preparation.
Comparative example 2 prepares ceftriaxone sodium for injection in patent CN201510104263.1, is prepared according to embodiment 1
Preparation method:
(1) at 20 DEG C, the crude product of ceftriaxone sodium raw material of precise 30g is added the distilled water of 50mL, opens stirring,
Be completely dissolved within about 10-15 minutes, then be added 3g active carbon, decolourize 30 minutes, filtering, with 60ml volume ratio be (acetone: water=
Mixed solvent 3:1) washs filter residue, filter flask 2 times, and filtrate enters in crystallization bottle.
(2) at 15 DEG C, mixing speed is under 300 turns/min, and dissolved agent acetone is added according to the form below flow rate:
(3) it is filtered after crystallizing, with 20ml*3 acetone washing filter cake, filter cake is put into vacuum oven,
Vacuum oven temperature is at 40 DEG C, vacuum drying, weighing, packing.
The ceftriaxone sodium for injection commercially available product of 3 Shanghai Co., Ltd, Roche Group of comparative example
Buy the commercial samples of Shanghai Co., Ltd, Roche Group, trade name: Ceftriaxone, lot number SH6193.
1 study on the stability of comparative experimental example
Embodiment 1-3 and comparative example 1-3 is chosen respectively and carries out accelerated test investigation simultaneously, and accelerated test condition is in temperature
40 ± 2 DEG C, under conditions of relative humidity 75 ± 5%, place 6 months.Clarity of solution, content are gathered in relation to object and ceftriaxone
The detection method for closing object (abbreviation polymer) is official method (Chinese Pharmacopoeia version two in 2015), the results are shown in Table 4.
4 accelerated test of table investigates data
From table 4: compared with comparative example 2 and comparative example 3, injection cephalo prepared by 1-3 of the embodiment of the present invention is bent
Loose sodium sample content is higher, impurity content is lower, better quality.After 6 months accelerated tests, prepared by embodiment 1-3
Ceftriaxone sodium for injection sample is slower compared with the reduction of comparative example 1-3 content, and impurity increase is slower, and for content 106% or more, list is miscellaneous
It is below 0.2%, always miscellaneous to be below 0.35%, polymer is below 0.1%.And although content is high at comparative example 10 months, it is miscellaneous
Matter is few, but stability is not good enough, and after 6 months accelerated tests, content is down to 105.7%, and list is miscellaneous to increase to 0.3%, total miscellaneous increasing
To 0.45%, polymer increases to 0.22%, illustrates steady using the ceftriaxone sodium for injection of untreated sodium hyaluronate preparation
It is qualitative to be still weak.The above results show that by the way that sodium hyaluronate is carried out specially treated, it is made by 1-3 of the embodiment of the present invention
Standby ceftriaxone sodium for injection is more preferable, further improves the quality and stability of product, has obvious effect, is
Clinical application provides better choice.
The above is only the preferred embodiment of the present invention, are not intended to limit the invention, and those skilled in the art are come
It says, without departing from the principle of the present invention, several improvement, the retouching, equivalent replacement that can also be made should be included in this
Within the protection scope of invention.
Claims (10)
1. a kind of ceftriaxone sodium for injection, which is characterized in that said preparation is made of Ceftriaxone Sodium and sodium hyaluronate, wherein glass
Glass acid sodium is the sodium hyaluronate solution obtained by ultrasonic vibration specially treated.
2. ceftriaxone sodium for injection according to claim 1, which is characterized in that the ultrasonic vibration specially treated is,
Recipe quantity sodium hyaluronate is taken, is slowly stirred and is dissolved in 6L distilled water, is carried out ultrasonic vibration 30 minutes under the conditions of 20 kHz,
It is carried out ultrasonic vibration 1 hour under the conditions of 30 kHz, is cooled to room temperature, obtains sodium hyaluronate solution.
3. ceftriaxone sodium for injection according to claim 2, which is characterized in that preparation method is, by recipe quantity head
Spore Qusong sodium crude product is dissolved in 2L distilled water and is made into aqueous solution, adds active carbon to handle, filters to get filtrate, by specially treated glass
Glass acid sodium solution is added in filtrate several times, and is slowly stirred, is stood, at the uniform velocity addition organic solvent, is slowly stirred, is stood,
It filters, dry, weighing, packing obtains.
4. ceftriaxone sodium for injection according to claim 3, which is characterized in that it is described by sodium hyaluronate solution several times
It is added in filtrate, 20% sodium hyaluronate solution specially is added to filtrate, after 30 revs/min are slowly stirred 15 minutes, then plus
Enter 38% sodium hyaluronate solution, after 40 revs/min are slowly stirred 35 minutes, adds 26% sodium hyaluronate solution, 36 revs/min
It is slowly stirred after forty minutes, adds remaining sodium hyaluronate solution, 30 revs/min are slowly stirred 60 minutes, quiet at room temperature
It sets 1 hour.
5. ceftriaxone sodium for injection according to claim 3, which is characterized in that it is described at the uniform velocity be added organic solvent be with
200mL/ minutes speed is at the uniform velocity added.
6. ceftriaxone sodium for injection according to claim 1, which is characterized in that the Ceftriaxone Sodium and sodium hyaluronate
Weight ratio be 1:0.035-0.045.
7. ceftriaxone sodium for injection according to claim 3, which is characterized in that the volume of the distilled water and organic molten
The volume ratio of agent is 8:42.
8. ceftriaxone sodium for injection according to claim 7, which is characterized in that the organic solvent is glycerine and second
The mixed solvent of alcohol, the two volume ratio are 1.5:2.2.
9. a kind of method for preparing ceftriaxone sodium for injection as claimed in any one of claims 1 to 7, which is characterized in that
Include the following steps:
Step 1: recipe quantity sodium hyaluronate is taken, is slowly stirred and is dissolved in 6L distilled water, ultrasonic vibration processing is cooled to room temperature,
Sodium hyaluronate solution is obtained, it is spare；
Step 2: weighing crude product of ceftriaxone sodium raw material 1000g, distilled water 2L is added, it is de- that 4-6% active carbon is added in stirring and dissolving
Pyrogen and impurity stir 30 minutes, and filtering with microporous membrane obtains filtrate；
Step 3: sodium hyaluronate solution prepared by 20% step 1 is added to gained filtrate in step 2,30 revs/min are slowly stirred
After mixing 15 minutes, sodium hyaluronate solution prepared by 38% step 1 is added, after 40 revs/min are slowly stirred 35 minutes, then plus
Enter sodium hyaluronate solution prepared by 26% step 1,36 revs/min are slowly stirred step 1 institute for adding residue after forty minutes
The sodium hyaluronate solution of preparation, 30 revs/min are slowly stirred 60 minutes, stand 1 hour at room temperature；
Step 4: into step 3 gained reaction solution, volume ratio is added at the uniform velocity with 200mL/ minutes speed as the third the three of 1.5:2.2
The mixed solvent 42L of alcohol and ethyl alcohol, while be slowly stirred 240 minutes with 25 revs/min of speed, stand 12 hours；
Step 5: filtering, wash filter cake in three times with 6L dehydrated alcohol, filter cake is put into vacuum oven, at 30-40 DEG C
Vacuum drying, obtains aseptic powder；
Step 6: taking the content of 10g aseptic powder measurement Ceftriaxone Sodium, then convert sterile needed for the powder injection formulation of different size
Powder dosage, weighing is aseptic subpackaged, and control ambient temperature and humidity is 18~24 DEG C, and humidity obtains injection ceftriaxone less than 30%
Sodium powder-needle preparation.
10. the preparation method of ceftriaxone sodium for injection according to claim 9, which is characterized in that in the step 1,
The ultrasonic vibration processing is carried out ultrasonic vibration 30 minutes under the conditions of 20 kHz, and ultrasound is carried out under the conditions of 30 kHz
Concussion 1 hour.
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| CN112675135A (en) * | 2021-01-11 | 2021-04-20 | 河北化工医药职业技术学院 | Freeze-dried powder injection preparation for treating bacterial infection and preparation method thereof |
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