CN105616350A - Preparation method of propofol medium/long-chain fat emulsion injection - Google Patents
Preparation method of propofol medium/long-chain fat emulsion injection Download PDFInfo
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- CN105616350A CN105616350A CN201410588936.0A CN201410588936A CN105616350A CN 105616350 A CN105616350 A CN 105616350A CN 201410588936 A CN201410588936 A CN 201410588936A CN 105616350 A CN105616350 A CN 105616350A
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Abstract
The invention relates to the field of technics and preparation of medicine carrying emulsion, in particular to a preparation method of a propofol medium/long-chain fat emulsion injection. According to the method, 8ppm of 97-percent sodium calcium edentate is added into the prepared water phase; nitrogen gas is inflated for protection in the whole preparation process of a water phase and an oil phase, and the preparation temperature is 55 DEG C; a 121 DEG C and 15min moist heat sterilization method is used for sterilization; and an excessive killing method is used. The preparation method of the propofol medium/long-chain fat emulsion injection has the advantages that the content of main medicine of propofol is protected; the contents of impurities of 2,6-diisopropyl-1,4-benzoquinone and 3,3',5,5'-tetraisopropyl xenol are reduced; the anisidine value content is reduced; and the stability of the medicine carrying emulsion is improved.
Description
Technical field
The present invention relates to drug loaded emulsion technique preparation field, particularly in a kind of propofol/preparation method of long chain fat emulsion injection.
Background technology
In propofol/long chain fat emulsion injection is applicable to the maintenance of induction of anesthesia and general intravenous anesthesia, it is also possible in strengthening calmness when monitoring patient accepts mechanical ventilation, and painless artificial abortion etc. The untoward reaction such as the pain when emulsus injection of this propofol significantly reduces the injection of patient.
In propofol/the emulsus injection that is made up of with fixed proportion propofol, injection soybean oil, injection median chain triglyceride oil, injection lecithin, glycerol for injection, injection oleic acid, water for injection of long chain fat emulsion injection, principal agent propofol is carried among the little oil droplet of Emulsion.
Preparation technology is Emulsion infusion solutions production technology. Weighing �� preparation �� filtration �� fill �� sterilizing �� lamp inspection �� packaging.
The many employings of process for producing of in the market in propofol/long chain fat emulsion injection are the preparation technologies of Propofol fat emulsion injection, and the latter does not contain injection median chain triglyceride oil, and the method preparation temperature is higher, control oxygen is looser, only at fill stage control dissolved oxygen, the method causes that principal agent propofol content is relatively low, impurity 2,6-diisopropyl-1,4-benzoquinone and 3,3', 5,5'-tetra isopropyl xenol is higher, and anisidine value is higher.
The reason that on market, examination and test of products index is undesirable have following some:
The preparation temperature of Emulsion is higher, it is typically in more than 60 degrees Celsius, the too low breast that is difficult to into of temperature, but propofol is had decomposition by higher preparation temperature, the method causes that principal agent propofol content is relatively low, impurity 2,6-diisopropyls-Isosorbide-5-Nitrae-benzoquinone and 3,3', 5,5'-tetra isopropyl xenols are higher, and anisidine value is higher.
The control of oxygen is more wide in range, only before fill, dissolved oxygen is controlled. This causes that propofol emulsion is just destroyed in preparation process and decomposes, and the method causes that principal agent propofol content is relatively low, impurity 2,6-diisopropyls-Isosorbide-5-Nitrae-benzoquinone and 3,3', 5, and 5'-tetra isopropyl xenol is higher, and anisidine value is higher.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, it is provided that in a kind of propofol/preparation method of long chain fat emulsion injection, protect the content of principal agent propofol, reduce impurity 2; 6-diisopropyl-Isosorbide-5-Nitrae-benzoquinone and 3,3'; 5,5'-tetra isopropyl biphenol content, reduce anisidine value content.
The technical scheme is that
In a kind of propofol/and the preparation method of long chain fat emulsion injection, the preparation process including following:
Step 1: prepared by oil phase: take three hole flasks, evacuation, inflated with nitrogen, replace 3 times; Continuous surface leads to nitrogen, puts into soybean oil and the median chain triglyceride oil MCT of recipe quantity, adds the propofol of recipe quantity, put water-bath, is warming up to 55 DEG C of lecithin putting into recipe quantity, adds oleic acid, shear uniform 10min; Oil phase is prepared complete, is filled with using nitrogen gas to seal off and places;
Step 2: prepared by aqueous phase: take three hole flasks, maintaining nitrogen purge, add the water for injection of 80% recipe quantity, 55 DEG C, the glycerol adding recipe quantity stirs, and adds 97% calcium disodium edetate 8ppm, control dissolved oxygen below 5%, add the sodium hydroxide solution 8��12 of 1mol/L;
Step 3: under nitrogen protection, pours into oil phase in glycerol aqueous phase, and with the water for injection of 20% recipe quantity, inflated with nitrogen removing dissolved oxygen, rinses oil phase bottle, and cleanout fluid proceeds to aqueous phase in the lump; High-speed stirred 15min, prepares colostrum; More than colostrum liquid level continue inflated with nitrogen protection;
Step 4: homogenizing, prepares into breast; Become breast temperature not higher than 50 DEG C, be continually fed into nitrogen;
Step 5:pH value regulates, and regulates pH to 9.5��10.0 with the sodium hydroxide solution of 1mol/L; After Emulsion cooling, nitrogen charging gas control oxygen is to less than 5%:; Sterilizing 121 DEG C, 15min nitrogen charging sterilizing;
Step 6: packaging, evacuation, sealing; Store less than 25 DEG C preservations, must not be freezing.
Preferably, the condition of homogenizing described in step 4 is low pressure 1 time 160/80, high pressure 4 times 700/80, low pressure 1 time 160/80.
Preferably, packaging described in step 6 adopts high-barrier outsourcing to add antioxidant form.
In propofol of the present invention/long chain fat emulsion injection prescription is as follows:
The prescription of 2% concentration
In production process, whether oil phase, the preparation temperature of aqueous phase, the high pressure even number of times of breast, the pH value of product, nitrogen charging etc. are all the technological parameters that comparison is crucial, the stability of several technological parameter joint effect finished product fat milks. Wherein, the stability of fat milk is affected relatively big by oxygen, and propofol is oxidizable, so that the technique adopting nitrogen charging. In addition the present invention is it is also contemplated that the conventional sterilant technique impact on emulsion stability. Consider that this product is fat emulsion injection, it is impossible to the technique that the activated carbon adsorption adopting solution-type injection conventional processes, need to by supplementary material being carried out respectively pyrogen control to realize the control to finished product.
The invention has the beneficial effects as follows:
Step 1: add the Ethylenediamine-tetraaceticacid, dicalciumsalt, 97% of 8ppm, pure (97% calcium disodium edetate), it is prevented that the metal ion Oxidation to principal agent and Emulsion in the aqueous phase of preparation; See attached list BBF1403001 and BBF1403002 lot inspection Comparative result in 1.
Step 2: overall process prepared by aqueous phase and oil phase is filled with nitrogen protection, it is prevented that the oxygen Oxidation to principal agent propofol and Emulsion. See attached list BBF1404001 and BBF1404002 lot inspection Comparative result in 1.
Step 3: preparation temperature fixes on 55 DEG C, has both ensured that Emulsion becomes breast, and guaranteed propofol is not by pyrolytic. See attached list BBF1405001, BBF1405002 and BBF1405003 lot inspection Comparative result in 1.
Step 4: sterilizing adopts the moist hear heat test of 121 DEG C of 15min, overkill method. Ensure that aseptic and thermal source reliability. See attached list BBF1405004 and BBF1405005 lot inspection Comparative result in 1.
Step 5:. packaging have employed high-barrier outsourcing form, it is ensured that the later stage deposits the stability of process herb liquid. See attached list BBF1403003 and BBF1403004 lot inspection Comparative result in 1.
In propofol of the present invention/preparation method of long chain fat emulsion injection, protect the content of principal agent propofol, reduce impurity 2,6-diisopropyl-1; 4-benzoquinone and 3,3', 5; 5'-tetra isopropyl biphenol content, reduces anisidine value content, improves the stability of drug loaded emulsion.
Detailed description of the invention
The specific embodiment of the present invention is as follows:
In propofol/long chain fat emulsion injection prescription:
The prescription of 2% concentration
Prepared by 1.1 oil phases: take 500ml tri-hole flask, evacuation, inflated with nitrogen, replace 3 times. Continuous surface leads to nitrogen, puts into soybean oil and the median chain triglyceride oil MCT of recipe quantity, adds the propofol of recipe quantity, put water-bath, is warming up to 55 DEG C of lecithin putting into recipe quantity, oleic acid 400mg, shears uniformly (10min). Oil phase is prepared complete, is filled with using nitrogen gas to seal off and places;
Prepared by 1.2 aqueous phases: take 1000mL tri-hole flask, maintaining nitrogen purge, add the water for injection of 80% recipe quantity, 55 DEG C, the glycerol adding recipe quantity stirs, and adds 97% calcium disodium edetate 8ppm, control dissolved oxygen below 5%, add the sodium hydroxide solution 8��12 of 1mol/L;
1.3 under nitrogen protection, is poured into by oil phase in glycerol aqueous phase, and with the water for injection of 20% recipe quantity, inflated with nitrogen removing dissolved oxygen, rinses oil phase bottle, and cleanout fluid proceeds to aqueous phase in the lump. High-speed stirred 15min, prepares colostrum. More than colostrum liquid level continue inflated with nitrogen protection;
1.4 homogenizing, low pressure is (160/80) once, high pressure 4 times (700/80), and low pressure is (160/80) once, prepares into breast. Become breast temperature not higher than 50 DEG C, and note nitrogen protection.
1.5pH value regulates, and regulates pH to 9.5��10.0. with the sodium hydroxide solution of 1mol/L
After 1.6 Emulsion coolings, nitrogen charging gas control oxygen is to less than 5%, and fill is in 50ml plastics LP soft bag.
1.7 sterilizings 121 DEG C, 15min nitrogen charging sterilizing.
1.8 packagings add antioxidant and the outer bag M312 outsourcing of label high-barrier, evacuation, sealing.
Wherein, high-barrier outer bag M312 outsourcing purchase producer is: Xi Yueer (China) company limited
1.9 store less than 25 DEG C preservations, must not be freezing.
Assay, in subordinate list 1, BBF1406001 criticizes assay, and through assay evaluation, every testing data meets the requirement of touchstone.
Experimental example:
1, first group of contrast test: the BBF1403002 batch of Ethylenediamine-tetraaceticacid adding 8ppm in the aqueous phase of preparation, dicalciumsalt, 97%, pure (97% calcium disodium edetate), preventing the metal ion Oxidation to principal agent and Emulsion, BBF1403001 batch is not added with EDTA (other process conditions are identical with BBF1403002 batch); By BBF1403001 and BBF1403002 lot inspection Comparative result in subordinate list 1 it can be concluded that add after EDTA, anisidine value and impurity 2,6-diisopropyls-Isosorbide-5-Nitrae-benzoquinone and 3,3', 5,5'-tetra isopropyl biphenol content substantially reduces.
2. second group of contrast test: overall process prepared by BBF1404002 batch of aqueous phase and oil phase is filled with nitrogen protection, the imitated oxygen Oxidation to principal agent propofol and Emulsion, BBF1404001 batch does not carry out nitrogen protection (other process conditions are identical with BBF1404002 batch); By BBF1404001 and BBF1404002 lot inspection Comparative result in subordinate list 1 it can be concluded that the overall process of preparation be filled with nitrogen protection batch, anisidine value and impurity 2,6-diisopropyl-1; 4-benzoquinone and 3; 3', 5,5'-tetra isopropyl biphenol content substantially reduce.
3. the 3rd group of contrast test: BBF1405001 50 DEG C carry out, BBF1405002 55 DEG C carry out, BBF1405003 batch of preparation temperature fixes on 60 DEG C and carries out, breast is not become it can be concluded that BBF1405001 temperature is too low by BBF1405001 and BBF1405002, BBF1405003 lot inspection Comparative result in subordinate list 1, BBF1405002 had both ensured that Emulsion became breast, guaranteed propofol is not by pyrolytic, and BBF1405003 temperature is too high causes that anisidine value exceeds standard.
4. the 4th group of contrast test: BBF1405005 sterilizing adopts the moist hear heat test of 121 DEG C of 15min, overkill method. Ensure that aseptic and thermal source reliability, content is qualified; BBF1405004 adopts the moist hear heat test of 117 DEG C of 30min, and assay content is defective, main propofol decomposed.
5.BBF1403004 packaging have employed high-barrier outsourcing form, it is ensured that the later stage deposits the stability of process herb liquid, and content is qualified. Seeing attached list BBF1403003 in 1 and adopt common outsourcing, content is defective.
Subordinate list 1:
Claims (3)
1. a preparation method in propofol/long chain fat emulsion injection, the preparation process including following:
Step 1: prepared by oil phase: take three hole flasks, evacuation, inflated with nitrogen, replace 3 times; Continuous surface leads to nitrogen, puts into soybean oil and the median chain triglyceride oil MCT of recipe quantity, adds the propofol of recipe quantity, put water-bath, is warming up to 55 DEG C of lecithin putting into recipe quantity, adds oleic acid, shear uniform 10min; Oil phase is prepared complete, is filled with using nitrogen gas to seal off and places;
Step 2: prepared by aqueous phase: take three hole flasks, maintaining nitrogen purge, add the water for injection of 80% recipe quantity, 55 DEG C, the glycerol adding recipe quantity stirs, and adds 97% calcium disodium edetate 8ppm, control dissolved oxygen below 5%, add the sodium hydroxide solution 8 ~ 12 of 1mol/L;
Step 3: under nitrogen protection, pours into oil phase in glycerol aqueous phase, and with the water for injection of 20% recipe quantity, inflated with nitrogen removing dissolved oxygen, rinses oil phase bottle, and cleanout fluid proceeds to aqueous phase in the lump; High-speed stirred 15min, prepares colostrum; More than colostrum liquid level continue inflated with nitrogen protection;
Step 4: homogenizing, prepares into breast; Become breast temperature not higher than 50 DEG C, be continually fed into nitrogen;
Step 5:pH value regulates, and regulates pH to 9.5 ~ 10.0 with the sodium hydroxide solution of 1mol/L; After Emulsion cooling, nitrogen charging gas control oxygen is to less than 5%:; Sterilizing 121 DEG C, 15min nitrogen charging sterilizing;
Step 6: packaging, evacuation, sealing; Store less than 25 DEG C preservations, must not be freezing.
2. the preparation method of in propofol according to claim 1/long chain fat emulsion injection, it is characterised in that the condition of homogenizing described in step 4 is low pressure 1 time 160/80, high pressure 4 times 700/80, low pressure 1 time 160/80.
3. the preparation method of in propofol according to claim 1/long chain fat emulsion injection, it is characterised in that packaging described in step 6 adopts high-barrier outsourcing to add antioxidant form.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110638755A (en) * | 2019-10-29 | 2020-01-03 | 江苏盈科生物制药有限公司 | Propofol medium-long chain fat emulsion and preparation method thereof |
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| CN110638755A (en) * | 2019-10-29 | 2020-01-03 | 江苏盈科生物制药有限公司 | Propofol medium-long chain fat emulsion and preparation method thereof |
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