A compound amino acid injection product and a method for preparing the amino acid injection product.

Abstract

This invention provides a compound amino acid injection product and a method for preparing the amino acid injection product. The compound amino acid injection product of this invention includes a three-layer co-extruded infusion membrane inner bag containing the compound amino acid injection, and an outer packaging bag is provided outside the three-layer co-extruded infusion membrane inner bag. An oxygen absorber and an optional oxygen indicator are placed between the inner bag and the outer packaging bag. The compound amino acid injection includes serine, threonine, tryptophan, valine, alanine, arginine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine acetate, methionine, phenylalanine, proline, ornithine hydrochloride, acetyltyrosine, acetylcysteine, asparagine, and water for injection. The method for preparing the amino acid injection product of this invention can effectively reduce the aluminum content in the amino acid injection, improve the oxidative degradation problem of acetylcysteine ​​in the product, and enhance the product's antioxidant properties and stability.

Description

Technical Field

[0001] The present invention relates to the technical field of injection solutions, and particularly to a compound amino acid injection solution product and a method for preparing an amino acid injection solution product. Background Art

[0002] Compound amino acid injection (20AA) is a commonly used parenteral nutrition infusion clinically, mainly providing parenteral nutrition for patients with severe liver insufficiency and those who are about to develop or have already developed hepatic encephalopathy. The original research drug of compound amino acid injection was developed by B. Braun Melsungen AG and was first approved for marketing in Germany in 1987. The import registration application of the original research product was approved in 2007, with the approved specification of 500 mL: 50 g, the English trade name being "Aminoplasmal Hepa-10%", and the Chinese trade name being "Anping", which was the first compound amino acid injection (20AA) to be marketed in China. Currently, there are multiple generic products marketed in China.

[0003] The packaging materials of the currently commercially available 20AA injection solutions are all soda-lime glass infusion bottles. Research shows that, including the original research product, the compound amino acid injection solutions (20AA) currently marketed in China all have the problem of excessive aluminum salts. The standard limit requirement of the United States Pharmacopeia for large-volume injections is not higher than 25 μg / L, while the aluminum content of the commercially available 20AA products exceeds this limit requirement during the expiration period. In addition, due to oxygen-sensitive materials such as acetylcysteine in the 20AA product formulation, the product is prone to oxidative degradation, resulting in a series of quality problems such as a decrease in amino acid content and an increase in impurities. Therefore, it is necessary to develop a suitable packaging material for the 20AA compound amino acid injection solution to ensure that the aluminum content is within the standard limit while guaranteeing the safety and stability of the product. Summary of the Invention

[0004] In order to solve one of the above technical problems existing in the prior art, the present invention provides a compound amino acid injection solution product and a method for preparing an amino acid injection solution product, which can reduce the aluminum content in the compound amino acid injection solution product and reduce product oxidation, especially reduce the oxidation of acetylcysteine in the product, and improve the quality stability of the product.

[0005] This invention reveals that aluminum in compound amino acid injections has multiple potential sources, such as raw materials and packaging materials. Aluminum introduced through raw materials and excipients is relatively limited and its level can be reduced by strictly controlling the quality of these materials. However, packaging materials, which come into direct contact with the drug solution, may become the main source of aluminum during storage. Sodium-calcium glass infusion bottles typically require the addition of aluminum oxide to improve their mechanical properties. However, due to the poor water resistance of the inner surface of sodium-calcium glass bottles and the high ionic strength of the compound amino acid solution, the amino acid solution can damage the inner surface of the glass during storage, directly leading to the leaching of aluminum and an increase in the aluminum content of the compound amino acid product. Therefore, this invention proposes a compound amino acid injection product using a three-layer co-extruded infusion film bag as the packaging material, which can effectively solve the above-mentioned technical problems.

[0006] In a first aspect, the present invention provides a compound amino acid injection product, comprising a three-layer co-extruded infusion membrane inner bag containing the compound amino acid injection, an outer packaging bag being provided outside the inner bag, and an oxygen absorber and an optional oxygen indicator being disposed between the inner bag and the outer packaging bag; wherein, the amino acid injection comprises serine, threonine, tryptophan, valine, alanine, arginine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine acetate, methionine, phenylalanine, proline, ornithine hydrochloride, acetyltyrosine, acetylcysteine, asparagine, and water for injection.

[0007] In this invention, the inner bag is a conventional three-layer co-extruded infusion film bag. The three-layer co-extruded infusion film is made of three polymer films with different functions (usually polyolefins, such as polyethylene, polypropylene, polyethylene terephthalate, etc.). It has high mechanical strength and excellent barrier properties, and can also effectively prevent drug penetration and contamination, ensuring the safety of the infusion process.

[0008] In this invention, the outer packaging bag serves to block external oxygen, preventing it from entering the three-layer co-extruded infusion membrane inner bag and causing oxidative degradation of the compound amino acid injection solution inside. The outer packaging bag can be made of conventional single-material polyolefin materials, and this invention does not impose any special limitations. In this invention, the oxygen permeability of the outer packaging bag is no higher than 10 cm³. 3 / (m 2 ·24h·0.1MPa).

[0009] In this invention, the oxygen absorbent can be a conventional oxygen absorbent for infusion packaging bags, such as, but not limited to, iron-based oxygen absorbents. In this invention, an oxygen indicator can be placed between the inner bag and the outer packaging bag, or it can be omitted. The oxygen indicator is used to monitor the presence and / or content of oxygen in the packaging bag. This application does not specifically limit the type of oxygen indicator; those skilled in the art can select conventional oxygen indicators according to actual needs.

[0010] Since the inner bag of the three-layer co-extruded infusion membrane usually has a certain degree of oxygen permeability, the present invention further sets an outer packaging bag on the outside of the inner bag of the three-layer co-extruded infusion membrane, and fills an oxygen absorber between the inner bag and the outer packaging bag, while selectively filling an oxygen indicator, which can effectively prevent the compound amino acid injection in the inner bag from being oxidized and degraded, and improve the stability of the 20AA product.

[0011] According to some embodiments of the present invention, each 1000 mL of compound amino acid injection contains: serine 3.70 g, threonine 4.60 g, tryptophan 1.50 g, valine 10.60 g, alanine 8.30 g, arginine 8.80 g, aspartic acid 2.50 g, glutamic acid 5.70 g, glycine 6.30 g, histidine 4.70 g, isoleucine 8.80 g, leucine 13.60 g, lysine acetate 10.60 g, methionine 1.20 g, phenylalanine 1.60 g, proline 7.10 g, ornithine hydrochloride 1.66 g, acetyltyrosine 0.86 g, acetylcysteine ​​0.80 g, and asparagine 0.55 g.

[0012] Optionally, the compound amino acid injection of the present invention further contains excipients, preferably including one or more of disodium edetate, calcium sodium edetate, sodium bisulfite, sodium metabisulfite, citric acid, and malic acid. In some embodiments, the excipients include one or two of disodium edetate and calcium sodium edetate. In some embodiments, the excipients include disodium edetate. In some embodiments, each 1000 mL of the compound amino acid injection contains 0-0.1 g of excipients, for example, 0 g, 0.01 g, 0.02 g, 0.04 g, 0.05 g, 0.08 g, 0.1 g, etc.

[0013] According to some embodiments of the present invention, each 1000 mL of compound amino acid injection contains: serine 3.70 g, threonine 4.60 g, tryptophan 1.50 g, valine 10.60 g, alanine 8.30 g, arginine 8.80 g, aspartic acid 2.50 g, glutamic acid 5.70 g, glycine 6.30 g, histidine 4.70 g, isoleucine 8.80 g, leucine 13.60 g, lysine acetate 10.60 g, methionine 1.20 g, phenylalanine 1.60 g, proline 7.10 g, ornithine hydrochloride 1.66 g, acetyltyrosine 0.86 g, acetylcysteine ​​0.80 g, asparagine 0.55 g, and disodium edetate 0.05 g.

[0014] According to some embodiments of the present invention, the pH of the compound amino acid injection solution is 5.5 to 6.5.

[0015] In a second aspect, the present invention provides a method for preparing an amino acid injection product, comprising the following steps:

[0016] (1) Preparation of amino acid injection: Add solid raw materials to the preparation tank and perform vacuuming and nitrogen filling treatment, then add water for injection to dissolve the solid raw materials to obtain amino acid injection; wherein, the solid raw materials include acetylcysteine; during the preparation process, the dissolved oxygen content in the preparation tank is controlled to be ≤3mg / L;

[0017] (2) Filling of amino acid injection: The three-layer co-extruded infusion membrane inner bag is vacuumed and filled with nitrogen, and then the amino acid injection is filled into the three-layer co-extruded infusion membrane inner bag and sealed with nitrogen. During the filling process, the residual oxygen content in the three-layer co-extruded infusion membrane inner bag is controlled to be no higher than 3% v / v.

[0018] (3) Outer Packaging: An outer packaging bag is placed outside the three-layer co-extruded infusion membrane inner bag, and an oxygen absorbent and optional oxygen indicator are placed between the three-layer co-extruded infusion membrane inner bag and the outer packaging bag. Then, the bag is vacuum-sealed with nitrogen. The residual oxygen content between the inner bag and the outer packaging bag does not exceed 5% v / v, and the oxygen permeability of the outer packaging bag does not exceed 10 cm. 3 / (m 2 ·24h·0.1MPa).

[0019] According to some embodiments of the present invention, the solid raw material further includes one or more of the following: serine, threonine, tryptophan, valine, alanine, arginine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine acetate, methionine, phenylalanine, proline, ornithine hydrochloride, acetyltyrosine, and asparagine.

[0020] According to some embodiments of the present invention, the solid raw materials include acetylcysteine, serine, threonine, tryptophan, valine, alanine, arginine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine acetate, methionine, phenylalanine, proline, ornithine hydrochloride, acetyltyrosine, and asparagine.

[0021] According to some embodiments of the present invention, in step (1), the solid raw materials, based on the amount of 1000 mL of amino acid injection solution prepared, include: 3.70 g serine, 4.60 g threonine, 1.50 g tryptophan, 10.60 g valine, 8.30 g alanine, 8.80 g arginine, 2.50 g aspartic acid, 5.70 g glutamic acid, 6.30 g glycine, 4.70 g histidine, 8.80 g isoleucine, 13.60 g leucine, 10.60 g lysine acetate, 1.20 g methionine, 1.60 g phenylalanine, 7.10 g proline, 1.66 g ornithine hydrochloride, 0.86 g acetyltyrosine, 0.80 g acetylcysteine, and 0.55 g asparagine.

[0022] According to some embodiments of the present invention, the solid raw material further includes excipients. The excipients of the present invention include, but are not limited to, antioxidants for injection, such as one or more of disodium edetate, calcium sodium edetate, sodium bisulfite, sodium metabisulfite, malic acid, and citric acid. In some preferred embodiments, the excipients include disodium edetate or calcium sodium edetate. It should be noted that the solid raw material of the present invention may also be without excipients. In the present invention, the amount of excipient used is 0-0.1g per 1000mL of compound amino acid injection.

[0023] According to some embodiments of the present invention, the solid raw materials include serine, threonine, tryptophan, valine, alanine, arginine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine acetate, methionine, phenylalanine, proline, ornithine hydrochloride, acetyltyrosine, acetylcysteine, asparagine, and disodium edetate.

[0024] According to some embodiments of the present invention, in step (1), the solid raw materials, based on the amount of 1000 mL of amino acid injection solution prepared, include: 3.70 g serine, 4.60 g threonine, 1.50 g tryptophan, 10.60 g valine, 8.30 g alanine, 8.80 g arginine, 2.50 g aspartic acid, 5.70 g glutamic acid, 6.30 g glycine, 4.70 g histidine, 8.80 g isoleucine, 13.60 g leucine, 10.60 g lysine acetate, 1.20 g methionine, 1.60 g phenylalanine, 7.10 g proline, 1.66 g ornithine hydrochloride, 0.86 g acetyltyrosine, 0.80 g acetylcysteine, 0.55 g asparagine, and 0.05 g disodium edetate.

[0025] In step (1) of this invention, the vacuuming and nitrogen filling process is performed once or multiple times, preferably multiple times, to ensure that the dissolved oxygen content is ≤3mg / L during the preparation process.

[0026] According to some embodiments of the present invention, in step (1), the dissolution temperature is not higher than 80°C, for example, 50°C, 60°C, 70°C, 80°C, or any value between them. In some embodiments, in step (1), the dissolution temperature is 50–80°C. According to some embodiments of the present invention, step (1) further includes: after dissolving the solid raw material with water for injection, adjusting the pH of the injection solution to 5.5–6.5. Optionally, in the present invention, the pH of the injection solution can be adjusted by adding an acid or a base, for example, by adding hydrochloric acid or sodium hydroxide.

[0027] In step (2) of this invention, the vacuuming and nitrogen filling process is performed once or multiple times, preferably multiple times, to ensure that the residual oxygen content is not higher than 3% v / v.

[0028] According to some embodiments of the present invention, step (2) further includes: filtering the amino acid injection solution before filling it into the three-layer co-extruded infusion membrane inner bag.

[0029] According to some embodiments of the present invention, step (2) further includes: purging the three-layer co-extruded fluid delivery membrane inner bag with nitrogen gas before sealing.

[0030] According to some embodiments of the present invention, the three-layer co-extruded infusion membrane inner bag in step (2) has an interface.

[0031] According to some embodiments of the present invention, the sealing in step (2) includes a gland seal.

[0032] According to some embodiments of the present invention, step (2) includes: adding an interface to the inner bag made of a three-layer co-extruded infusion membrane, performing one or more (preferably multiple) vacuuming and nitrogen filling treatments on the inner bag, then filtering the amino acid injection solution and filling it into the inner bag, purging nitrogen and capping; controlling the residual oxygen content of the inner bag to be no higher than 3% v / v.

[0033] According to some embodiments of the present invention, step (3) further includes: performing one or more vacuuming and nitrogen filling treatments on the outer packaging bag before filling it with oxygen absorber and optional oxygen indicator.

[0034] According to some embodiments of the present invention, step (3) further includes: sealing the outer packaging bag (e.g., plastic sealing).

[0035] According to some embodiments of the present invention, step (3) includes: setting an outer packaging bag outside the inner bag, inserting an oxygen absorbent and an optional oxygen indicator between the inner bag and the outer packaging bag, performing one or more (preferably multiple) vacuuming and nitrogen filling treatments on the outer packaging bag, and then sealing it, controlling the residual oxygen content between the inner and outer bags to not exceed 5% v / v, wherein the oxygen permeability of the outer packaging bag is not higher than 10 cm. 3 / (m 2 ·24h·0.1MPa).

[0036] According to some embodiments of the present invention, the method further includes step (4): subjecting the packaged amino acid injection solution to heat sterilization.

[0037] In some embodiments, the sterilization conditions are: a temperature of 115–125°C (e.g., 115°C, 116°C, 117°C, 118°C, 119°C, 120°C, 121°C, 122°C, 123°C, 124°C, 125°C, etc.); and an F0 value of not less than 8 minutes (e.g., 8 minutes, 10 minutes, 12 minutes, 15 minutes, 18 minutes, 20 minutes, 25 minutes, 30 minutes, etc.).

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] 1. This invention uses a three-layer co-extruded infusion film bag as the packaging material for 20AA compound amino acid injection. The material contains almost no aluminum, which can reduce the source of aluminum from the root and significantly reduce the aluminum content of 20AA compound amino acid injection product, so that the aluminum content meets the United States Pharmacopeia standard requirements during the shelf life.

[0040] 2. This invention uses a three-layer co-extruded infusion membrane bag as the packaging material for 20AA compound amino acid injection, which can improve the degradation problem of oxygen-sensitive materials (such as acetylcysteine ​​and tryptophan) caused by the use of soft bag packaging in the prior art, and improve the high-temperature stability of the product. In addition, by adding an oxygen absorbent between the inner bag and the outer bag, since the inner bag is a semi-permeable membrane bag, residual oxygen in the inner bag can permeate through the membrane bag and be absorbed by the oxygen absorbent, further improving the stability during storage.

[0041] 3. This invention provides a soft-bag packaged 20AA compound amino acid injection product. Compared with glass bottle packaging, it eliminates the need for ventilation tubes during clinical use, reducing the risk of particulate contamination and improving the safety of clinical medication.

[0042] 4. The method for preparing amino acid injection products according to the present invention optimizes the process by first feeding solid materials and using powder deoxygenation technology during the preparation of amino acid injection products, and then adding water to dissolve the solid raw materials. This can reduce the air introduced during the feeding process and avoid the rapid dissolution of oxygen into the water oxides during the water dissolution process. This can significantly improve the oxidative degradation problem of acetylcysteine ​​in the injection and ensure the oxidative stability of the amino acid injection product during the preparation process. Attached Figure Description

[0043] Figure 1 The results show the changes in aluminum content of the compound amino acid injection solutions prepared in Example 1, Comparative Example 1 and Comparative Example 3 of the present invention at 25°C for different time periods.

[0044] Figure 2 The results show the changes in aluminum content of the compound amino acid injection solutions prepared in Example 1, Comparative Example 1 and Comparative Example 3 of the present invention at 40°C for different time periods.

[0045] Figure 3 The results show the changes in the content of acetylcysteine ​​oxidative impurities in the compound amino acid injections prepared in Example 1 and Comparative Example 2 of the present invention at 25°C for different time periods.

[0046] Figure 4 The results show the changes in the content of acetylcysteine ​​oxidative impurities in the compound amino acid injections prepared in Example 1 and Comparative Example 2 of the present invention at 40°C for different time periods.

[0047] Figure 5 The results show the changes in acetylcysteine ​​content of the compound amino acid injections prepared in Example 1 and Comparative Example 2 of the present invention at 25°C for different time periods.

[0048] Figure 6 The results show the changes in acetylcysteine ​​content in the compound amino acid injections prepared in Example 1 and Comparative Example 2 of the present invention at 40°C for different time periods. Detailed Implementation

[0049] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments and accompanying drawings. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention in any way.

[0050] Packaging materials directly affect the safety, efficacy, and stability of compound amino acid injections. Currently, compound amino acid injections are still mainly packaged in glass bottles. The main reason for the widespread use of glass bottles as packaging materials for compound amino acids is their good sealing properties, which can effectively prevent the oxidative degradation of amino acids by external air, thereby maintaining the safety and efficacy of amino acids. In addition, glass bottles also have the advantages of being widely available and low in cost.

[0051] While flexible infusion bags are lighter, more convenient to transport and use, and easier to recycle compared to glass bottles, studies have shown that 20AA compound amino acid injection, when packaged in ordinary non-PVC multilayer co-extruded infusion bags, fails to meet the required standards for properties, light transmittance, and tryptophan content. Therefore, 20AA compound amino acid injection is not suitable for packaging in ordinary non-PVC multilayer co-extruded infusion bags. This is because the components of 20AA compound amino acid injection are complex and have high quality requirements. Packaging in ordinary non-PVC co-extruded infusion bags makes it susceptible to the effects of strong light, oxygen, and temperature, easily causing oxidative degradation of tryptophan, acetylcysteine, and other components. Even under light-protected storage conditions, this degradation remains unchanged (Wang Yinjuan et al., Stability Study of 20AA Compound Amino Acid Injection with Non-PVC Co-extruded Infusion Bags, Central South Pharmaceutical Journal, May 2013, Vol. 11, No. 5). Therefore, simply using ordinary non-PVC co-extruded infusion bags to package 20AA compound amino acid injection cannot solve the stability problem of the amino acid components.

[0052] Acetylcysteine ​​and tryptophan are easily oxidized components in 20AA compound amino acid injection, and their stability is affected by oxygen content. Oxygen can easily enter the drug solution through the non-PVC multilayer co-extruded infusion bag, causing oxidative degradation. This application creatively discovers that by selecting a three-layer co-extruded infusion film inner bag as the packaging material for 20AA compound amino acid injection, and setting an outer packaging bag to block external oxygen on the outside of the three-layer co-extruded infusion film inner bag, and adding an oxygen absorber and optional oxygen indicator between the inner bag and the outer packaging bag, not only can the problem of high aluminum content caused by using glass bottle packaging be solved, but the oxidative degradation problem of acetylcysteine ​​in the injection can also be significantly improved. During long-term (6 months) and accelerated (40°C) storage, the level of oxygen-sensitive acetylcysteine ​​impurities is low, ensuring the oxidative stability of the compound amino acid injection product.

[0053] Furthermore, this application also found that in the preparation process of compound amino acid injection products, when preparing amino acid injections, by first feeding solid materials, then using powder deoxygenation technology, and then adding water to dissolve the solid raw materials, the air introduced during the feeding process can be further reduced, and oxygen can be prevented from rapidly dissolving into the water oxides during the water dissolution process, thus ensuring the stability of the compound amino acid product preparation process.

[0054] As one specific embodiment, the present invention provides a method for preparing a 20AA compound amino acid injection product, comprising the following steps:

[0055] Step 1: Add 3.70g serine, 4.60g threonine, 1.50g tryptophan, 10.60g valine, 8.30g alanine, 8.80g arginine, 2.50g aspartic acid, 5.70g glutamic acid, 6.30g glycine, 4.70g histidine, 8.8g isoleucine, 13.60g leucine, 10.60g lysine acetate, 1.20g methionine, 1.60g phenylalanine, 7.10g proline, 1.66g ornithine hydrochloride, 0.86g acetyltyrosine, 0.80g acetylcysteine, 0.55g asparagine, and 0.050g disodium edetate to a preparation vessel. Repeatedly vacuum and nitrogen-filled the solid powder, then add water for injection to dissolve the solid powder to obtain the drug solution. In Step 1, the dissolved oxygen content should be controlled to be ≤3mg / L.

[0056] Step 2: Take a three-layer co-extruded infusion membrane inner bag and add an interface. Repeatedly vacuum and nitrogen-fill the inner bag, then fill it with the filtered drug solution prepared in Step 1, then purge with nitrogen, and cap it. Throughout the process, control the oxygen content of the three-layer co-extruded infusion membrane inner bag to be no higher than 3% v / v.

[0057] Step 3: Add an outer bag to the inner bag, and put an oxygen absorbent and an optional oxygen indicator between the inner bag and the outer bag. Perform multiple vacuuming and nitrogen filling treatments on the outer bag, and then seal it. Control the oxygen content between the inner bag made of the three-layer co-extruded infusion film and the outer packaging bag to be no higher than 5% v / v.

[0058] Step 4: Sterilize the sample prepared in Step 3 by autoclaving.

[0059] Furthermore, in step 1, the solid powder is repeatedly vacuumed and nitrogen-purged at least once, and the dissolution temperature is not higher than 80℃, for example, 50℃-80℃.

[0060] Further, in step 1, after dissolving the solid powder with water for injection, the pH is adjusted to 5.5–6.5 using a pH adjuster. Even further, the pH adjuster is hydrochloric acid or sodium hydroxide.

[0061] Furthermore, in step 2, the inner bag is repeatedly vacuumed and filled with nitrogen at least once.

[0062] Furthermore, in step 3, the outer bag is repeatedly vacuumed and filled with nitrogen at least once.

[0063] Furthermore, in step 3, the oxygen permeability of the outer bag should not exceed 10 cm. 3 / (m 2 ·24h·0.1MPa).

[0064] Furthermore, in step 4, the sterilization conditions are 121°C and F0 for no less than 8 minutes.

[0065] Unless otherwise specified, all reagents used in the following experiments of this invention are commercially available products or reagents prepared according to conventional methods. Unless otherwise specified, all methods used in the experiments are conventional experimental methods. Unless otherwise specified, all instruments used in the experiments are commercially available.

[0066] Example 1

[0067] This embodiment provides a method for producing compound amino acid injection (20AA) packaged in bags using a three-layer co-extruded infusion film. The specific steps are as follows:

[0068] Step 1: Solution Preparation: Weigh the prescribed amounts of serine 3.70g, threonine 4.60g, tryptophan 1.50g, valine 10.60g, alanine 8.30g, arginine 8.80g, aspartic acid 2.50g, glutamic acid 5.70g, glycine 6.30g, histidine 4.70g, isoleucine 8.8g, leucine 13.60g, lysine acetate 10.60g, methionine 1.20g, phenylalanine 1.60g, and proline. 7.10g of acid, 1.66g of ornithine hydrochloride, 0.86g of acetyltyrosine, 0.80g of acetylcysteine, 0.55g of asparagine, and 0.050g of disodium edetate were added to a container. The solid powder was repeatedly vacuumed and purged with nitrogen at least once. Then, water for injection was added to dissolve it. The dissolution temperature was not higher than 80℃. Nitrogen protection was maintained during the dissolution process. The pH was adjusted to 5.5-6.5. The dissolved oxygen during the dissolution process was not greater than 3mg / L, and the resulting drug solution was obtained. The production batch was 200L.

[0069] Step 2: Take a three-layer co-extruded infusion membrane to make a 500mL inner bag and add an interface. Repeatedly vacuum and nitrogen-fill the inner bag at least once. Then fill it with the filtered drug solution, purge with nitrogen, and cap it. Throughout the process, strictly control the residual oxygen content of the inner bag to ≤3% v / v.

[0070] Step 3: Add an outer bag outside the inner bag, and add an iron-based oxygen absorbent and oxygen indicator between the inner and outer bags. Repeatedly vacuum and nitrogen-fill the outer bag, then seal it. Throughout the process, strictly control the residual oxygen content between the inner bag and the outer bag to ≤5% v / v, and the oxygen permeability of the outer bag to no more than 10 cm. 3 / (m 2 ·24h·0.1MPa).

[0071] Step 4: Sterilize the prepared sample by autoclaving at 121°C for 8 minutes with an F0 value of not less than 8 minutes.

[0072] Comparative Example 1

[0073] This comparative example provides a method for producing compound amino acid injection (20AA) packaged in infusion bottles. The specific steps are compared with those in Example 1 as follows:

[0074] Step 1: Same as in Example 1, production batch size 200L.

[0075] Step 2: Take a 500mL soda-lime glass infusion bottle, repeatedly purge it with nitrogen to remove oxygen, then pour in the filtered medicine solution, purge with nitrogen again, press the rubber stopper and aluminum cap, and control the residual oxygen content in the bottle to be no higher than 3% v / v.

[0076] Step 3: Outer bag packaging is not suitable for glass bottle samples.

[0077] Step 4: Same as in Example 1.

[0078] Comparative Example 2

[0079] This comparative example provides a method for producing compound amino acid injection (20AA) packaged in infusion bottles. The specific steps are compared with those in Example 1 as follows:

[0080] Step 1: Same as Example 1, production batch 2500L.

[0081] Step 2: Take a 500mL soda-lime glass infusion bottle, repeatedly evacuate and purge with nitrogen at least once, then pour in the filtered medicine, purge with nitrogen again, press the rubber stopper and aluminum cap, and control the residual oxygen content in the bottle to be no higher than 3% v / v.

[0082] Step 3: Outer bag packaging is not suitable for glass bottle samples.

[0083] Step 4: Same as in Example 1.

[0084] Comparative Example 3

[0085] This comparative example provides a method for producing compound amino acid injection (20AA) packaged in infusion bottles. The specific steps are compared with those in Example 1 as follows:

[0086] Step 1: Same as in Example 1, production batch size 200L.

[0087] Step 2: Take a 500mL borosilicate glass infusion bottle, repeatedly purge it with nitrogen to remove oxygen, then pour in the filtered medicine solution, purge with nitrogen again, press the rubber stopper and aluminum cap, and control the residual oxygen content in the bottle to be no higher than 3% v / v.

[0088] Step 3: Outer bag packaging is not suitable for glass bottle samples.

[0089] Step 4: Same as in Example 1.

[0090] Experiment 1: Aluminum Element Content Test

[0091] The aluminum content in the compound amino acid injection solutions of Examples 1, Comparative Example 1, and Comparative Example 3 was determined by inductively coupled plasma mass spectrometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0412). The specific method is as follows:

[0092] The test solution was injected into an inductively coupled plasma mass spectrometer (ICP-MS), and the response values ​​of aluminum and the internal standard were recorded. A linear regression was performed with the aluminum concentration (μg / L) in the standard curve solution as the x-axis and the ratio of the corresponding aluminum response value to the internal standard response value as the y-axis to obtain the linear regression equation. The measured ratio of the aluminum response value of the test solution to the internal standard response value was substituted into the linear regression equation to calculate the aluminum content in the test solution. The aluminum content in the blank solution was then subtracted, and the result was multiplied by the dilution factor to obtain the aluminum content in the test solution.

[0093] Table 1 summarizes the aluminum element results of the samples from Example 1 and Comparative Examples 1 and 3. Figure 1 and Figure 2 The graph shows the trend of aluminum content in the samples of Example 1, Comparative Example 1, and Comparative Example 3 during long-term and accelerated stability placement.

[0094] Table 1. Stability data of aluminum content

[0095]

[0096] The results showed that the 20AA compound amino acid injection prepared in Example 1 using a three-layer co-extruded infusion film bag as the packaging material did not show a significant increase in aluminum content during long-term and accelerated storage, and remained within the limits required by the United States Pharmacopeia (25 μg / L). Its stability results were significantly better than those of the samples in Comparative Example 1 using soda-lime glass infusion bottles and Comparative Example 3 using borosilicate glass infusion bottles as packaging materials, and the product quality was greatly improved.

[0097] Experiment 2: Test of Acetylcysteine ​​and its Oxidized Impurities

[0098] The contents of acetylcysteine ​​and acetylcysteine ​​oxidation impurities in the compound amino acid injections of Examples 1 and Comparative Example 2 were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The test method is as follows:

[0099] Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the result by peak area using the external standard method.

[0100] Table 2 summarizes the results of acetylcysteine ​​oxidation impurity content in the samples of Example 1 and Comparative Example 2. Figure 3 and Figure 4 The graph shows the trend of acetylcysteine ​​oxidative impurity content changes in the samples of Example 1 and Comparative Example 2 during long-term and accelerated stability storage.

[0101] Table 2. Stability data of acetylcysteine ​​oxidative impurities

[0102]

[0103]

[0104] Table 3 summarizes the results of acetylcysteine ​​content in the samples of Example 1 and Comparative Example 2. Figure 5 and Figure 6 The graph shows the trend of acetylcysteine ​​content changes in the samples of Example 1 and Comparative Example 2 during long-term and accelerated stability storage.

[0105] Table 3. Stability data of acetylcysteine ​​content

[0106]

[0107] The results showed that the 20AA compound amino acid injection prepared using a three-layer co-extruded infusion film bag as packaging material in Example 1 had a lower level of acetylcysteine ​​impurity during long-term and accelerated storage, while the acetylcysteine ​​content was higher. In other words, the product quality was better than that of the sample in Comparative Example 2 which used a soda-lime glass infusion bottle as packaging material, and the product quality was improved.

[0108] The technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made in accordance with the technical solutions of the present invention fall within the protection scope of the present invention.

Claims

1. A compound amino acid injection product, comprising a three-layer co-extruded infusion film inner bag containing the compound amino acid injection, an outer packaging bag being provided outside the inner bag, and an oxygen absorbent and an optional oxygen indicator being disposed between the inner bag and the outer packaging bag; in, The compound amino acid injection includes serine, threonine, tryptophan, valine, alanine, arginine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine acetate, methionine, phenylalanine, proline, ornithine hydrochloride, acetyltyrosine, acetylcysteine, asparagine, and water for injection.

2. The compound amino acid injection product according to claim 1, characterized in that, Each 1000mL of compound amino acid injection contains: serine 3.70g, threonine 4.60g, tryptophan 1.50g, valine 10.60g, alanine 8.30g, arginine 8.80g, aspartic acid 2.50g, glutamic acid 5.70g, glycine 6.30g, histidine 4.70g, isoleucine 8.80g, leucine 13.60g, lysine acetate 10.60g, methionine 1.20g, phenylalanine 1.60g, proline 7.10g, ornithine hydrochloride 1.66g, acetyltyrosine 0.86g, acetylcysteine ​​0.80g, and asparagine 0.55g.

3. The compound amino acid injection product according to claim 1 or 2, characterized in that, The pH of the compound amino acid injection is 5.5-6.5; and / or, the oxygen absorbent includes an iron-based oxygen absorbent; and / or, the compound amino acid injection also contains excipients, preferably including one or more of disodium edetate, calcium sodium edetate, sodium bisulfite, sodium metabisulfite, citric acid, and malic acid; preferably, each 1000 mL of the compound amino acid injection contains 0-0.1 g of excipients.

4. A method for preparing an amino acid injection product, comprising the following steps: (1) Preparation of amino acid injection: Solid raw materials are added to a preparation vessel and the vessel is evacuated and purged with nitrogen. Then, water for injection is added to the preparation vessel to dissolve the solid raw materials, yielding the amino acid injection solution; wherein, The solid raw material includes acetylcysteine; the dissolved oxygen content in the preparation tank is controlled to be ≤3mg / L during the preparation process; (2) Filling of amino acid injection: The three-layer co-extruded infusion membrane inner bag is vacuumed and filled with nitrogen, and then the amino acid injection is filled into the three-layer co-extruded infusion membrane inner bag and sealed with nitrogen. During the filling process, the residual oxygen content in the three-layer co-extruded infusion membrane inner bag is controlled to be no higher than 3% v / v. (3) Outer Packaging: An outer packaging bag is placed outside the three-layer co-extruded infusion membrane inner bag, and an oxygen absorbent and optional oxygen indicator are placed between the three-layer co-extruded infusion membrane inner bag and the outer packaging bag. Then, the bag is vacuum-sealed with nitrogen. The residual oxygen content between the inner bag and the outer packaging bag does not exceed 5% v / v, and the oxygen permeability of the outer packaging bag does not exceed 10 cm. 3 / (m 2 ·24h·0.1MPa).

5. The method according to claim 4, characterized in that, The solid raw materials also include one or more of the following: serine, threonine, tryptophan, valine, alanine, arginine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine acetate, methionine, phenylalanine, proline, ornithine hydrochloride, acetyltyrosine, and asparagine. Preferably, in step (1), the solid raw materials, based on the amount of 1000 mL of amino acid injection solution prepared, include: 3.70 g serine, 4.60 g threonine, 1.50 g tryptophan, 10.60 g valine, 8.30 g alanine, 8.80 g arginine, 2.50 g aspartic acid, 5.70 g glutamic acid, 6.30 g glycine, 4.70 g histidine, 8.80 g isoleucine, 13.60 g leucine, 10.60 g lysine acetate, 1.20 g methionine, 1.60 g phenylalanine, 7.10 g proline, 1.66 g ornithine hydrochloride, 0.86 g acetyltyrosine, 0.80 g acetylcysteine, and 0.55 g asparagine.

6. The method according to claim 4 or 5, characterized in that, The solid raw materials may also include auxiliary materials; Preferably, the excipients include one or more of disodium edetate, calcium sodium edetate, sodium bisulfite, sodium metabisulfite, citric acid, and malic acid; Preferably, the amount of excipients used in each 1000mL compound amino acid injection is 0-0.1g; Preferably, the solid raw materials include serine, threonine, tryptophan, valine, alanine, arginine, aspartic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine acetate, methionine, phenylalanine, proline, ornithine hydrochloride, acetyltyrosine, acetylcysteine, asparagine, and disodium edetate. Preferably, in step (1), the solid raw materials, based on the amount of 1000 mL of amino acid injection solution prepared, include: 3.70 g serine, 4.60 g threonine, 1.50 g tryptophan, 10.60 g valine, 8.30 g alanine, 8.80 g arginine, 2.50 g aspartic acid, 5.70 g glutamic acid, 6.30 g glycine, 4.70 g histidine, 8.80 g isoleucine, 13.60 g leucine, 10.60 g lysine acetate, 1.20 g methionine, 1.60 g phenylalanine, 7.10 g proline, 1.66 g ornithine hydrochloride, 0.86 g acetyltyrosine, 0.80 g acetylcysteine, 0.55 g asparagine, and 0.05 g disodium edetate.

7. The method according to any one of claims 4 to 6, characterized in that, In step (1), the dissolution temperature is not higher than 80°C, preferably 50-80°C.

8. The method according to any one of claims 4 to 7, characterized in that, Step (1) further includes: adding water for injection to dissolve the solid raw material, and then adjusting the pH of the injection solution to 5.5-6.5; Preferably, an acid or alkali is added to adjust the pH of the injection solution; Preferably, the acid includes hydrochloric acid, and the base includes sodium hydroxide.

9. The method according to any one of claims 4 to 8, characterized in that, In step (2), the three-layer co-extruded infusion membrane inner bag is purged with nitrogen before sealing; And / or, Step (2) further includes: filtering the amino acid injection solution before filling it into the three-layer co-extruded infusion membrane inner bag; And / or, In step (3), the outer packaging bag is vacuum-sealed and nitrogen-filled before the oxygen absorber and optional oxygen indicator are added.

10. The method according to any one of claims 4 to 9, characterized in that, It also includes step (4): subjecting the packaged amino acid injection solution to heat sterilization; Preferably, the sterilization conditions are: temperature 115-125℃, preferably 120-122℃; F0 value not less than 8 minutes.

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