CN108911981B - Preparation method of omega-3-fatty acid triglyceride for injection - Google Patents
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Abstract
The invention discloses a preparation method of omega-3-fatty acid triglyceride for injection, which comprises the following steps: (1) under the condition of nitrogen or vacuum, uniformly mixing fatty acid ester and a catalyst, heating, adding a low-carbon alcohol solution containing glycerol, reacting for 2-7 hours, cooling to room temperature, filtering, and washing with water to obtain a crude triglyceride product; (2) centrifuging the material obtained in the step (1), transferring the material to a distillation device, inserting a nitrogen pipe below the liquid level of the material, filling nitrogen, opening vacuum, heating to the temperature required by distillation after the pressure is stable, maintaining the temperature and the pressure for distillation for 2-5 hours, and cooling the material to room temperature after the distillation is finished; (3) and (3) adsorbing the material obtained in the step (2) for 3-5 hours by using an adsorbent under the condition of nitrogen filling or vacuum, and filtering to obtain the omega-3-fatty acid triglyceride for injection. The method solves the problem of over-dark system color caused by alkali catalysis, reduces the treatment difficulty, has high yield, is simple and convenient to operate, has controllable reaction, and is easy to realize industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a preparation method of omega-3-fatty acid triglyceride for injection.
Background
Triglycerides (TG) are components of lipids, formed from glycerol and 3 fatty acids, and their main function is to supply and store energy. Omega-3 fatty acid triglycerides, mainly triglycerides composed of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which can promote the lowering of plasma triglycerides for the benefit of heart health, reduce blood lipids and enhance cell function, and have therapeutic effects on various diseases of the human body.
There are two main ways to obtain the corresponding fatty acids: 1. natural triglycerides, such as fish oil, algae oil, etc., have low content of specific (such as EPA or DHA) fatty acids, and thus, if a certain fatty acid is needed and taken in a large amount, other redundant fatty acids increase the metabolic pressure of the body; 2. hydrolyzing natural triglyceride, and enriching processed oil such as concentrated fish oil. Since the content of specific fatty acid in natural triglyceride is not high, the triglyceride needs to be processed to enrich the components, so that fatty acid type, fatty acid methyl ester type, fatty acid ethyl ester type and triglyceride type products with high content of specific fatty acid are derived. Because the fatty acid methyl ester type and the fatty acid ethyl ester type do not have naturally-occurring structures, methanol or ethanol is generated after the fatty acid methyl ester type and the fatty acid ethyl ester type are decomposed in vivo, and the bioavailability is not high. The fatty acid type has problems of bad odor, certain irritation to blood vessels and mucous membranes, and the like. The triglyceride with high content of specific fatty acid is a natural structure, can avoid the defects and is easy to be absorbed by human body, so the triglyceride type product with high content of specific fatty acid is a hot point of research in the field.
The prior art methods for preparing high content of specific fatty acid triglyceride mainly have two kinds: enzymatic catalysis: for example, patent CN 104846023 a "method for preparing concentrated fish oil fatty acid glyceride" discloses a method for synthesizing triglyceride type fish oil by using penicillium expansum lipase to catalyze fish oil ethyl ester and glycerol, which does not include impurity removal treatment process, and the residual fish oil ethyl ester, glycerol, enzyme and other introduced impurities cannot be controlled, so that it is difficult to ensure safety; patent CN 103436563B "method for preparing glyceride type fish oil rich in n-3 polyunsaturated fatty acids" discloses a method for synthesizing triglyceride type fish oil by using immobilized lipase to catalyze the reaction of short-chain acid glyceride and fish oil ethyl ester, the raw material used in the method is short-chain fatty acid ester, and lipase-catalyzed transesterification can not completely exchange target fatty acid, so that the glyceride type fish oil is mixed with a large amount of short-chain fatty acid triglyceride. Patent CN 10181876B "method for converting fatty acid ethyl ester into glyceride" discloses a method for synthesizing triglyceride type fish oil by catalyzing glycerol and fish oil ethyl ester with complete equipment such as an immobilized enzyme bed reactor, and the like, the method has long reaction time consumption and low efficiency, and does not remove components such as fish oil ethyl ester, glycerol, enzyme and other introduced impurities. In addition, the preparation and immobilization processes of the lipase are complex, high in cost, easy to inactivate and the like. Catalyzing by a chemical method: for example, patent CN 103242969B "preparation method of triglyceride type fish oil and prepared triglyceride type fish oil" discloses a method for synthesizing triglyceride by using alkali catalysis and obtaining triglyceride type fish oil by clay adsorption and decolorization, the method cannot completely convert ethyl ester type fish oil into triglyceride, and the use of activated clay also causes the oil to have earthy taste; the document 1005-9989(2016)08-0075-04 of the preparation process of high-content EPA/DHA triglyceride discloses a triglyceride type fish oil synthesized by using alkali catalysis, wherein the total content of glyceride of the method is about 70 percent, the impurities are more, and the catalyst except the residual catalyst is not treated. In addition, after the ester exchange reaction is completed by the method, the color of the system is dark brown to black, and even if a large amount of decolorant is used, the requirement of higher level (such as raw material medicine for injection) is difficult to achieve. The prior art disclosed is difficult to prepare omega-3-fatty acid triglycerides that meet the requirements for injection. Therefore, the development of the preparation technology of omega-3-fatty acid triglyceride meeting the requirement for injection and the product thereof have important significance for the development of novel fat emulsion injection in China.
Disclosure of Invention
Based on the above, the invention aims to overcome the defects of the prior art and provide a preparation method of omega-3-fatty acid triglyceride for injection, which utilizes alkali catalysis and a controllable ester exchange process to improve the content of triglyceride as a main component of a product, reduce the production of colored harmful substances in the process, remove impurity residues of ethyl ester, diglyceride, monoglyceride and the like, reduce oxidation indexes and obtain the omega-3-fatty acid triglyceride for injection with quality indexes meeting the requirements of European pharmacopoeia 8.0.
In order to achieve the purpose, the invention adopts the technical scheme that: a method for preparing omega-3-fatty acid triglycerides for injection, comprising the steps of:
(1) under the condition of nitrogen or vacuum, uniformly mixing fatty acid ester and a catalyst, heating, adding a low-carbon alcohol solution containing glycerol, reacting for 2-7 hours, cooling to room temperature, filtering, and washing with water to obtain a crude triglyceride product;
(2) centrifuging the material obtained in the step (1), transferring the material to a distillation device, inserting a nitrogen pipe below the liquid level of the material, filling nitrogen, opening vacuum, heating to the temperature required by distillation after the pressure is stable, maintaining the temperature and the pressure for distillation for 2-5 hours, and cooling the material to room temperature after the distillation is finished;
(3) and (3) adsorbing the material obtained in the step (2) for 3-5 hours by using an adsorbent under the condition of nitrogen filling or vacuum, and filtering to obtain the omega-3-fatty acid triglyceride for injection.
Preferably, the fatty acid ester in the step (1) is at least one selected from fatty acid methyl ester with 8-24 carbon atoms and fatty acid ethyl ester with 8-24 carbon atoms.
More preferably, the fatty acid ester is fish oil of ethyl ester type or fish oil of methyl ester type.
Preferably, the catalyst in step (1) is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide and sodium ethoxide.
Preferably, in the step (1), the lower alcohol is at least one selected from methanol, ethanol and 95% ethanol.
Preferably, the concentration of the glycerol in the low carbon alcohol solution containing the glycerol in the step (1) is 0.1 g/ml-0.5 g/ml.
Preferably, the adding speed of the low carbon alcohol solution containing glycerol in the step (1) is as follows: the total volume of the glycerol-containing low-carbon alcohol solution is x (0.34-1%)/min.
Preferably, the heating temperature in the step (1) is 124-150 ℃.
Preferably, the distillation pressure in the step (2) is 0.095MPa to-0.1 MPa; the distillation temperature is 165-205 ℃.
Preferably, the adsorbent in the step (3) is selected from at least one of alumina, silica gel, activated carbon and amino silica gel.
Preferably, the weight of the adsorbent in the step (3) is 0.5-10% of the weight of the fatty acid ester in the step (1).
Preferably, the adsorption mode in the step (3) is stirring adsorption under vacuum or nitrogen charging condition.
Preferably, the adsorption mode is stirring adsorption for 0.5-1.5 hours, standing for 0.5-2 hours, and then circulating filtration for 1.5-2 hours.
Compared with the prior art, the invention has the beneficial effects that: (1) the preparation method of the invention utilizes a controllable reaction process, solves the problem of over-dark system color caused by alkali catalysis, not only improves the yield of omega-3-fatty acid triglyceride, but also reduces the treatment difficulty of subsequent impurity removal and decoloration, and reduces the loss of materials; (2) the preparation method does not use enzyme and argil, avoids the introduction of residual enzyme and decomposition products thereof, bad smell of argil source and other element impurities, and ensures the safety of the product for injection; (3) the preparation method has simple equipment requirement, simple and convenient operation, controllable reaction and easy realization of industrial production.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
One embodiment of the method for preparing omega-3-fatty acid triglycerides for injection according to the invention comprises the following steps:
(1) taking 100g of fish oil ethyl ester, adding 0.5g of sodium methoxide, and placing in a reaction kettle; dissolving 5g of glycerol in 50ml of absolute ethyl alcohol, placing the solution in a constant-pressure dripping device, introducing nitrogen into a reaction kettle, starting stirring, heating the solution until the temperature reaches 124 ℃, dripping absolute ethyl alcohol solution containing glycerol at the speed of 0.17ml/min, reacting for 7 hours, cooling, filtering and washing with water to obtain a crude triglyceride product;
(2) transferring the material obtained in the step (1) to a distillation device after centrifugal treatment, inserting a nitrogen pipe below the liquid level of the material, filling nitrogen, gradually opening vacuum, gradually reducing the nitrogen flow, heating to 205 ℃ after the pressure is stabilized at 0.095Mpa, distilling for 5 hours, and cooling the material to room temperature after the distillation is finished;
(3) and (3) transferring the material obtained in the step (2) to an adsorption device, filling nitrogen, adding 0.5g of silica gel, stirring, adsorbing for 5 hours, filtering by a filter element, and performing precise filtration to obtain the omega-3-fatty acid triglyceride for injection.
Through detection, the content of triglyceride in the omega-3-fatty acid triglyceride for injection is 68.4%, the content of diglyceride and monoglyceride is 30.5%, the oligomer is less than 0.02%, the absorbance is 0.26, the acid value is 0.3, the peroxide value is 0.5, the anisidine value is 3.5, the residue of fish oil ethyl ester is 0.8%, and the overall yield is 79.1%.
Example 2
One embodiment of the method for preparing omega-3-fatty acid triglycerides for injection according to the invention comprises the following steps:
(1) taking 10kg of fish oil methyl ester, adding 0.2kg of sodium hydroxide, and placing in a reaction kettle; dissolving 5kg of glycerol in 10L of 95% ethanol, placing in a constant-pressure dripping device, introducing nitrogen into a reaction kettle, stirring, heating to 150 ℃, dripping 95% ethanol solution containing glycerol at a speed of 100ml/min, reacting for 2 hours, cooling, filtering, and washing with water to obtain crude triglyceride;
(2) transferring the material obtained in the step (1) to a distillation device after centrifugal treatment, inserting a nitrogen pipe below the liquid level of the material for filling nitrogen, gradually opening vacuum and gradually reducing the nitrogen flow, heating to 165 ℃ after the pressure is stabilized at-0.1 Mpa, distilling for 5 hours, and cooling the material to room temperature after the distillation is finished;
(3) and (3) transferring the material obtained in the step (2) to an adsorption device, charging nitrogen, adding 1kg of alumina, stirring, adsorbing for 2 hours, filtering by a filter element, and performing precise filtration to obtain the omega-3-fatty acid triglyceride for injection.
Through detection, the content of triglyceride in the omega-3-fatty acid triglyceride for injection is 65.8%, the content of diglyceride and monoglyceride is 33.1%, the oligomer is less than 0.02%, the absorbance is 0.28, the acid value is 0.04, the peroxide value is 1.5, the anisidine value is 6.8, the residue of fish oil ethyl ester is 0.9%, and the overall yield is 76.3%.
Example 3
(1) Taking 10kg of fish oil ethyl ester, adding 0.1kg of sodium ethoxide, and placing the fish oil ethyl ester into a reaction kettle; dissolving 1kg of glycerol in 10L of absolute ethyl alcohol, placing the mixture in a constant-pressure dripping device, vacuumizing a reaction kettle, starting stirring, heating the mixture until the temperature reaches 135 ℃, dripping absolute ethyl alcohol solution containing the glycerol at a speed of 50ml/min, reacting for 4.5 hours, cooling, filtering and washing to obtain a crude triglyceride product;
(2) transferring the material obtained in the step (1) to a distillation device after centrifugal treatment, inserting a nitrogen pipe below the liquid level of the material for filling nitrogen, gradually opening vacuum and simultaneously gradually reducing the nitrogen flow, heating to 180 ℃ after the pressure is stabilized at 0.098Mpa, distilling for 3 hours, and cooling the material to room temperature after the distillation is finished;
(3) and (3) transferring the material obtained in the step (2) to an adsorption device, charging nitrogen, adding 1kg of silica gel, stirring, adsorbing for 0.5 hour, standing for 0.5 hour, circularly filtering for 2 hours, and finally filtering by a filter element and precisely filtering to obtain the omega-3-fatty acid triglyceride for injection.
Through detection, the content of triglyceride in the omega-3-fatty acid triglyceride for injection is 70.8%, the content of diglyceride and monoglyceride is 28.8%, the oligomer is less than 0.02%, the absorbance is 0.21, the acid value is 0.2, the peroxide value is 0.3, the anisidine value is 2.8, the residue of fish oil ethyl ester is 0.2%, and the overall yield is 73.7%.
Example 4
(1) Taking 100kg of fish oil ethyl ester, adding 1kg of potassium hydroxide, and placing in a reaction kettle; dissolving 7kg of glycerol in 23L of 95% ethanol, placing the solution in a constant-pressure dripping device, vacuumizing a reaction kettle, starting stirring, heating the reaction kettle until the temperature reaches 130 ℃, dripping 95% ethanol solution containing the glycerol at the speed of 100ml/min, reacting for 4.5 hours, cooling, filtering and washing to obtain a crude triglyceride product;
(2) transferring the material obtained in the step (1) to a distillation device after centrifugal treatment, inserting a nitrogen pipe below the liquid level of the material for filling nitrogen, gradually opening vacuum and simultaneously gradually reducing the nitrogen flow, heating to 180 ℃ after the pressure is stabilized at 0.098Mpa, distilling for 3.5 hours, and cooling the material to room temperature after the pressure is stabilized;
(3) and (3) transferring the material obtained in the step (2) to an adsorption device, charging nitrogen, adding 5kg of activated carbon, stirring, adsorbing for 1.5 hours, standing for 2 hours, circularly filtering for 1.5 hours, and finally filtering by a filter element and precisely filtering to obtain the omega-3-fatty acid triglyceride for injection.
Through detection, the content of triglyceride in the omega-3-fatty acid triglyceride for injection is 66.4%, the content of diglyceride and monoglyceride is 32.8%, the oligomer is less than 0.02%, the absorbance is 0.44, the acid value is 0.8, the peroxide value is 0.6, the anisidine value is 4.7, the residue of fish oil ethyl ester is 0.6%, and the overall yield is 76.0%.
Example 5
(1) Taking 100kg of fish oil ethyl ester, adding 2kg of calcium hydroxide, and placing in a reaction kettle; dissolving 7kg of glycerol in 23L of 95% ethanol, placing the solution in a constant-pressure dripping device, vacuumizing a reaction kettle, starting stirring, heating the reaction kettle until the temperature reaches 140 ℃, dripping 95% ethanol solution containing the glycerol at the speed of 100ml/min, reacting for 4.5 hours, cooling, filtering and washing to obtain a crude triglyceride product;
(2) transferring the material obtained in the step (1) to a distillation device after centrifugal treatment, inserting a nitrogen pipe below the liquid level of the material for filling nitrogen, gradually opening vacuum and gradually reducing the nitrogen flow, heating to 200 ℃ after the pressure is stabilized at 0.097Mpa, distilling for 3.5 hours, and cooling the material to room temperature after the pressure is stabilized;
(3) and (3) transferring the material obtained in the step (2) to an adsorption device, filling nitrogen, adding 2kg of amino silica gel, 2kg of silica gel and 1kg of alumina, stirring and adsorbing for 1 hour, standing for 1.5 hours, circularly filtering for 1.8 hours, and finally filtering by a filter element and precisely filtering to obtain the omega-3-fatty acid triglyceride for injection.
Through detection, the content of triglyceride in the omega-3-fatty acid triglyceride for injection is 70.8%, the content of diglyceride and monoglyceride is 28.5%, the oligomer is less than 0.02%, the absorbance is 0.22, the acid value is 0.05, the peroxide value is 0.2, the anisidine value is 2.3, the residue of fish oil ethyl ester is 0.5%, and the overall yield is 72.8%.
Comparative example 1
To compare the effect of different addition modes on the quality of omega-3-fatty acid triglycerides for injection, the following experimental groups were set up:
experimental group 1: omega-3-fatty acid triglycerides for injection were prepared as described in example 1.
Control group 1: omega-3-fatty acid triglycerides for injection were prepared using the following method: dissolving 5g of glycerol in 50ml of absolute ethanol, adding 0.5g of sodium methoxide, and placing in a reaction kettle; taking 100g of fish oil ethyl ester, placing the fish oil ethyl ester in a constant-pressure dripping device, introducing nitrogen into a reaction kettle, starting stirring, heating until the temperature reaches 124 ℃, dripping a glycerol solution at the speed of 0.17ml/min, reacting for 7 hours, cooling, filtering, washing with water, transferring the material into a distillation device after centrifugal treatment, inserting a nitrogen pipe below the liquid level of the material, filling nitrogen, gradually opening vacuum, gradually reducing the nitrogen flow, heating to 205 ℃ after the pressure is stabilized at 0.095MPa, distilling for 5 hours, cooling the material after the distillation is finished, transferring the material into an adsorption device, filling nitrogen, adding 0.5g of silica gel, stirring, adsorbing for 5 hours, filtering by a filter element, and precisely filtering to obtain the omega-3-fatty acid triglyceride for injection.
Control group 2: omega-3-fatty acid triglycerides for injection were prepared as described in chinese patent CN 103242969B.
Control group 3: omega-3-fatty acid triglyceride for injection is prepared according to the method described in the literature "preparation process of high content EPA/DHA triglyceride 1005-9989(2016) 08-0075-04.
The quality of the prepared OMEGA-3-fatty acid triglyceride for injection is tested according to the requirements of European pharmacopoeia 8.0OMEGA-3-ACID TRIGLYCERIDES, and the results are shown in Table 1:
TABLE 1 quality test results of omega-3-fatty acid triglyceride for injection prepared from each group
The result shows that the omega-3-fatty acid triglyceride for injection prepared by the method (experimental group 1) meets the standard requirement of European pharmacopoeia 8.0, and has light color, and low fish oil ethyl ester residue, absorbance and oxidation index. The omega-3-fatty acid triglyceride for injection prepared by the method of the control groups 1-3 is brown yellow to brown black, a large amount of pigment residues exist, the residue of fish oil ethyl ester and the oxidation index are high, and the safety of the omega-3-fatty acid triglyceride for injection is difficult to ensure. Therefore, compared with the product in the prior art, the omega-3-fatty acid triglyceride for injection prepared by the method has obvious quality advantage.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (11)
1. A method for preparing omega-3-fatty acid triglycerides for injection, comprising the steps of:
(1) under the condition of nitrogen or vacuum, uniformly mixing fatty acid ester and a catalyst, heating, dropwise adding a low-carbon alcohol solution containing glycerol, reacting for 2-7 hours, cooling to room temperature, filtering, and washing with water to obtain a crude triglyceride product;
(2) centrifuging the material obtained in the step (1), transferring the material to a distillation device, inserting a nitrogen pipe below the liquid level of the material, filling nitrogen, opening vacuum, heating to the temperature required by distillation after the pressure is stable, maintaining the temperature and the pressure for distillation for 2-5 hours, and cooling the material to room temperature after the distillation is finished;
(3) adsorbing the material obtained in the step (2) by using an adsorbent for 3-5 hours under the condition of nitrogen filling or vacuum, and filtering to obtain the omega-3-fatty acid triglyceride for injection;
the catalyst in the step (1) is selected from at least one of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide and sodium ethoxide;
the adding speed of the low-carbon alcohol solution containing glycerol in the step (1) is as follows: the total volume of the glycerol-containing low-carbon alcohol solution is x (0.34-1%)/min.
2. The method for preparing omega-3-fatty acid triglyceride for injection according to claim 1, wherein the fatty acid ester in the step (1) is at least one selected from fatty acid methyl ester of 8 to 24 carbon atoms and fatty acid ethyl ester of 8 to 24 carbon atoms.
3. The method for preparing omega-3-fatty acid triglycerides for injection according to claim 2, wherein the fatty acid ester in the step (1) is ethyl ester type fish oil or methyl ester type fish oil.
4. The method for preparing omega-3-fatty acid triglycerides for injection according to claim 1, wherein the lower alcohol in step (1) is at least one selected from methanol, ethanol and 95% ethanol.
5. The method for preparing omega-3-fatty acid triglyceride for injection according to claim 1, wherein the concentration of glycerol in the low carbon alcohol solution containing glycerol in the step (1) is 0.1g/ml to 0.5 g/ml.
6. The method for preparing omega-3-fatty acid triglycerides for injection according to claim 1, wherein the heating temperature in step (1) is 124-150 ℃.
7. The method for preparing omega-3-fatty acid triglycerides for injection according to claim 1, wherein the distillation pressure in the step (2) is 0.095Mpa to-0.1 Mpa; the distillation temperature is 165-205 ℃.
8. The method of preparing omega-3-fatty acid triglycerides for injection according to claim 1, wherein the adsorbent in the step (3) is at least one selected from the group consisting of alumina, silica gel, activated carbon and amino silica gel.
9. The method for preparing omega-3-fatty acid triglyceride for injection according to claim 1, wherein the weight of the adsorbent in the step (3) is 0.5-10% of the weight of the fatty acid ester in the step (1).
10. The method for preparing omega-3-fatty acid triglyceride for injection according to claim 1, wherein the adsorption manner in the step (3) is stirring adsorption under vacuum or nitrogen charging condition.
11. The method for preparing omega-3-fatty acid triglyceride for injection according to claim 10, wherein the adsorption manner is stirring for adsorption for 0.5 to 1.5 hours, standing for 0.5 to 2 hours, and then circulating for filtration for 1.5 to 2 hours.
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| CN103242969A (en) * | 2013-05-24 | 2013-08-14 | 四川欣美加生物医药有限公司 | Preparation method of triglyceride type fish oil and prepared triglyceride type fish oil |
| CN103436563A (en) * | 2013-09-20 | 2013-12-11 | 中国海洋大学 | Method for preparing glyceride-type fish oil rich in n-3 polyunsaturated fatty acids |
| CN103897811A (en) * | 2014-04-02 | 2014-07-02 | 河北康睿达脂质有限公司 | Production method for medium-chain and long-chain oil fatty acid |
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