CN101874770A - Clindamycin phosphate injection and preparation method thereof - Google Patents
Clindamycin phosphate injection and preparation method thereof Download PDFInfo
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- CN101874770A CN101874770A CN200910074280XA CN200910074280A CN101874770A CN 101874770 A CN101874770 A CN 101874770A CN 200910074280X A CN200910074280X A CN 200910074280XA CN 200910074280 A CN200910074280 A CN 200910074280A CN 101874770 A CN101874770 A CN 101874770A
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Abstract
The invention discloses a clindamycin phosphate injection and a preparation method thereof. The clindamycin phosphate injection comprises an effective dose of clindamycin phosphate, wherein the solvent of the injection is solution of propylene glycol with mass-volume percentage concentration of 0.3 to 4 percent or solution of ethanol with mass-volume percentage concentration of 0.5 to 4 percent. The method comprises the following steps of: a, selecting the solution of propylene glycol with mass-volume percentage concentration of 0.3 to 4 percent or solution of ethanol with mass-volume percentage concentration of 0.375 to 5 percent as the solvent of the injection; b, dissolving the propylene glycol or absolute ethyl alcohol in the mass ratio in injection water in an amount which accounts for 80 percent of the total volume; adding sodium hydroxide into the solution according to the mass ratio of the sodium hydroxide to clindamycin phosphate of 1:67-69; stirring the mixture uniformly; adding the clindamycin phosphate into the mixture and stirring the mixture to dissolve the clindamycin phosphate; and then adding the remaining injection water. The injection can effectively suppress the hydrolysis of the clindamycin phosphate, so that the related substances produced by the clindamycin phosphate injection during the storage are effectively controlled.
Description
Technical field
The present invention relates to medicine and preparation method thereof, especially relate to clindamycin phosphate injection and preparation method thereof.
Background technology
Clindamycin phosphate is chemical semisynthetic clindamycin derivant, and it is in external no antibiotic activity, enters to be hydrolyzed to clindamycin rapidly behind the body under phosphoesterase action and to show its pharmacologically active.Thereby its antimicrobial spectrum, antibacterial activity and therapeutic effect are identical with clindamycin.But its fat-soluble and permeability is better than crin mycin, so more be subjected to clinically to favor.Clinical pharmaceutical dosage form commonly used is a clindamycin phosphate injection.The Main Ingredients and Appearance of clindamycin phosphate injection is a clindamycin phosphate.Its chemical name is: (2S-is trans)-6-(1-methyl-4-propyl group-2-pyrrolidine carbonic acid amido)-1-sulfo--methyl-7-chloro-6,7,8-three deoxidations-L-Su Shi-α-D-galactose pyranoside-2-dihydrogen phosphoric acid ester.Adjuvant is generally benzyl alcohol, water for injection.At present domestic adopt clindamycin phosphate and analgesic benzyl alcohol added in the water for injection stir, regulate pH with sodium hydroxide, method prepare clindamycin phosphate injection.
Because clindamycin phosphate is to thermo-responsive, in preparation process, during higher or long period, usually can cause the medicine degraded when sterilising temp.If but lower high temperature sterilize temperature or minimizing high temperature sterilize time in order to reduce degraded, then be difficult to guarantee sterilization effect.The clindamycin phosphate preparation of producing as Anhui Huayuan Biological Pharmaceutical Industry Co., Ltd. in 2006 has caused serious clinical adverse thus owing to reduced sterilising temp in preparation technology, shortened sterilization time.In order to guarantee the stability of product quality, many manufacturers feed intake by increasing and to control drug content when adopting high-temperature sterilizing process.But even so also uncontrollable related substance effect in the phase be on the increase and drug content descends (2008 the 5th the 2nd phases of volume of quality evaluation " medicine evaluation " of seeing 69 batches of homemade clindamycin phosphate injections of Li Wei for details) with the increase of holding time.
In order to address these problems, CN1969875 discloses a kind of preparation technology of clindamycin phosphate injection.This technology is under the condition of hundred grades of cleanliness class, earlier that a certain amount of clindamycin phosphate raw material is soluble in water, clindamycin phosphate and an amount of sodium hydroxide alternately add, keep between pH6.0～6.4, stir, be settled to liquor strength with water for injection, 0.05% activated carbon adsorption 10～20 minutes will be added in the medicinal liquid, filter cartridge coarse filtration with 0.45 μ m filter membrane or 0.45 μ m filter element, with the filter cartridge fine straining degerming of 0.22 μ m microporous filter membrane or 0.22 μ m filter element, filling and sealing promptly under hundred grades of conditions again.The purpose of this technical scheme is to overcome the defective that traditional clindamycin phosphate injection high-temperature sterilizing process is produced.But find that through investigating with the product of this method preparation, under 20 ± 2 ℃, 30 ± 2 ℃ conditions, place a year and a half, the product related substance surpasses 8%.This shows that though this method has been avoided high temperature sterilize, its product can not be stored at normal temperatures.
In order effectively to prevent the rising of related substance, research worker adds an amount of antioxidant (sodium sulfite), chelating agent (disodium edetate or calcium disodium edetate) in the preparation prescription of clindamycin phosphate injection.But find that through investigating sample is after 1 year, related substance approaches the quality standard edge.This shows that adding antioxidant, chelating agent still can't effectively be controlled the clindamycin phosphate injection quality of stability.
Purpose of the present invention will provide a kind of stay-in-grade clindamycin phosphate injection exactly, and a kind of method for preparing this injection is provided simultaneously.
The object of the present invention is achieved like this:
Clindamycin phosphate injection provided by the present invention contains the clindamycin phosphate of effective dose, and the solvent of its injection is that mass volume ratio concentration is that 0.3～4% propylene glycol solution or mass volume ratio concentration are 0.5～4% alcoholic solution.
The preparation method of clindamycin phosphate injection provided by the present invention, it may further comprise the steps:
A, to select mass volume ratio concentration for use be that 0.3～4% propylene glycol solution or mass volume ratio concentration are that 0.375～5% alcoholic solution is the solvent of injection;
B, the propylene glycol or the dehydrated alcohol of above-mentioned mass parts ratio is dissolved in the water for injection of 80% cumulative volume, according to sodium hydroxide: the mass ratio meter of clindamycin phosphate=1: 67～69, add sodium hydroxide, after stirring evenly, add clindamycin phosphate, after the stirring and dissolving, add the water for injection of surplus again, pH is controlled at 5.5-7.0, and the active carbon of adding 0.02% stirred 20～30 minutes;
C, take off charcoal, filter, fill is sealed.
The effective dose of clindamycin phosphate of the present invention is meant the consumption in the clinical common dosage forms specification, as 2ml:0.3g/ prop up, 4ml:0.6g/ props up (all in clindamycin).
Innovation part of the present invention is that selecting the propylene glycol solution of debita spissitudo or alcoholic solution is the solvent of this injection, effectively suppress the hydrolysis of clindamycin phosphate, thereby the related substance that clindamycin phosphate injection is produced in storage process is effectively controlled, and (10～30 ℃) are stored at normal temperatures.
The inventive method, at first propylene glycol solution or alcoholic solution are mixed with certain valid density, effectively prevent the hydrolysis of clindamycin phosphate in process for preparation, and before not adding clindamycin phosphate, add in the water for injection with quantitative sodium hydroxide earlier, can avoid when preparation, adding the excessive and partial over-alkali of clindamycin phosphate when dissolving of sodium hydroxide again, thereby control the increase of clindamycin phosphate hydrolytic degradation and related substance from the source.
The solvent preferred mass volume by volume concentration of injection is that 1～2% propylene glycol solution or mass volume ratio concentration are 1～2% alcoholic solution among the present invention.
This selects the propylene glycol solution of concentration or the increase that alcoholic solution can be controlled clindamycin phosphate hydrolytic degradation and related substance better for use.
Injection of the present invention can intramuscular injection also can intravenous drip, general 0.6～2.7g every day (clindamycin meter) that is grown up divides 2～3 times.Child 15～40mg/kg divides 2～4 times.Or follow the doctor's advice.
Injection of the present invention stable very good placed its related substance heterozygosis of December and do not changed substantially under 30 ± 2 ℃ of temperature conditions, the clindamycin phosphate injection that its effect obviously is better than prior art and is provided.
Beneficial effect of the present invention has obtained checking by actual monitoring under 30 ± 2 ℃ of conditions.(monitoring result sees table 1 for details).
The detection method of related substance is:
Related substance is got this product, adds mobile phase and makes the solution that contains 3mg among every 1Ml, and as need testing solution, precision is measured in right amount, adds mobile phase and is diluted to the solution that contains 0.03mg among every 1ml, solution in contrast.According to the method test under the assay item, get contrast solution 10 μ l and inject chromatograph of liquid, regulate instrumental sensitivity, make the peak height at main constituent peak be about 10%～25% of full scale, get each 10 μ l of need testing solution and contrast solution again and inject chromatograph of liquid, record chromatogram to main peak is visited 2 times that stay the time, and need testing solution is as showing impurity peaks, compare with contrast solution main peak area, single impurity peak area must not be greater than 4.0 times (4.0%) of contrast solution main peak area; The summation of each impurity peak area must not be greater than 6.0 times (6.0%) of contrast solution main peak area.Ignore less than the chromatographic peak of contrast solution main peak area 10.0%.
Table 1
The sample quality of embodiment 1,2 is stable as can be seen from above-mentioned tabulation, under 30 ± 2 ℃ of temperature conditions, investigate 1 year, related substance heterozygosis (summation of each impurity peak area) does not change substantially, illustrates that the present invention can effectively control product quality, and the control related substance increases.Related substance in Comparative Examples 1 and Comparative Examples 2, the Comparative Examples 3 increases than very fast, and the quality less stable is described, also needs further to improve stability.
Be described in further detail the present invention by the following examples, but the present invention do not carried out any restriction with this.
The specific embodiment
Embodiment 1
Clindamycin phosphate 360g
4% propylene glycol solution 2000ml
Sodium hydroxide 5.29g
Preparation: earlier the 80g propylene glycol is dissolved in the 1600ml water for injection, add sodium hydroxide 5.29g stirring and dissolving again, add the clindamycin phosphate stirring and dissolving, replenish injection to 2000ml, add active carbon and stirred 30 minutes, take off charcoal, pH is controlled at 6.2～6.4 scope, cross 0.22 μ m filter cartridge and filter, filling and sealing promptly gets clindamycin phosphate injection.
Embodiment 2
Clindamycin phosphate 360g
2% alcoholic solution 2000ml
Sodium hydroxide 5.3g
The 40g dehydrated alcohol is dissolved in the water for injection of 1600ml, add sodium hydroxide 5.3g stirring and dissolving again, add clindamycin phosphate, after the stirring and dissolving, add water for injection again to 2000ml (be mixed with concentration of alcohol be 2% alcoholic solution), add 0.02% active carbon and stirred 20～30 minutes; Take off charcoal, filter, fill is sealed.
Embodiment 3
Clindamycin phosphate 360g
1% propylene glycol solution 2000ml
Sodium hydroxide 5.28g
Preparation method reference example 1.
Embodiment 4
Clindamycin phosphate 360g
2% propylene glycol solution 2000ml
Sodium hydroxide 5.29g
Preparation method reference example 1.
Embodiment 5
Clindamycin phosphate 360g
0.3% propylene glycol solution 2000ml
Sodium hydroxide 5.26g
Preparation method reference example 1.
Embodiment 6
Clindamycin phosphate 360g
5% alcoholic solution 2000ml
Sodium hydroxide 5.26g
Preparation method reference example 2.
Embodiment 7
Clindamycin phosphate 360g
0.5% alcoholic solution 2000ml
Sodium hydroxide 5.28g
Preparation method reference example 2.
Embodiment 8
Clindamycin phosphate 360g
1% alcoholic solution 2000ml
Sodium hydroxide 5.28g
Preparation method reference example 2.
Embodiment 9
Clindamycin phosphate 360g
5% alcoholic solution 2000ml
Sodium hydroxide 5.27g
Preparation method reference example 2.
Embodiment 3～9 of the present invention all has 1, the 2 essentially identical beneficial effects with embodiment, and this is repeated no more.
Embodiment 1～9 prepared clindamycin phosphate injection does not all find to have the toxic action that is unfavorable for health through acute, subacute and long-term toxicological experiment.
Comparative Examples 1
According to application number is the described method preparation of embodiment 1 in 200610134458.1 description.
Comparative Examples 2
Clindamycin phosphate 360g
2% sodium sulfite (antioxidant)
Benzyl alcohol 4g
2000ml adds to the full amount of water for injection
Prepare according to conventional method.
Comparative Examples 3
Clindamycin phosphate 360g
Benzyl alcohol 4g
0.1％EDTA-2Na
2000ml adds to the full amount of water for injection
Prepare according to conventional method.
Claims (3)
1. clindamycin phosphate injection contains the clindamycin phosphate of effective dose, and the solvent that it is characterized in that its injection is that mass volume ratio concentration is that 0.3～4% propylene glycol solution or mass volume ratio concentration are 0.5～4% alcoholic solution.
2. clindamycin phosphate injection according to claim 1, the solvent that it is characterized in that said injection are that mass volume ratio concentration is that 1～2% propylene glycol solution or mass volume ratio concentration are 1～2% alcoholic solution.
3. the preparation method of the described clindamycin phosphate injection of claim 1 is characterized in that it may further comprise the steps:
A, to select mass volume ratio concentration for use be that 0.3～4% propylene glycol solution or mass volume ratio concentration are that 0.375～5% alcoholic solution is the injection solvent;
B, the propylene glycol or the dehydrated alcohol of above-mentioned mass parts ratio is dissolved in the water for injection of 80% cumulative volume, according to sodium hydroxide: the mass ratio meter of clindamycin phosphate=1: 67～69, add sodium hydroxide, after stirring evenly, add clindamycin phosphate again, after the stirring and dissolving, add the water for injection of surplus again, pH is controlled at 5.5～7.0, and the active carbon of adding 0.02% stirred 20～30 minutes;
C, take off charcoal, filter, fill is sealed.
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| Application Number | Priority Date | Filing Date | Title |
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| CN200910074280XA CN101874770A (en) | 2009-04-30 | 2009-04-30 | Clindamycin phosphate injection and preparation method thereof |
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| CN200910074280XA CN101874770A (en) | 2009-04-30 | 2009-04-30 | Clindamycin phosphate injection and preparation method thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102133178A (en) * | 2011-03-09 | 2011-07-27 | 成都普什制药有限公司 | Clindamycin phosphate injection and preparation method thereof |
| CN102144966A (en) * | 2011-04-08 | 2011-08-10 | 沈阳格林制药有限公司 | Preparation method of clindamycin phosphate injection |
| CN102525956A (en) * | 2011-12-15 | 2012-07-04 | 苏州二叶制药有限公司 | Preparation process of clindamycin phosphate injection |
| CN102552180A (en) * | 2012-01-17 | 2012-07-11 | 山东罗欣药业股份有限公司 | Clindamycin phosphate composition liensinine freeze-dried powder and preparation method thereof |
| CN103072932A (en) * | 2013-01-15 | 2013-05-01 | 江苏大红鹰恒顺药业有限公司 | Aseptic packaging method of clindamycin phosphate injection |
| CN103142507A (en) * | 2011-12-07 | 2013-06-12 | 重庆药友制药有限责任公司 | Clindamycin phosphate preparation for injection and preparation method thereof |
| CN113694018A (en) * | 2021-09-08 | 2021-11-26 | 海南制药厂有限公司制药二厂 | Chloramphenicol injection and preparation method thereof |
-
2009
- 2009-04-30 CN CN200910074280XA patent/CN101874770A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102133178A (en) * | 2011-03-09 | 2011-07-27 | 成都普什制药有限公司 | Clindamycin phosphate injection and preparation method thereof |
| CN102133178B (en) * | 2011-03-09 | 2013-03-27 | 成都普什制药有限公司 | Clindamycin phosphate injection and preparation method thereof |
| CN102144966A (en) * | 2011-04-08 | 2011-08-10 | 沈阳格林制药有限公司 | Preparation method of clindamycin phosphate injection |
| CN102144966B (en) * | 2011-04-08 | 2013-03-20 | 沈阳格林制药有限公司 | Preparation method of clindamycin phosphate injection |
| CN103142507A (en) * | 2011-12-07 | 2013-06-12 | 重庆药友制药有限责任公司 | Clindamycin phosphate preparation for injection and preparation method thereof |
| CN102525956A (en) * | 2011-12-15 | 2012-07-04 | 苏州二叶制药有限公司 | Preparation process of clindamycin phosphate injection |
| CN102552180A (en) * | 2012-01-17 | 2012-07-11 | 山东罗欣药业股份有限公司 | Clindamycin phosphate composition liensinine freeze-dried powder and preparation method thereof |
| CN102552180B (en) * | 2012-01-17 | 2013-08-14 | 山东罗欣药业股份有限公司 | Clindamycin phosphate composition liensinine freeze-dried powder and preparation method thereof |
| CN103072932A (en) * | 2013-01-15 | 2013-05-01 | 江苏大红鹰恒顺药业有限公司 | Aseptic packaging method of clindamycin phosphate injection |
| CN113694018A (en) * | 2021-09-08 | 2021-11-26 | 海南制药厂有限公司制药二厂 | Chloramphenicol injection and preparation method thereof |
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Open date: 20101103 |