CN105147724B - A kind of Mannitol sodium chloride injection and preparation method thereof - Google Patents
A kind of Mannitol sodium chloride injection and preparation method thereof Download PDFInfo
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- CN105147724B CN105147724B CN201510515596.3A CN201510515596A CN105147724B CN 105147724 B CN105147724 B CN 105147724B CN 201510515596 A CN201510515596 A CN 201510515596A CN 105147724 B CN105147724 B CN 105147724B
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Abstract
The invention discloses a kind of Mannitol sodium chloride injection and preparation method thereof, the hydroxy stearic acid ester of polyethylene glycol 12 is with the addition of in the parenteral solution, while uses citric acid solution to adjust pH as 4.0 6.0.Compared with prior art, invention formulation stability is good, and 5 HMF do not increase substantially；Preparation method is simple, it is not necessary to complicated preparation equipment, is easy to industrialized production；Sterilizing uses terminal sterilization, Product Safety height.
Description
Technical field
The invention belongs to technical field of medicine, in particular to a kind of parenteral solution, more particularly to a kind of glycerine fruit
Sugared sodium chloride injection and preparation method thereof.
Background technology
Mannitol sodium chloride injection clinically belongs to drop intracranial pressure medicine, curative for effect, firmly gets doctor and patient
Favorable comment.The parenteral solution is hypertonic preparation, is dehydrated by high osmosis, can reduce brain water content, reduces intracranial pressure.This product
Reduction intracranial pressure onset of action is slow, and the duration is longer.Indication is：For cerebrovascular disease, brain trauma, brain tumor, encephalic
The disease such as acute and chronic increased intracranial pressure, encephaledema caused by inflammation and other reasonses.Glycerine existing thing originally in human organism
Matter, it is the mesostate of syrup solution, while is the precursor substance of machine body fat or lipid synthesis again.Fructose is glucose
Isomers, have levorotation, pharmacological action and application it is substantially same with glucose, have directly feed heat energy, supplement body fluid and
The effect of nutrition whole body, and glycogen can be metabolized in the case of without insulin, therefore be easier to absorb than glucose.So
And 5 hydroxymethyl furfural (5-HMF) is fructose aldehyde compound (Nanjing pharmacy caused by dehydration under the conditions of high temperature or weak acid etc.
Pharmacy teaching and research group of institute pharmacies [M] Beijing：People's Health Publisher, 1985：509-11.), the conduct in containing sugared parenteral solution
One important relevant material is controlled.
CN104666340A discloses a kind of Mannitol sodium chloride injection, using low temperature prepare and ultrafiltration new technology,
Any auxiliary material is not added with preparation process, is not added with activated carbon, this addresses the problem fructose instability problem (to produce 5- methylol chaffs
Aldehyde) and activated carbon residual safety issue.But low temperature is prepared and requires harsh to production environment, improves production cost, no
Mass produced beneficial to industrialization.
CN103417568A discloses a kind of product and does not add the trap of stabilizer and 5 hydroxymethyl furfural less than 0.6
Preparation method, including accounted for successively to access the cumulative volume 30% that makes up a prescription water for injection dense preparing tank in add recipe quantity chlorination
Sodium, glycerine, fructose, after raw material all dissolving, dense preparing tank liquid outlet, dilute preparing tank inlet are opened, squeezes into dilute preparing tank；With injection
With water complement product to 99%, regulation pH value is between 3.8~4.2；Filtered through the inline final filter equipped with 0.22 μm of polyether sulfone filter core
Afterwards enter it is filling, produce the parenteral solution.The lengthy and tedious complexity of preparation technology of the patented technology, it is unfavorable for Workshop Production operation.
The Mannitol sodium chloride injection stability that method disclosed in CN102188437A and CN1864693A produces is poor,
It is higher to be mainly manifested in 5 hydroxymethyl furfural, in addition production and in storage period it is exceeded, do not meet the regulation of Chinese Pharmacopoeia, reduce
The security of medication.
The stabilizer for proposing to use in CN101991589A is natrium adetate, mosatil, trisodium citrate, lemon
Sour potassium, wherein natrium adetate, mosatil are mainly used in being combined into stable and solvable complex compound with metal, to remove
Metal ion in solution, trisodium citrate, potassium citrate are as pH stabilizers, for stablizing pH, but to the guarantor of fructose degraded
Shield effect is limited.
The content of the invention
Because the quality requirement of Mannitol sodium chloride injection is very high, the wherein limitation requirement pole of 5 hydroxymethyl furfural
Sternly, thus the present inventor in view of the shortcomings of the prior art, by prescription carry out lot of experiments research, there is provided a kind of stabilization it is sweet
Oily fructose sodium chloride injection.
In order to realize the purpose of the present invention, inventor is in test it is considered that 5-HMF is generated by fructose dehydration, in molecule
Containing a furan nucleus, an aldehyde radical and a methylol, if adding a kind of material, suppress the dehydration, then can be from
Fundamentally reduce 5-HMF content.By many experiments, inventor is found surprisingly that HS15 can
Effectively to suppress fructose dehydration.Even if in this way, catabolite 5-HMF still has increased trend, in above-mentioned experimental study
On the basis of, inventor has attempted other method again, finally found that under the synergy with citron acid for adjusting pH, 5-HMF is long-term
It is basically unchanged in storage process.
Specifically, the purpose of the present invention is achieved by the following technical solution：A kind of Glycerin Fructose chloride injection
Liquid, contain HS15 in the parenteral solution.
More have preferably, the purpose of the present invention can also be achieved in that：Described Mannitol sodium chloride injection, wherein
The weight of fructose and HS15 ratio is 1：0.05-0.6.
It is further preferred that Mannitol sodium chloride injection as described above, wherein fructose and polyethylene glycol -12- hydroxyls
The weight ratio of base stearate is 1：0.1-0.3.
In the embodiment of all choosings of the present invention, Mannitol sodium chloride injection as described above, it is by glycerine, fruit
Sugar, sodium chloride, HS15, pH adjusting agent and water for injection are formulated.Still further preferably,
Described pH adjusting agent is citric acid.
Still further preferably, Mannitol sodium chloride injection as described above, pH adjusting agent therein adjust the note
The pH for penetrating liquid is 4.0-6.0.
Present invention also offers a kind of preparation method of above-mentioned Mannitol sodium chloride injection, this method includes following step
Suddenly：Glycerine, sodium chloride are added in water for injection and dissolved, then adds HS15 dissolving, then
Fructose dissolving is added, pH value is adjusted as 4.0-6.0 using aqueous citric acid solution, added to the full amount of water for injection, charcoal absorption, mistake
Filter, filling, sterilizing, lamp inspection, packaging.
It is further preferred that the preparation method of Mannitol sodium chloride injection as described above, wherein with citric acid water
Solution is 4.0-5.0 as pH adjusting agent regulation pH value.
Compared with prior art, Mannitol sodium chloride injection of the present invention and preparation method thereof has following excellent
Point and marked improvement：(1) medicine stability is good, and 5-HMF does not increase substantially；(2) preparation method is simple, it is not necessary to complicated system
Agent equipment, is easy to industrialized production；(3) sterilizing uses terminal sterilization, Product Safety height.
Embodiment
The preparation process of invention formulation and implementation result now are further described by following examples, is familiar with this area
The personnel of technology obviously can easily make various modifications to these embodiments, and General Principle described herein is applied to
Without by performing creative labour in other embodiment.Therefore, the invention is not restricted to embodiment here, people in the art
Member does not depart from improvement that scope made and modification all should be in protection scope of the present invention according to the announcement of the present invention
Within.
Embodiment 1
Preparation method：
Recipe quantity weighs raw material and auxiliary material, glycerine, sodium chloride is added to 30% dissolving of water for injection total amount, to above-mentioned molten
After HS15 dissolving is added in liquid, fructose dissolving is added, 1mol/ is added into the solution prepared
L citric acid solutions regulation pH value is 4.0, adds to the full amount of water for injection, adds activated carbon, stir and evenly mix, measure glycerine, chlorination
Sodium, fructose sign content are in 95.0-105.0%, and by above-mentioned decoction coarse filtration, refined filtration is filling, and sealing, 121 DEG C of moist heat sterilizations 15 divide
Clock, lamp inspection, packaging.
Embodiment 2
Preparation method：
Recipe quantity weighs raw material and auxiliary material, glycerine, sodium chloride is added to 30% dissolving of water for injection total amount, to above-mentioned molten
After HS15 dissolving is added in liquid, fructose dissolving is added, 2mol/ is added into the solution prepared
L citric acid solutions regulation pH value is 6.0, adds to the full amount of water for injection, adds activated carbon, stir and evenly mix, measure glycerine, chlorination
Sodium, fructose sign content are in 95.0-105.0%, and by above-mentioned decoction coarse filtration, refined filtration is filling, and sealing, 121 DEG C of moist heat sterilizations 15 divide
Clock, lamp inspection, packaging.
Embodiment 3
Preparation method：
Recipe quantity weighs raw material and auxiliary material, glycerine, sodium chloride is added to 30% dissolving of water for injection total amount, to above-mentioned molten
After HS15 dissolving is added in liquid, fructose dissolving is added, 1mol/ is added into the solution prepared
L citric acid solutions regulation pH value is 5.0, adds to the full amount of water for injection, adds activated carbon, stir and evenly mix, measure glycerine, chlorination
Sodium, fructose sign content are in 95.0-105.0%, and by above-mentioned decoction coarse filtration, refined filtration is filling, and sealing, 121 DEG C of moist heat sterilizations 15 divide
Clock, lamp inspection, packaging.
Embodiment 4
Preparation method：
Recipe quantity weighs raw material and auxiliary material, glycerine, sodium chloride is added to 40% dissolving of water for injection total amount, to above-mentioned molten
After HS15 dissolving is added in liquid, fructose dissolving is added, 1mol/ is added into the solution prepared
L citric acid solutions regulation pH value is 5.0, adds to the full amount of water for injection, adds activated carbon, stir and evenly mix, measure glycerine, chlorination
Sodium, fructose sign content are in 95.0-105.0%, and by above-mentioned decoction coarse filtration, refined filtration is filling, and sealing, 121 DEG C of moist heat sterilizations 15 divide
Clock, lamp inspection, packaging.
Comparative example 1
Preparation method：
Recipe quantity weighs raw material and auxiliary material, and glycerine, sodium chloride are added to 30% dissolving of water for injection total amount, add fructose
Dissolving, it is 5.0 that 1mol/L aqueous hydrochloric acid solutions regulation pH value is added into above-mentioned solution, adds to the full amount of water for injection, adds activity
Charcoal, stir and evenly mix, measure glycerine, sodium chloride, fructose sign content by above-mentioned decoction coarse filtration, refined filtration, are filled in 95.0-105.0%
Dress, sealing, 121 DEG C of moist heat sterilizations 15 minutes, lamp inspection, packaging.
Comparative example 2
Preparation method：
Recipe quantity weighs raw material and auxiliary material, glycerine, sodium chloride is added to 30% dissolving of water for injection total amount, to above-mentioned molten
After HS15 dissolving is added in liquid, fructose dissolving is added, 1mol/L salt is added into above-mentioned solution
Aqueous acid regulation pH value is 5.0, adds to the full amount of water for injection, adds activated carbon, stir and evenly mix, measure glycerine, sodium chloride, fruit
Sugar sign content is in 95.0-105.0%, and by above-mentioned decoction coarse filtration, refined filtration is filling, sealing, 121 DEG C of moist heat sterilizations 15 minutes, lamp
Inspection, packaging.
Embodiment 5：The 5-HMF determination tests of Mannitol sodium chloride injection
Chromatographic condition and system fleet testing：Using octadecylsilane chemically bonded silica as filler；With methanol -0.1%
Citric acid soln (25: 75) is mobile phase；Detection wavelength is 284nm.Number of theoretical plate is calculated by 5 hydroxymethyl furfural peak should not be low
In 2500.
The preparation of reference substance solution：Take 5 hydroxymethyl furfural reference substance appropriate, it is accurately weighed, it is dissolved in water and every 1mL is made
Solution containing 10 μ g, as reference substance solution.
The preparation of need testing solution：Sample solution is taken as need testing solution.
Precision measures the μ L of reference substance solution 20 injection liquid chromatographs, conditioning instrumentation sensitivity, makes principal component chromatographic peak
Peak height is the 10%-20% of full scale, then precision measures need testing solution and each 20 μ L of reference substance solution, is injected separately into liquid phase color
Spectrometer, record chromatogram.Limit is 0.1%.Mannitol sodium chloride injection prepared by each embodiment and comparative example is through experiment
The result of detection is as shown in table 1.
The embodiment measurement result of table 1
| Sample source | 0 day result (%) | 40 DEG C of acceleration, 6 months results (%) |
| Embodiment 1 | 0.013 | 0.016 |
| Embodiment 2 | 0.011 | 0.014 |
| Embodiment 3 | 0.012 | 0.015 |
| Embodiment 4 | 0.012 | 0.015 |
| Comparative example 1 | 0.036 | 0.473 |
| Comparative example 2 | 0.014 | 0.118 |
The product stability prepared from the results showed that embodiment of the present invention 1-3 of table 1 is good, and 5-HMF is basic after acceleration
Do not increase；HS15 is not added in the prescription of comparative example 1, is also adjusted without using citric acid as pH
Agent is saved, finally 5-HMF increases are rapid after accelerated test；Comparative example 2 by the use of hydrochloric acid replace citric acid as pH adjusting agent, although plus
5-HMF contents are relatively low after speed experiment, but fast compared with embodiment 1-3 increases.
Claims (7)
1. a kind of Mannitol sodium chloride injection, it is characterised in that contain polyethylene glycol -12- hydroxy stearates in the parenteral solution
The weight ratio of acid esters, wherein fructose and HS15 is 1：0.05-0.6.
2. Mannitol sodium chloride injection according to claim 1, it is characterised in that fructose and poly- second in the parenteral solution
The weight ratio of glycol -12- hydroxy stearic acid esters is 1：0.1-0.3.
3. Mannitol sodium chloride injection according to claim 1 or 2, it is characterised in that the parenteral solution is by glycerine, fruit
Sugar, sodium chloride, HS15, pH adjusting agent and water for injection are formulated.
4. Mannitol sodium chloride injection according to claim 3, it is characterised in that described pH adjusting agent is lemon
Acid.
5. Mannitol sodium chloride injection according to claim 3, it is characterised in that described pH adjusting agent regulation should
The pH of parenteral solution is 4.0-6.0.
6. a kind of preparation method of Mannitol sodium chloride injection according to claim 1 or 2, it is characterised in that should
Method comprises the following steps：Glycerine, sodium chloride are added in water for injection and dissolved, then adds polyethylene glycol -12- hydroxy stearates
Acid esters dissolves, and is subsequently added into fructose dissolving, adjusts pH value as 4.0-6.0 using aqueous citric acid solution, adds to the full amount of water for injection, living
Property charcoal absorption, filtering, it is filling, sterilizing, lamp inspection, packaging.
7. the preparation method of Mannitol sodium chloride injection according to claim 6, it is characterised in that with citric acid water
Solution regulation pH value is 4.0-5.0.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101138550A (en) * | 2007-09-18 | 2008-03-12 | 沈阳药科大学 | Mixed glue bundle pharmaceutical preparations produced in combination use of multiple surfactant and processes for their preparation |
| CN102188437A (en) * | 2010-03-11 | 2011-09-21 | 江苏润邦药业有限公司 | Glycerol fructose injection and preparation method thereof |
| CN102488696A (en) * | 2011-12-30 | 2012-06-13 | 南京正大天晴制药有限公司 | Glycerin-fructose composition injection and its preparation method |
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- 2015-08-20 CN CN201510515596.3A patent/CN105147724B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101138550A (en) * | 2007-09-18 | 2008-03-12 | 沈阳药科大学 | Mixed glue bundle pharmaceutical preparations produced in combination use of multiple surfactant and processes for their preparation |
| CN102188437A (en) * | 2010-03-11 | 2011-09-21 | 江苏润邦药业有限公司 | Glycerol fructose injection and preparation method thereof |
| CN102488696A (en) * | 2011-12-30 | 2012-06-13 | 南京正大天晴制药有限公司 | Glycerin-fructose composition injection and its preparation method |
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