CN113384523A - Production and preparation method of compound amino acid (15) dipeptide (2) injection - Google Patents
Production and preparation method of compound amino acid (15) dipeptide (2) injection Download PDFInfo
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- CN113384523A CN113384523A CN202110729770.XA CN202110729770A CN113384523A CN 113384523 A CN113384523 A CN 113384523A CN 202110729770 A CN202110729770 A CN 202110729770A CN 113384523 A CN113384523 A CN 113384523A
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Abstract
The invention discloses a production and preparation method of compound amino acid (15) dipeptide (2) injection, which comprises the following steps: adding water for injection to 70-80% of the total amount, continuously charging nitrogen, and heating to above 80 ℃; feeding citric acid, leucine, valine, threonine, tryptophan, arginine, alanine, isoleucine, phenylalanine, methionine, lysine acetate, histidine, proline, serine and aspartic acid in a closed feeding tank, and stirring for dissolving; cooling to below 60 deg.C, adding glutamic acid, glycyl glutamyl, and glycyl tyrosine; stirring to dissolve, adding water for injection to full dose, and adding citric acid to adjust pH to 5.5-6.0. Filling the liquid medicine into a three-layer co-extrusion transfusion film bag, and sealing; carrying out hot-pressing sterilization and packaging on the filled sample; the preparation process controls the dissolved oxygen and residual oxygen of the liquid medicine. The invention is beneficial to ensuring the quality stability of the product in the period of validity and the safety of clinical medication.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a method for producing and preparing compound amino acid (15) dipeptide (2) injection, belonging to the technical field of parenteral nutrition preparations.
Background
The compound amino acid (15) dipeptide (2) injection is a parenteral nutrition drug, is suitable for patients who can not take orally or supply nutrition through intestinal tracts, can not meet the requirement of nutrition supply through the routes, and is particularly suitable for patients with moderate to severe catabolic conditions.
This product was developed by the company felon yusbane, trade name: glamin (Validago), approved 5 months in 1995, was marketed in Germany, Switzerland, Sweden, Finland, Denmark, Austria. The import registration is first approved in China in 4 months in 2004.
However, the original product may have the problems of excessive aluminum salt, excessive oxidation degradation of impurities of amino acid products, decreased light transmittance of the product during placement, and the like.
Disclosure of Invention
Based on the technical background: the invention provides a production preparation method of compound amino acid (15) dipeptide (2) injection, which can effectively solve the problems of oxidative degradation and overproof aluminum salt of a product, so that the product meets the requirements of FDA (food and drug administration) on parenteral nutrition preparations, and the content of the aluminum salt can be controlled below 25 mu g/L; the preparation process adopts a direct dilution preparation method and an activated carbon-free process, so that the product safety is improved, the treatment of medical wastes (activated carbon) is reduced, and the environmental protection is facilitated; 0.25g/L citric acid is added before feeding of each amino acid, which is beneficial to dissolving the amino acid and saves the production and preparation time.
The invention is realized by the following technical scheme:
a method for preparing compound amino acid (15) dipeptide (2) injection comprises the following steps:
step A: starting a preparation tank for stirring, adding water for injection into the preparation tank to 70-80% of the total amount, continuously filling nitrogen, and heating to more than 80 ℃;
and B: feeding citric acid, leucine, valine, threonine, tryptophan, arginine, alanine, isoleucine, phenylalanine, methionine, lysine acetate, histidine, proline, serine and aspartic acid in a closed feeding tank, and stirring for dissolving;
and C: cooling to below 60 deg.C, adding glutamic acid, glycyl glutamyl, and glycyl tyrosine; stirring to dissolve, adding water for injection to full dose, and adding citric acid to adjust pH to 5.5-6.0.
Step D: filling the liquid medicine into a three-layer co-extrusion transfusion film bag, and sealing;
step E: and (5) carrying out hot-pressing sterilization on the filled sample.
Step F: filling the sterilized sample and the oxygen absorbent into a barrier bag for vacuum packaging;
the preparation process controls the dissolved oxygen content of the liquid medicine to be less than or equal to 3mg/L and the residual oxygen content to be less than or equal to 1 percent.
Further preferably, in the step B, the citric acid is added in an amount which meets the requirement that the concentration of the citric acid in the current water for injection is 0.25 g/L.
More preferably, in step B and step C, the composition of the amount of each raw material charged, calculated as a total amount of 500ml of water for injection, is as follows: 3.95g leucine, 3.65g valine, 2.80g threonine, 0.95g tryptophan, 5.65g arginine, 8.00g alanine, 2.80g glutamic acid, 2.80g isoleucine, 2.93g phenylalanine, 2.8g methionine, 6.35g lysine acetate, 3.40g histidine, 3.40g proline, 2.25g serine, 1.70g aspartic acid, 1.73g glycyl tyrosine, 15.14g glycyl glutamine.
Further preferably, in step E, the filled sample is sterilized by autoclaving at 121 ℃ for 8 min.
Preferably, in the step B and the step C, the light transmittance of each raw material solution is controlled to be not lower than 98.5%, and the internal control standard strictly in Chinese pharmacopoeia is established to control the limit of bacterial endotoxin and microorganism.
Further preferably, the control of bacterial endotoxin in the three-layer co-extrusion transfusion film bag-making inner bag is less than 0.25 EU.
Further preferably, in the step B, the feeding method by using the closed feeding tank is as follows:
installing a closed feeding tank on a feeding port of the preparation tank, and connecting nitrogen, water for injection and a pressure gauge on the closed feeding tank;
before feeding, checking and confirming whether a butterfly valve below a closed feeding tank is closed completely;
opening a pressure relief valve on the closed feeding tank to relieve pressure, opening a tank cover to feed materials, closing the closed feeding tank cover after a closed feeding tank is filled, vacuumizing the preparation tank, opening nitrogen of the closed feeding tank, opening a butterfly valve of the closed feeding tank, and conveying the raw materials into the thin preparation tank; and closing a butterfly valve of the closed feeding tank after the raw materials are fed, and completing feeding.
The invention has the following advantages and beneficial effects:
1. the preparation process of the invention adopts a direct dilution preparation method and an activated carbon-free process. The conventional amino acid preparation method comprises concentrated preparation and diluted preparation, and the one-step diluted preparation method can reduce the operation link, save the preparation time and reduce the microbial pollution risk. In addition, the active carbon has good pyrogen adsorption and decoloration effects. The active carbon is widely used in the production process of high-capacity injection, but new impurities are introduced into the product due to the use of the active carbon, so that the safety risk and the pressure of environment-friendly treatment are brought, and in addition, the active carbon has stronger adsorption capacity on tryptophan and influences on the content of the tryptophan. Therefore, the safety of the product can be further ensured by adopting the process without the activated carbon, and in addition, the treatment of medical waste (activated carbon) is reduced, thereby being beneficial to environmental protection.
After the activated carbon is removed, the indexes which have the greatest influence on the product quality are light transmittance and bacterial endotoxin. In order to ensure that the product produced by the production and preparation method is safer and more reliable. The light transmittance, bacterial endotoxin and microorganism of the raw and auxiliary materials for producing the product are all strictly controlled and brought into the internal control standard for control; and controlling bacterial endotoxin (less than 0.25EU) in the inner bag made of the three-layer co-extrusion transfusion film for the outer barrier bag of the packaging material so as to reduce microbial load of products and reduce pyrogen risk. The raw and auxiliary materials and the inner packing material which accord with the internal control standard are adopted to produce three batches of samples according to the production and preparation method, the indexes of properties, light transmittance, bacterial endotoxin, related substances and the like which have large influence on the activated carbon are detected, and the indexes are compared with the samples produced by the carbon production process, and the result shows that the properties, the light transmittance and the bacterial endotoxin of the samples produced and prepared by the method accord with the regulations, are basically consistent with the carbon process, but the tryptophan content is obviously lower than that of the process of the invention when the carbon process is used. The product quality can be ensured by canceling the active carbon on the basis of increasing the internal control standard of the original auxiliary packaging material. Meanwhile, the adsorption influence of the activated carbon on the tryptophan can be avoided.
2. In the invention, citric acid is used as a pH regulator, and as part of amino acid has poor solubility, 0.25g/L of citric acid is added before feeding of each amino acid, which is beneficial to dissolving the amino acid and saves the production and preparation time.
3. The closed feeding tank is adopted for feeding, so that air is prevented from being introduced into the preparation tank in the feeding process, and the possibility of oxidation of the liquid medicine is reduced; controlling the dissolved oxygen of the liquid medicine to be less than 3mg/L and the residual oxygen to be less than 1 percent in the whole process of preparation and filling; the three-layer co-extrusion transfusion film bag is used for packaging the infusion bag by adopting the outer barrier bag (the three-layer co-extrusion transfusion film bag can effectively prevent residual oxygen in an inner packaging container from introducing liquid medicine, is superior to glass bottle packaging, is extremely sensitive to oxygen, is easy to generate degradation impurities, and causes the aluminum salt to exceed the standard.
Drawings
The accompanying drawings, which are included to provide a further understanding of the embodiments of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the principles of the invention. In the drawings:
FIG. 1 is a schematic structural view of a three-layer co-extrusion transfusion film bag-making package; reference numbers and corresponding part names in fig. 1: 1-bag body, 2-input pipe orifice, 3-output pipe orifice, 4-medicine adding plug, 5-medicine conveying plug and 6-separation bag.
FIG. 2 is a schematic diagram of a front view structure of a closed feeding tank;
FIG. 3 is a schematic top view of the enclosed feed tank; reference numerals and corresponding part names in fig. 2 and 3: reference numbers and corresponding part names in the drawings: 1-water port for injection, 2-vacuumizing and nitrogen filling port, 3-pressure relief port, 4-hand hole, 5-discharge port and 6-blasting sheet port.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples and accompanying drawings, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not meant to limit the present invention.
Example 1
The embodiment provides a production and preparation method of a compound amino acid (15) dipeptide (2) injection, which is used for preparing 10L of the compound amino acid (15) dipeptide (2) injection, and the specific steps are as follows:
weighing: 2.5g of citric acid (added for the first time), 79.0g of leucine, 73.0g of valine, 56.0g of threonine, 19.0g of tryptophan, 113.0g of arginine, 160.0g of alanine, 56.0g of glutamic acid, 56.0g of isoleucine, 58.5g of phenylalanine, 127.0g of lysine acetate, 68.0g of histidine, 56.0g of methionine, 68.0g of proline, 45.0g of serine, 34.0g of aspartic acid, 34.5g of glycyltyrosine and 302.7g of glycylglutamine.
Preparation: 7000ml of water for injection was measured, continuously charged with nitrogen, and heated to 80 ℃. Adding citric acid (0.25g/L), leucine, valine, threonine, tryptophan, arginine, alanine, isoleucine, phenylalanine, methionine, lysine acetate, histidine, proline, serine, and aspartic acid into a sealed feeding tank, stirring, and dissolving.
Cooling the medicinal liquid to 60 deg.C, and adding glutamic acid, glycyl glutamyl, and glycyl tyrosine. Stirring for dissolving, adding water for injection to 10L, and adding citric acid to adjust pH to 5.8.
Filling: the dissolved oxygen of the liquid medicine is controlled to be less than 3mg/L and the residual oxygen is controlled to be less than 1 percent in the whole preparation and canning process. Filling the liquid medicine into a three-layer co-extrusion transfusion bag, and sealing.
And (3) sterilization: the samples were autoclaved at 121 ℃ for 8 min.
Packaging: and bagging the sterilized product and the oxygen absorbent one by one into a barrier bag for vacuum packaging.
The samples from the 3 th test run were tested according to quality standards and the results are shown in table 1.
TABLE 1 test results of 3 samples prepared in example 1
Example 2
The embodiment provides a production and preparation method of a compound amino acid (15) dipeptide (2) injection, which is used for preparing 2500L of the compound amino acid (15) dipeptide (2) injection and comprises the following specific steps:
weighing: 0.625Kg of citric acid (put for the first time), 19.75Kg of leucine, 14.00Kg of isoleucine, 8.50Kg of aspartic acid, 14.625Kg of phenylalanine, 14.00Kg of methionine, 18.25Kg of valine, 14.00Kg of threonine, 31.75Kg of lysine acetate, 28.25Kg of arginine, 40.00Kg of alanine, 17.00Kg of proline, 11.25Kg of serine, 17.00Kg of histidine, 14.00Kg of glutamic acid, 4.75Kg of tryptophan, 75.675Kg of glycylglutamine, 8.625Kg of glycyltyrosine
Preparation: 1850L of water for injection was added to the preparation tank, and nitrogen was continuously added thereto and the mixture was heated to 80 ℃. Adding citric acid (0.25g/L), leucine, valine, threonine, tryptophan, arginine, alanine, isoleucine, phenylalanine, methionine, lysine acetate, histidine, proline, serine, and aspartic acid into a sealed feeding tank, stirring, and dissolving.
Cooling the medicinal liquid to 60 deg.C, and adding glutamic acid, glycyl glutamyl, and glycyl tyrosine. Stirring for dissolving, adding water for injection to 2500L, and adding citric acid to adjust pH to 5.8.
Filling: the dissolved oxygen of the liquid medicine is controlled to be less than 3mg/L and the residual oxygen is controlled to be less than 1 percent in the whole preparation and canning process. Filling the liquid medicine into a three-layer co-extrusion transfusion bag, and sealing.
And (3) sterilization: the samples were autoclaved at 121 ℃ for 8 min.
Packaging: and bagging the sterilized product and the oxygen absorbent one by one into a barrier bag for vacuum packaging.
The key items of the 3 batches of samples amplified in the test were tested according to the quality standards, and the test results are shown in table 2.
Table 2 results of the tests using 3 batches of samples prepared in example 2
The results in the table show that all indexes of the sample prepared by the invention meet the standard requirements, and related substances are in lower levels.
Further, the three-layer co-extruded infusion film bag-making package used in examples 1 and 2 is shown in fig. 1, and the closed feed tank used is shown in fig. 2. In particular, the amount of the solvent to be used,
as shown in fig. 1, the three-layer co-extrusion film bag-making package for transfusion comprises a transfusion bag body 1, a blocking bag 6 is arranged outside the bag body 1, an input pipe orifice 2 and an output pipe orifice 3 are arranged on the bag body, a medicine adding plug 4 is arranged on the input pipe orifice 2, and a medicine conveying plug 5 is arranged on the output pipe orifice 3.
As shown in figure 2, the closed feeding tank comprises a tank body, wherein the top of the tank body is provided with an injection water port 1, a vacuumizing and nitrogen charging air port 2, a pressure relief port 3, a hand hole 4 and a blasting sheet port 6, and the bottom of the tank body is provided with a discharge port 5 and a blasting sheet port 6. Wherein, water injection mouth 1 is used for throwing the material jar internal water injection to sealed, and evacuation, nitrogen filling gas port 2 are used for to jar interior evacuation and fill nitrogen, and release port 3 is used for connecting and washs in the jar behind the cleaning ball, and hand hole 4 is used for throwing the material in the jar and observing the jar interior condition, and discharge gate 5 is used for exporting the material of throwing in the material jar, and blasting piece mouth 6 is used for filling the safe explosion vent that the nitrogen superpressure was.
The feeding method adopting the closed feeding tank is as follows:
installing a closed feeding tank on a feeding port of the preparation tank, and connecting nitrogen, water for injection and a pressure gauge on the closed feeding tank; before feeding, checking and confirming whether a butterfly valve below a closed feeding tank is closed completely; opening a pressure relief valve on the closed feeding tank to relieve pressure, opening a tank cover to feed materials, closing the closed feeding tank cover after a closed feeding tank is filled, vacuumizing the preparation tank, opening nitrogen of the closed feeding tank, opening a butterfly valve of the closed feeding tank, and conveying the raw materials into the thin preparation tank; and closing a butterfly valve of the closed feeding tank after the raw materials are fed, and completing feeding.
Comparative example 1
The comparison case provides a production and preparation method of compound amino acid (15) dipeptide (2) injection, 2500L of compound amino acid (15) dipeptide (2) injection is prepared by adopting the original process, and the specific steps are as follows compared with the steps in the example 1:
(1) the original process prescription contains sodium bisulfite and active carbon; for sodium bisulfite, when the water temperature is raised to above 80 ℃, sodium bisulfite (0.5g/L) is added firstly, and then each amino acid raw material is added; example 1 sodium bisulfite, activated carbon, was eliminated.
(2) The original process does not adopt a closed feeding tank to feed materials; example 1 a closed batch charging tank was used for the batch charging.
(3) The glutamic acid, glycyl glutamine and glycyl tyrosine of the original process are fed at the temperature of more than 80 ℃; the feeding temperature of the example 1 is below 60 ℃.
(4) After the volume is determined by the original process, adjusting the pH value by using dilute hydrochloric acid, adding active carbon for adsorption for 30min, filtering and filling; example 1 after the volume is fixed, the pH value is adjusted by citric acid, and then the mixture is filtered and filled.
(5) After the volume is determined by the original process, filling the solution into a glass infusion bottle; example 1 was filled in a three-layer co-extruded film bag for infusion, sterilized, filled in a barrier bag together with an oxygen absorbent, and vacuum-sealed.
(6) The original process sterilization condition is 115 ℃, 30 min; example 1 the sterilization conditions were 121 ℃ for 8 min.
TABLE 3 detection results of key indexes of samples produced by the original process
The results of comparing table 1 and table 3 show that the indexes of aluminum salt, related substances (pyroglutamic acid, cyclic glycyl-glutamine, cyclic glycyl-tyrosine), light transmittance and the like of the injection prepared by the process of the embodiment 1 are obviously superior to those of the injection prepared by the original process.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (7)
1. A production and preparation method of compound amino acid (15) dipeptide (2) injection is characterized by comprising the following steps:
step A: starting a preparation tank for stirring, adding water for injection into the preparation tank to 70-80% of the total amount, continuously filling nitrogen, and heating to more than 80 ℃;
and B: feeding citric acid, leucine, valine, threonine, tryptophan, arginine, alanine, isoleucine, phenylalanine, methionine, lysine acetate, histidine, proline, serine and aspartic acid in a closed feeding tank, and stirring for dissolving;
and C: cooling to below 60 deg.C, adding glutamic acid, glycyl glutamyl, and glycyl tyrosine; stirring to dissolve, adding water for injection to full dose, and adding citric acid to adjust pH to 5.5-6.0.
Step D: filling the liquid medicine into a three-layer co-extrusion transfusion film bag, and sealing;
step E: and (5) carrying out hot-pressing sterilization on the filled sample.
Step F: filling the sterilized sample and the oxygen absorbent into a barrier bag for vacuum packaging;
the preparation process controls the dissolved oxygen content of the liquid medicine to be less than or equal to 3mg/L and the residual oxygen content to be less than or equal to 1 percent.
2. The production and preparation method of the compound amino acid (15) dipeptide (2) injection as claimed in claim 1, wherein in the step B, the amount of citric acid added is such that the concentration of citric acid in the current water for injection is 0.25 g/L.
3. The production and preparation method of the compound amino acid (15) dipeptide (2) injection according to claim 1, characterized in that in the steps B and C, the input amount of each raw material is calculated by the total amount of water for injection of 500ml, and the composition is as follows:
3.95g leucine, 3.65g valine, 2.80g threonine, 0.95g tryptophan, 5.65g arginine, 8.00g alanine, 2.80g glutamic acid, 2.80g isoleucine, 2.93g phenylalanine, 2.8g methionine, 6.35g lysine acetate, 3.40g histidine, 3.40g proline, 2.25g serine, 1.70g aspartic acid, 1.73g glycyl tyrosine, 15.14g glycyl glutamine.
4. The method for producing the compound amino acid (15) dipeptide (2) injection according to claim 1, wherein in step E, the filled sample is autoclaved at 121 ℃ for 8 min.
5. The method for producing and preparing the compound amino acid (15) dipeptide (2) injection according to claim 1, wherein in the step B and the step C, the light transmittance of each raw material solution is controlled to be not less than 98.5%, and the internal control standard strict with the chinese pharmacopoeia is established to control the limit of bacterial endotoxin and microorganism.
6. The production and preparation method of the compound amino acid (15) dipeptide (2) injection as claimed in claim 5, wherein the control of bacterial endotoxin in the inner bag made by the membrane for three-layer co-extrusion transfusion is less than 0.25 EU.
7. The method for preparing the compound amino acid (15) dipeptide (2) injection according to claim 1, wherein in the step B, a closed feeding tank feeding method is adopted as follows:
installing a closed feeding tank on a feeding port of the preparation tank, and connecting nitrogen, water for injection and a pressure gauge on the closed feeding tank;
before feeding, checking and confirming whether a butterfly valve below a closed feeding tank is closed completely;
opening a pressure relief valve on the closed feeding tank to relieve pressure, opening a tank cover to feed materials, closing the closed feeding tank cover after a closed feeding tank is filled, vacuumizing the preparation tank, opening nitrogen of the closed feeding tank, opening a butterfly valve of the closed feeding tank, and conveying the raw materials into the thin preparation tank;
and closing a butterfly valve of the closed feeding tank after the raw materials are fed, and completing feeding.
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| PCT/CN2022/084967 WO2023273484A1 (en) | 2021-06-29 | 2022-04-02 | Method for producing and preparing compound amino acid (15) dipeptide (2) injection |
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