Compound amino acid and glucose injection and preparation method thereof

Abstract

The invention provides a compound amino acid and glucose injection and a preparation method thereof, the compound amino acid and glucose injection is packaged by a double-cavity bag, the amino acid injection contains an antioxidant, and the antioxidant is selected from ascorbic acid and / or acetylcysteine; the glucose injection comprises glucose and water. The invention provides a preparation process of amino acid injection and glucose injection packaged by a double-cavity bag made of a non-PVC three-layer co-extrusion infusion bag, and compared with a traditional preparation process, the composition prepared by the preparation process has good safety, stability and material compatibility.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a compound amino acid and glucose injection and a preparation method thereof. Background Art

[0002] Parenteral nutrition therapy is an important means of providing nutritional support to hospitalized patients, especially for patients with tumors and gastrointestinal diseases who cannot take in adequate nutrition orally. Compound amino acid injection (15-HBC) is mainly used clinically to provide nutritional support for patients with muscle hypercatabolism, digestive system dysfunction, nutritional deterioration and decreased immune function under stress conditions such as large-area burns, trauma and severe infection, as well as to improve nutrition in patients after surgery.

[0003] With the widespread application of amino acid infusion products, the infusion method has also evolved from open to semi-open, and finally to fully enclosed. The packaging materials have evolved from soda-lime glass infusion bottles to PVC soft bags, to polypropylene infusion bottles, and finally to the world's most advanced and environmentally friendly non-PVC soft bags. Glass bottle infusion has defects in packaging materials and infusion methods, and the plastic bottle packaging infusion packaging method has not fundamentally changed the traditional infusion method and existing problems.

[0004] Traditional compound amino acid injection (15-HBC) must be mixed with other carrier solutions before infusion, such as diluted with an equal amount of 5% glucose injection commonly used in clinical practice, and then slowly dripped. In the above mixing and preparing process, problems such as prescription incompatibility or errors, preparation or dosage errors are prone to occur, and the storage time of the mixed liquid becomes shorter, the stability is poor, and it is not easy to store for a long time.

[0005] In domestic hospitals, parenteral nutrition is administered through multiple bottles of infusion, that is, the bottled total parenteral nutrition - amino acids and glucose are connected in series for infusion. The biggest drawback of this infusion method is that it requires a mixing tube with three needles, two of which are inserted through the rubber stoppers of the two products to be mixed into the liquid medicine, and the third needle is inserted into the mixing bag. The liquid medicine flows into the mixing bag through the catheter and is mixed evenly. Obviously, since the entire mixing process is manually operated, multiple punctures destroy the seal of the product. A slight mistake can easily cause microbial contamination to the product, which in turn brings serious consequences such as infusion reactions, blood infections, and sepsis to patients. For this reason, large hospitals usually perform mixing operations under sterile conditions in a specially established sterile preparation room. However, even if sterile operating conditions are used, the probability of contaminating microorganisms is more than one in a thousand. In addition, the construction and maintenance costs of the sterile preparation room are quite high, which will be a considerable burden for some small and medium-sized hospitals and hospitals in economically underdeveloped areas, and to a certain extent hinder the promotion of mixed infusion methods. Another disadvantage of this mixed method is that the rotational infusion of multiple bottles not only brings troubles to medical staff in repeatedly changing bottles, constantly checking, and adjusting the drip rate, but more importantly, multiple punctures of the stopper during the operation inevitably produce a large number of stopper particles, which can easily clog the capillaries after dripping into the blood, causing microcirculation embolism, and adding greater treatment risks to patients.

[0006] The multi-chamber liquid infusion bag belongs to the category of ready-to-use multi-chamber bags. Each chamber is filled with liquid medicine, and the chambers are separated by openable weak welding rods. When in use, the weak welding rods can be opened by applying pressure to the bag body to mix the medicines. After the medicine liquid is fully mixed, it is infused into the human body from the medicine liquid discharge port. Generally, there is a contradiction between the weak welding rods in the prior art being opened by mistake and not easy to open during use. Therefore, it is necessary to finely control the welding strength of the weak welding rods of the double-chamber bag to ensure the controllable opening of the weak welding rods and the mixing of medicines, while avoiding the accidental opening of the weak welding rods during storage and transportation.

[0007] The reaction between the raw materials of compound amino acid (15HBC-SF) / glucose (5%) injection, glucose and cysteine, is mainly the Maillard reaction, which is a non-enzymatic reaction involving glycosylation and oxidation processes, usually occurring between reducing sugars and amino acids, and is a common biochemical reaction. In injections, this reaction may lead to drug degradation, affecting its efficacy and safety. Summary of the invention

[0008] The technical problem to be solved by the present invention is to provide a compound amino acid and glucose injection and a preparation method thereof in view of the above-mentioned deficiencies in the prior art. The injection of the present invention is packaged in a double-chamber bag made of a non-PVC three-layer co-extruded infusion bag, and is suitable for patients who need to supplement parenteral nutrition or complete enteral nutrition.

[0009] The technical solution of the present invention is implemented as follows: the present invention provides a compound amino acid (15-HBC) and glucose injection, which is packaged in a double-chamber bag and includes an amino acid injection and a glucose injection;

[0010] The amino acid injection comprises leucine, isoleucine, valine, phenylalanine, threonine, methionine, lysine acetate, glycine, proline, alanine, serine, histidine, arginine, tryptophan, cysteine ​​hydrochloride and water;

[0011] The amino acid injection further comprises an antioxidant, wherein the antioxidant is selected from ascorbic acid and / or acetylcysteine;

[0012] The glucose injection contains glucose and water.

[0013] On the basis of the above technical solution, preferably, the percentage of the antioxidant to the amino acid injection is 0.02% to 1.0%.

[0014] On the basis of the above technical scheme, preferably, for each preparation of 1000 mL of the amino acid injection, the amount of each raw material is: leucine 12.402g~15.158g, isoleucine 6.894g~8.426g, valine 7.974g~9.746g, phenylalanine 2.88g~3.52g, threonine 1.8g~2.2g, methionine 2.25g~2.75g, vinegar Lysine acid 5.22g~6.38g, glycine 2.97g~3.63g, proline 5.67g~6.93g, alanine 3.6g~4.4g, serine 2.97g~3.63g, histidine 1.44g~1.76g, arginine 5.22g~6.38g, tryptophan 0.81g~0.99g, cysteine ​​hydrochloride 0.18g~0.22g, and the rest is water.

[0015] On the basis of the above technical solution, preferably, the amino acid injection solution further contains glacial acetic acid, and the glacial acetic acid can adjust the pH value of the amino acid injection solution to 5.5-6.5.

[0016] On the basis of the above technical solution, preferably, each 1000 mL of the glucose injection contains 45-55 g of glucose.

[0017] On the basis of the above technical solution, preferably, the glucose injection solution further contains dilute hydrochloric acid, and the dilute hydrochloric acid can adjust the pH value of the glucose injection solution to 3.2-6.8.

[0018] On the basis of the above technical solution, preferably, the concentration of the dilute hydrochloric acid is 0.01-1 mol / L.

[0019] According to another aspect of the present invention, the present invention provides a method for preparing the above-mentioned compound amino acid (15-HBC) and glucose injection, the preparation method comprising:

[0020] The amino acid injection and the glucose injection are prepared in different liquid preparation tanks respectively, and then filled into the two chambers of the double-chamber bag respectively.

[0021] On the basis of the above technical solution, preferably, the preparation method of the amino acid injection comprises:

[0022] Under a nitrogen atmosphere, the temperature of water is controlled to temperature 1, leucine, isoleucine, valine, phenylalanine, threonine and methionine are added, stirred for 1, cooled to temperature 2, lysine acetate, glycine, proline, alanine, serine, histidine, arginine and tryptophan are added, stirred for 2, glacial acetic acid is added to adjust the pH value to 5.5-6.5, stirred for 3, cysteine ​​hydrochloride and an antioxidant are added, water is added to make up the volume, and an amino acid injection is obtained.

[0023] On the basis of the above technical solution, preferably, the temperature of temperature 1 is 70-80°C, and the temperature of temperature 2 is 40-50°C.

[0024] On the basis of the above technical solution, preferably, the rotation speeds of stirring 1, stirring 2 and stirring 3 are independently selected from 50 to 400 rpm.

[0025] On the basis of the above technical scheme, preferably, the preparation method of the glucose injection comprises: under a nitrogen atmosphere, dissolving glucose in water, adding dilute hydrochloric acid to adjust the pH value to 3.2-6.8, adding water to make up the volume, and obtaining the glucose injection.

[0026] As an optional implementation mode, the present invention is implemented by the following technical solution:

[0027] A compound amino acid and glucose injection, the injection is packaged in a double-chamber bag, the two chambers of the bag are respectively and independently filled with the compound amino acid injection and the glucose injection, the chambers are separated by a diaphragm or a spacer, wherein the main component of the glucose injection is 45-55g of glucose per 1000ml, and the main component of the compound amino acid injection is the following components per 1000ml:

[0028] Leucine 12.402g ~ 15.158g, isoleucine 6.894g ~ 8.426g, valine 7.974g ~ 9.746g, phenylalanine 2.88g ~ 3.52g, threonine 1.8g ~ 2.2g, methionine 2.25g ~ 2.75g, lysine acetate 5.22g ~ 6.38g, glycine 2.97g ~ 3.63g, proline 5.67g ~ 6.93g, alanine 3.6g ~ 4.4g, serine 2.97g ~ 3.63g, histidine 1.44g ~ 1.76g, arginine 5.22g ~ 6.38g, tryptophan 0.81g ~ 0.99g, cysteine ​​hydrochloride 0.18g ~ 0.22g, and the rest is water.

[0029] The glucose injection contains dilute hydrochloric acid which can adjust the pH value of the injection to 3.2-6.8, and the compound amino acid injection contains glacial acetic acid which can adjust the pH value of the injection to 5.5-6.5.

[0030] The preparation method of the double-chamber packaged amino acid and glucose injection is as follows:

[0031] Step 1: Bag making;

[0032] Take the non-PVC three-layer co-extruded film for the inner bag, press it into shape on a bag-making hot press and connect it with a three-layer co-extruded infusion tube, a drug adding plug and a drug infusion plug.

[0033] Step 2: Prepare liquid;

[0034] a. Preparation of compound amino acid injection;

[0035] Prepare the following raw materials:

[0036] Leucine 12.402g~15.158g, isoleucine 6.894g~8.426g, valine 7.974g~9.746g, phenylalanine 2.88g~3.52g, threonine 1.8g~2.2g, methionine 2.25g~2.75g, lysine acetate 5.22g~6.38g, glycine 2.97g~3.63g, proline 5.67g~6.93g, alanine 3.6g~4.4g, serine 2.97g~3.63g, histidine 1.44g~1.76g, arginine 5.22g~6.38g, tryptophan 0.81g~0.99g, cysteine ​​hydrochloride 0.18g~0.22g;

[0037] Take about 80% of the prescribed amount of water for injection into the liquid preparation tank, continue to fill with nitrogen, and start stirring. Control the water temperature at 70-80°C, add leucine, isoleucine, valine, phenylalanine, threonine and methionine, and stir to dissolve them all. Cool down to 40-50°C, add lysine acetate, glycine, proline, alanine, serine, histidine, arginine and tryptophan, and stir to dissolve them all. Slowly add glacial acetic acid to adjust the pH value of the solution to 5.5-6.5, stir and mix, then add the prescribed amount of cysteine ​​hydrochloride and antioxidant, stir until dissolved, and add water for injection to make up to volume.

[0038] b. Preparation of glucose injection;

[0039] Take about 80% of the injection water of the prescription into the liquid preparation tank, continue to fill with nitrogen, and start stirring. Add glucose to the injection water to dissolve, and prepare a glucose injection solution containing 45-55g of glucose per 1000ml of solution, add dilute hydrochloric acid to adjust the pH value of the solution to 3.2-6.8, stir and mix, and then add injection water to make up to volume.

[0040] Step 3: Filling, sealing and outer bagging

[0041] The prepared compound amino acid injection and glucose injection are connected to a filling machine with two pipelines and a filling unit through a liquid medicine filter. The filling machine is equipped with a vacuum pumping-nitrogen filling system, a liquid medicine metering system, and a heating and sealing system, which respectively complete the functions of vacuum pumping-nitrogen filling of the inner bag, liquid medicine mass calculation and filling quantity control, inner bag sealing, etc. The filling volume of each liquid medicine is adjusted according to the needs, and the pre-made inner bag is loaded on the filling machine, filled and sealed. The filling process is carried out under nitrogen protection;

[0042] The filled inner bag is placed into a high-barrier outer bag, a deoxidizer is added between the inner and outer bags, and the oxygen between the inner and outer bags is removed and heat-sealed using a heat sealing machine with the function of vacuuming and nitrogen filling the outer bag.

[0043] Step 4: Sterilization

[0044] The sterilization equipment is a water bath sterilizer. The packaged products are laid flat on the shelves of the sterilizer. The circulating water for sterilization is pressurized and heated to a high temperature and sprayed onto the products. Finally, the products are kept at a high temperature for 8 to 15 minutes to completely kill the microorganisms in the products and achieve the sterilization effect.

[0045] This double-chamber bag packaging product uses two chambers separated by a diaphragm to respectively load the compound amino acid injection and glucose injection. When in use, just squeeze the virtual welding rods in each chamber to mix the two injections and then inject them into the human body intravenously. The volume of the liquid medicine in the two chambers can be of various specifications to meet the metabolic needs of different patients.

[0046] The packaging bag used in the product of the present invention is divided into an inner bag and an outer bag. The inner bag is composed of a non-PVC three-layer co-extruded film and is used to fill the liquid medicine. The inner bag is separated by hot pressing to form two chambers, which can withstand long-term contact with amino acids and glucose solutions without chemical reactions, and no substances are dissolved in the above solutions. The two liquid medicines are respectively loaded into the two chambers. The inner bag filled with liquid medicine and sealed is loaded into a high-barrier outer bag as a whole. The outer bag has an excellent physical barrier effect on oxygen, carbon dioxide and other gases, which can prevent the penetration of these gases and ensure the stability of the product during sterilization and storage. Putting a deoxidizer between the inner bag and the outer bag can better reduce the residual oxygen content of the inner and outer bags, and effectively inhibit or alleviate the degradation of unstable amino acids. Both the inner bag and the outer bag can withstand high-temperature sterilization at 121°C. The packaged products are sterilized in a 121°C water bath sterilizer to completely kill microorganisms. The inner bag can be opened when subjected to a certain size of tension perpendicular to the seal, so that the contents can be mixed with each other. The mixture ensures that the probability of contaminating microorganisms is less than one in a million.

[0047] Since the reaction between the raw materials glucose and cysteine ​​of the compound amino acid (15HBC-SF) / glucose (5%) injection is mainly the Maillard reaction, which is a non-enzymatic reaction involving glycosylation and oxidation processes, usually occurring between reducing sugars and amino acids, which is a common biochemical reaction. In injections, this reaction may lead to drug degradation, affecting its efficacy and safety. Therefore, the present invention provides a method for solving the biochemical reaction of reducing sugars and amino acids by adding an antioxidant to the amino acid injection.

[0048] Ascorbic acid (vitamin C) is a water-soluble vitamin. In the reaction of glucose and cysteine, the generation of free radicals may promote the reaction. By eliminating these free radicals, ascorbic acid can slow down or even inhibit the progress of the reaction. Ascorbic acid can reduce oxidized cysteine ​​back to its active form. Glucose may cause cysteine ​​oxidation in the reaction, and the reducing ability of ascorbic acid can reverse this process, thereby protecting the activity of cysteine ​​and reducing its reaction with glucose. There may be a competitive relationship between ascorbic acid and glucose and cysteine. Since the structure of ascorbic acid is similar to that of glucose, it may compete with glucose at the active sites of certain enzymes, thereby reducing the reaction rate between glucose and cysteine. In injections, ascorbic acid helps maintain the stability of the drug by slowing down oxidation and degradation reactions and preventing the degradation of drug ingredients.

[0049] Acetylcysteine ​​(NAC) is a sulfur-containing amino acid derivative that inhibits the Maillard reaction through the following mechanisms: 1. The role of the thiol group: The thiol group (-SH) in acetylcysteine ​​can react with the carbonyl group (C=O) of the reducing sugar in the Maillard reaction. This process leads to the inactivation of the carbonyl group, which in turn prevents the reaction with the amino acid, thereby inhibiting the initial reaction. 2. Formation of colorless reaction products: Under the action of acetylcysteine, some intermediates generated by the Maillard reaction may be converted into colorless reaction products, which not only reduces the formation of pigments, but also may reduce the production of potentially harmful substances. 3. Antioxidant effect: Acetylcysteine ​​can scavenge free radicals generated during the reaction and reduce oxidative stress, thereby reducing the incidence of the Maillard reaction.

[0050] The compound amino acid (15-HBC) and glucose injection of the present invention has the following advantages over the prior art:

[0051] Beneficial effects:

[0052] (1) The amino acid infusion and glucose infusion provided by the present invention are used simultaneously, which can meet the patient's needs for protein and sugar, is scientific and reasonable for clinical use, and has stable compatibility and is easy to use.

[0053] (2) The double-chamber bag packaging provided by the present invention can completely avoid the risk of product microbial and particulate contamination caused by traditional mixing operations, and can perform mixing operations under any environmental conditions, so that small and medium-sized hospitals that do not have aseptic preparation conditions can also conveniently use parenteral nutrition that conforms to the characteristics of human nutritional metabolism, which can bring huge benefits to patients and greatly reduce the serious adverse reactions such as infusion pyrogen reactions, blood infections, sepsis, etc. caused by traditional mixing operations that are prone to microbial contamination.

[0054] (3) The double-chamber bag provided by the present invention is an industrially produced sealing system that can be completely closed without damaging the product, and can mix the products packaged independently in the two chambers during clinical use. The two chambers can be filled with different types and amounts of amino acids and glucose infusions according to the clinical needs of the patient to meet different clinical needs.

[0055] (4) The non-PVC packaging material provided by the present invention is stable, non-toxic, has low water permeability, air permeability and migration, and is suitable for most liquid medicine packaging. The soft bag is co-extruded with multi-layer films, does not use adhesives, does not need to be cleaned, and the soft bag is formed in a Class 100 environment, without heat sources and particles. Its infusion method adopts non-air-intake packaging to ensure the safety of medication.

[0056] (5) The present invention provides a preparation process for amino acid injection and glucose injection packaged in double-chamber bags made of non-PVC three-layer co-extruded infusion bags. Compared with the traditional preparation process, the composition prepared by this preparation process has good safety, stability and material compatibility.

[0057] (6) The amino acid injection provided by the present invention solves the biochemical reaction between glucose and cysteine ​​by adding an antioxidant. DETAILED DESCRIPTION

[0058] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0059] The reagents and raw materials used in the present invention are commercially available.

[0060] Example 1

[0061] Step 1: Bag making;

[0062] Take the non-PVC three-layer co-extruded film for the inner bag, press it into shape on a bag-making hot press and connect it with a three-layer co-extruded infusion tube, a drug adding plug and a drug infusion plug.

[0063] Step 2: Prepare liquid;

[0064] a. Preparation of compound amino acid injection;

[0065] Prepare the following raw materials:

[0066] For each preparation of 1000 mL of the amino acid injection, the amount of each raw material is:

[0067] Leucine 12.402g, isoleucine 6.894g, valine 7.974g, phenylalanine 2.88g, threonine 1.8g, methionine 2.25g, lysine acetate 5.22g, glycine 2.97g, proline 5.67g, alanine 3.6g, serine 2.97g, histidine 1.44g, arginine 5.22g, tryptophan 0.81g, cysteine ​​hydrochloride 0.18g, ascorbic acid antioxidant 0.2g, the rest is water;

[0068] Take about 80% of the prescribed amount of water for injection into a liquid preparation tank, continue to charge with nitrogen, start stirring, control the water temperature at 70°C, add leucine, isoleucine, valine, phenylalanine, threonine and methionine, and stir at 50rpm to dissolve all of them; cool to 40°C, add lysine acetate, glycine, proline, alanine, serine, histidine, arginine and tryptophan, and stir at 50rpm to dissolve all of them, slowly add glacial acetic acid to adjust the pH value of the solution to 5.5, stir at 50rpm to mix, add the prescribed amount of cysteine ​​hydrochloride and ascorbic acid antioxidant, stir to dissolve, and add water for injection to make up to volume.

[0069] b. Preparation of glucose injection;

[0070] Take about 80% of the injection water of the prescription into the liquid preparation tank, continue to fill with nitrogen, and start stirring. Add glucose to the injection water to dissolve it, and prepare a glucose injection solution containing 45g of glucose per 1000ml of solution. Add dilute hydrochloric acid to adjust the pH value of the solution to 3.2, stir and mix, and then add injection water to make up to volume.

[0071] Step 3: Filling, sealing and outer bagging

[0072] The prepared compound amino acid injection and glucose injection are connected to a filling machine with two pipelines and a filling unit through a liquid medicine filter. The filling machine is equipped with a vacuum pumping-nitrogen filling system, a liquid medicine metering system, and a heating and sealing system, which respectively complete the functions of vacuum pumping-nitrogen filling of the inner bag, liquid medicine mass calculation and filling quantity control, inner bag sealing, etc. The filling volume of each liquid medicine is adjusted according to the needs, and the pre-made inner bag is loaded on the filling machine, filled and sealed. The filling process is carried out under nitrogen protection;

[0073] The filled inner bag is placed into a high-barrier outer bag, a deoxidizer is added between the inner and outer bags, and the oxygen between the inner and outer bags is removed and heat-sealed using a heat sealing machine with the function of vacuuming and nitrogen filling the outer bag.

[0074] Step 4: Sterilization

[0075] The sterilization equipment is a water bath sterilizer. The packaged products are laid flat on the shelves of the sterilizer. The circulating water for sterilization is pressurized and heated to a high temperature and sprayed onto the products. Finally, the products are kept at a high temperature for 8 minutes to completely kill the microorganisms in the products and achieve the sterilization effect.

[0076] Example 2

[0077] Step 1: Bag making;

[0078] Take the non-PVC three-layer co-extruded film for the inner bag, press it into shape on a bag-making hot press and connect it with a three-layer co-extruded infusion tube, a drug adding plug and a drug infusion plug.

[0079] Step 2: Prepare liquid;

[0080] a. Preparation of compound amino acid injection;

[0081] Prepare the following raw materials:

[0082] For each preparation of 1000 mL of the amino acid injection, the amount of each raw material is:

[0083] Leucine 14.402g, isoleucine 7.894g, valine 8.974g, phenylalanine 3.08g, threonine 2.0g, methionine 2.45g, lysine acetate 5.82g, glycine 3.33g, proline 6.67g, alanine 4.0g, serine 3.27g, histidine 1.54g, arginine 5.82g, tryptophan 0.89g, cysteine ​​hydrochloride 0.20g, ascorbic acid antioxidant 0.5g, the rest is water;

[0084] Take about 80% of the prescribed amount of water for injection into the liquid preparation tank, continue to charge with nitrogen, start stirring, control the water temperature at 75°C, add leucine, isoleucine, valine, phenylalanine, threonine and methionine, stir at 300rpm to dissolve all; cool to 45°C, add lysine acetate, glycine, proline, alanine, serine, histidine, arginine and tryptophan, stir at 300rpm to dissolve all. Slowly add glacial acetic acid to adjust the pH value of the liquid to 6.2, stir at 300rpm to mix, add the prescribed amount of cysteine ​​hydrochloride and ascorbic acid antioxidant, stir to dissolve, and add water for injection to volume.

[0085] b. Preparation of glucose injection;

[0086] Take about 80% of the injection water of the prescription into the liquid preparation tank, continue to fill with nitrogen, and start stirring. Add glucose to the injection water to dissolve it, and prepare a glucose injection solution containing 50g of glucose per 1000ml of solution. Add dilute hydrochloric acid to adjust the pH value of the solution to 5, stir and mix, and then add injection water to make up to volume.

[0087] Step 3: Filling, sealing and outer bagging

[0088] The prepared compound amino acid injection and glucose injection are connected to a filling machine with two pipelines and a filling unit through a liquid medicine filter. The filling machine is equipped with a vacuum pumping-nitrogen filling system, a liquid medicine metering system, and a heating and sealing system, which respectively complete the functions of vacuum pumping-nitrogen filling of the inner bag, liquid medicine mass calculation and filling quantity control, inner bag sealing, etc. The filling volume of each liquid medicine is adjusted according to the needs, and the pre-made inner bag is loaded on the filling machine, filled and sealed. The filling process is carried out under nitrogen protection;

[0089] The filled inner bag is placed into a high-barrier outer bag, a deoxidizer is added between the inner and outer bags, and the oxygen between the inner and outer bags is removed and heat-sealed using a heat sealing machine with the function of vacuuming and nitrogen filling the outer bag.

[0090] Step 4: Sterilization

[0091] The sterilization equipment is a water bath sterilizer. The packaged products are laid flat on the shelves of the sterilizer. The circulating water for sterilization is pressurized and heated to a high temperature and sprayed onto the products. Finally, the products are kept at a high temperature for 12 minutes to completely kill the microorganisms in the products and achieve the sterilization effect.

[0092] Example 3

[0093] Step 1: Bag making;

[0094] Take the non-PVC three-layer co-extruded film for the inner bag, press it into shape on a bag-making hot press and connect it with a three-layer co-extruded infusion tube, a drug adding plug and a drug infusion plug.

[0095] Step 2: Prepare liquid;

[0096] a. Preparation of compound amino acid injection;

[0097] Prepare the following raw materials:

[0098] For each preparation of 1000 mL of the amino acid injection, the amount of each raw material is:

[0099] Leucine 15.158g, isoleucine 8.426g, valine 9.746g, phenylalanine 3.52g, threonine 2.2g, methionine 2.75g, lysine acetate 6.38g, glycine 3.63g, proline 6.93g, alanine 4.4g, serine 3.63g, histidine 1.76g, arginine 6.38g, tryptophan 0.99g, cysteine ​​hydrochloride 0.22g, ascorbic acid antioxidant 10g, the rest is water;

[0100] Take about 80% of the prescribed amount of water for injection into the liquid preparation tank, continue to fill with nitrogen, and start stirring. Control the water temperature at 80°C, add leucine, isoleucine, valine, phenylalanine, threonine and methionine, and stir at 400rpm to dissolve them all; cool to 50°C, add lysine acetate, glycine, proline, alanine, serine, histidine, arginine and tryptophan, and stir at 400rpm to dissolve them all, slowly add glacial acetic acid to adjust the pH value of the liquid to 6.5, stir at 400rpm to mix, add the prescribed amount of cysteine ​​hydrochloride and ascorbic acid antioxidant, stir to dissolve, and add water for injection to volume.

[0101] b. Preparation of glucose injection;

[0102] Take about 80% of the injection water of the prescription into the liquid preparation tank, continue to fill with nitrogen, and start stirring. Add glucose to the injection water to dissolve, and prepare a glucose injection solution containing 55g of glucose per 1000ml of solution. Add dilute hydrochloric acid to adjust the pH value of the solution to 6.8, stir and mix, and then add injection water to make up to volume.

[0103] Step 3: Filling, sealing and outer bagging

[0104] The prepared compound amino acid injection and glucose injection are connected to a filling machine with two pipelines and a filling unit through a liquid medicine filter. The filling machine is equipped with a vacuum pumping-nitrogen filling system, a liquid medicine metering system, and a heating and sealing system, which respectively complete the functions of vacuum pumping-nitrogen filling of the inner bag, liquid medicine mass calculation and filling quantity control, inner bag sealing, etc. The filling volume of each liquid medicine is adjusted according to the needs, and the pre-made inner bag is loaded on the filling machine, filled and sealed. The filling process is carried out under nitrogen protection;

[0105] The filled inner bag is placed into a high-barrier outer bag, a deoxidizer is added between the inner and outer bags, and the oxygen between the inner and outer bags is removed and heat-sealed using a heat sealing machine with the function of vacuuming and nitrogen filling the outer bag.

[0106] Step 4: Sterilization

[0107] The sterilization equipment is a water bath sterilizer. The packaged products are laid flat on the shelves of the sterilizer. The circulating water for sterilization is pressurized and heated to a high temperature and sprayed onto the products. Finally, the products are kept at a high temperature for 15 minutes to completely kill the microorganisms in the products and achieve the sterilization effect.

[0108] Example 4

[0109] Step 1: Bag making;

[0110] Take the non-PVC three-layer co-extruded film for the inner bag, press it into shape on a bag-making hot press and connect it with a three-layer co-extruded infusion tube, a drug adding plug and a drug infusion plug.

[0111] Step 2: Prepare liquid;

[0112] a. Preparation of compound amino acid injection;

[0113] Prepare the following raw materials:

[0114] For each preparation of 1000 mL of the amino acid injection, the amount of each raw material is:

[0115] Leucine 12.402g, isoleucine 6.894g, valine 7.974g, phenylalanine 2.88g, threonine 1.8g, methionine 2.25g, lysine acetate 5.22g, glycine 2.97g, proline 5.67g, alanine 3.6g, serine 2.97g, histidine 1.44g, arginine 5.22g, tryptophan 0.81g, cysteine ​​hydrochloride 0.18g, acetylcysteine ​​antioxidant 0.5g, the rest is water;

[0116] Take about 80% of the prescribed amount of water for injection into a liquid preparation tank, continue to charge with nitrogen, start stirring, control the water temperature at 70°C, add leucine, isoleucine, valine, phenylalanine, threonine and methionine, and stir at 400rpm to dissolve all of them; cool to 40°C, add lysine acetate, glycine, proline, alanine, serine, histidine, arginine and tryptophan, and stir at 400rpm to dissolve all of them, slowly add glacial acetic acid to adjust the pH value of the solution to 5.5, stir at 400rpm to mix, add the prescribed amount of cysteine ​​hydrochloride and ascorbic acid antioxidant, stir to dissolve, and add water for injection to make up to volume.

[0117] b. Preparation of glucose injection;

[0118] Take about 80% of the injection water of the prescription into the liquid preparation tank, continue to fill with nitrogen, and start stirring. Add glucose to the injection water to dissolve it, and prepare a glucose injection solution containing 45g of glucose per 1000ml of solution. Add dilute hydrochloric acid to adjust the pH value of the solution to 3.2, stir and mix, and then add injection water to make up to volume.

[0119] Step 3: Filling, sealing and outer bagging

[0120] The prepared compound amino acid injection and glucose injection are connected to a filling machine with two pipelines and a filling unit through a liquid medicine filter. The filling machine is equipped with a vacuum pumping-nitrogen filling system, a liquid medicine metering system, and a heating and sealing system, which respectively complete the functions of vacuum pumping-nitrogen filling of the inner bag, liquid medicine mass calculation and filling quantity control, inner bag sealing, etc. The filling volume of each liquid medicine is adjusted according to the needs, and the pre-made inner bag is loaded on the filling machine, filled and sealed. The filling process is carried out under nitrogen protection;

[0121] The filled inner bag is placed into a high-barrier outer bag, a deoxidizer is added between the inner and outer bags, and the oxygen between the inner and outer bags is removed and heat-sealed using a heat sealing machine with the function of vacuuming and nitrogen filling the outer bag.

[0122] Step 4: Sterilization

[0123] The sterilization equipment is a water bath sterilizer. The packaged products are laid flat on the shelves of the sterilizer. The circulating water for sterilization is pressurized and heated to a high temperature and sprayed onto the products. Finally, the products are kept at a high temperature for 8 minutes to completely kill the microorganisms in the products and achieve the sterilization effect.

[0124] According to the usage and dosage in the instructions for use of the compound amino acid injection (15-HBC-SF), the amino acid chamber solution and the glucose chamber solution were mixed in equal amounts, and the stability of the combined solution was examined.

[0125] Test Example 1

[0126] The amino acid chamber (without antioxidant (i.e., comparative example 1), with antioxidant-ascorbic acid, and with antioxidant-acetylcysteine) was mixed with the glucose chamber. At different clinical infusion times, samples were taken to detect key quality indicators such as properties, pH value, transmittance, related substances (sulfocysteine, 5-hydroxymethylfurfural), content (cysteine ​​hydrochloride, glucose) of the mixed drug solution. The stability of the drug solution was evaluated by comparing the change trend. The specific experimental conditions are shown in Table 1, and the experimental results are shown in Table 2.

[0127] In Table 1, in Test Group 1 (Comparative Example 1), no antioxidant was added to the amino acid injection, and the remaining preparation steps were consistent with those in Example 1; Test Group 2 was Example 1, and Test Group 3 was Example 4.

[0128] Table 1 Raw material usage of the experimental group

[0129]

[0130] Table 2 Test group test results

[0131]

[0132]

[0133] The results in Table 2 show that the properties, pH value, visible foreign matter, glucose content, and amino acid content (except cysteine ​​hydrochloride) of the drug solutions of test group 1, test group 2, and test group 3 are basically the same, and there is no significant difference between the results of 24 hours and 48 hours of compatibility and 0 hours; in test group 1 without antioxidant, the impurity content of sulfocysteine ​​gradually increases with the extension of compatibility time, and in test group 2 and test group 3 with antioxidant, the results of 24 hours and 48 hours of compatibility are basically unchanged compared with 0 hours; the content of cysteine ​​hydrochloride in test group 1 without antioxidant decreases from 94.2% to 82.3% with the extension of compatibility time, which is a decrease of 11.9%, and in test group 2 and test group 3 with antioxidant, the results of 24 hours and 48 hours of compatibility are no significant difference compared with 0 hours. This shows that the addition of antioxidants slows down the reaction rate between glucose and cysteine, prevents the degradation of cysteine, and maintains the stability of the drug solution.

[0134] Comparative Example 2

[0135] In the step 2, the amount of ascorbic acid antioxidant 0.2g is replaced by 0.1g, and the rest of the preparation method is consistent with that in Example 1. The specific experimental results are shown in Table 3 and Test Group 3 in Table 4.

[0136] Table 3 Raw material usage of the experimental group

[0137]

[0138]

[0139] Table 4 Test group results

[0140]

[0141] The results in Table 4 show that the properties, pH value, visible foreign matter, glucose content, and amino acid content (except cysteine ​​hydrochloride) of the drug solutions in test groups 1, 2, and 3 are basically the same. There is no significant difference between the results after 24 hours and 48 hours of compatibility and those after 0 hours. In test group 1 without antioxidants, the impurity content of insoluble particles, sulfocysteine, and 5-hydroxymethylfurfural gradually increases with the extension of compatibility time. In test groups 2 and 3 with antioxidants, the results after 24 hours and 48 hours of compatibility are compared with those after 0 hours. With the increase of antioxidant dosage, the impurity content decreased significantly; in the test group 1 without antioxidant, the content of cysteine ​​hydrochloride decreased from 94.2% to 82.3% with the extension of compatibility time, a decrease of 11.9%; in the test group 2 with antioxidant, the content decreased from 94.0% to 92.0% after 24 hours and 48 hours compared with 0 hours, a decrease of 2%; in the test group 3 with antioxidant, the content decreased from 93.6% to 85.0% after 24 hours and 48 hours compared with 0 hours, a decrease of 8.6%. It shows that the addition of antioxidants slows down the reaction rate between glucose and cysteine ​​to a certain extent, and with the increase of antioxidant dosage, the effect of slowing down the reaction rate gradually increases, and the inhibitory effect on cysteine ​​degradation is also significantly enhanced.

[0142] Comparative Example 3

[0143] In the step 2, the amount of ascorbic acid antioxidant 10g is replaced by 15g, and the rest of the preparation method is consistent with that in Example 1. The specific experimental results are shown in Table 5 and Test Group 3 in Table 6.

[0144] Table 5 Raw material usage of the experimental group

[0145]

[0146] Table 6 Test group results

[0147]

[0148]

[0149] The research results in Table 6 show that the properties, pH value, visible foreign matter, glucose content, and amino acid content (except cysteine ​​hydrochloride) of the drug solutions of test group 1, test group 2, and test group 3 are basically the same, and there is no significant difference between the results of 24 hours and 48 hours of compatibility and those of 0 hours; in test group 1 without adding antioxidants, the impurity content of insoluble particles, sulfocysteine, and 5-hydroxymethylfurfural gradually increased with the extension of the compatibility time, and in test group 2 and test group 3 with antioxidants, the results of 24 hours and 48 hours of compatibility were basically unchanged compared with those of 0 hours; the content of cysteine ​​hydrochloride in test group 1 without adding antioxidants decreased from 94.2% to 82.3% with the extension of the compatibility time, a decrease of 11.9%, and there is no significant difference between the results of 24 hours and 48 hours of compatibility and those of 0 hours in test groups 2 and test groups 3 with antioxidants. This indicates that when the amount of antioxidant added reaches 1.0%, further increasing the amount of antioxidant has no obvious effect on inhibiting the reaction rate between glucose and cysteine, and the effect of inhibiting the degradation reaction of cysteine ​​is also not obvious.

[0150] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A compound amino acid and glucose injection, characterized in that: The compound amino acid and glucose injection is packaged in a double-chamber bag, including amino acid injection and glucose injection; The amino acid injection comprises leucine, isoleucine, valine, phenylalanine, threonine, methionine, lysine acetate, glycine, proline, alanine, serine, histidine, arginine, tryptophan, cysteine ​​hydrochloride and water; The amino acid injection further comprises an antioxidant, wherein the antioxidant is selected from ascorbic acid and / or acetylcysteine; The glucose injection contains glucose and water.

2. The compound amino acid and glucose injection according to claim 1, characterized in that: The percentage of the antioxidant to the amino acid injection is 0.02% to 1.0%.

3. The compound amino acid and glucose injection according to claim 1, characterized in that: For each preparation of 1000 mL of the amino acid injection, the amount of each raw material is: Leucine 12.402g~15.158g, isoleucine 6.894g~8.426g, valine 7.974g~9.746g, phenylalanine 2.88g~3.52g, threonine 1.8g~2.2g, methionine 2.25g~2.75g, lysine acetate 5.22g~6.38g, glycine 2.97g~3.63g, proline 5.67g~6.93g, alanine 3.6g~4.4g, serine 2.97g~3.63g, histidine 1.44g~1.76g, arginine 5.22g~6.38g, tryptophan 0.81g~0.99g, cysteine ​​hydrochloride 0.18g~0.22g, and the rest is water; The amino acid injection also contains glacial acetic acid, which adjusts the pH value of the amino acid injection to 5.5-6.

5.

4. The compound amino acid and glucose injection according to claim 1, characterized in that: Each 1000 mL of the glucose injection contains 45 to 55 g of glucose.

5. The compound amino acid and glucose injection according to claim 1, characterized in that: The glucose injection solution also contains dilute hydrochloric acid, and the dilute hydrochloric acid adjusts the pH value of the glucose injection solution to 3.2-6.8; The concentration of the dilute hydrochloric acid is 0.01-1 mol / L.

6. The method for preparing the compound amino acid and glucose injection according to any one of claims 1 to 5, characterized in that: The preparation method comprises: The amino acid injection and the glucose injection are prepared in different liquid preparation tanks respectively, and then filled into the two chambers of the double-chamber bag respectively.

7. The preparation method according to claim 6, characterized in that: The preparation method of the amino acid injection comprises: Under a nitrogen atmosphere, the temperature of water is controlled to temperature 1, leucine, isoleucine, valine, phenylalanine, threonine and methionine are added, stirred for 1, cooled to temperature 2, lysine acetate, glycine, proline, alanine, serine, histidine, arginine and tryptophan are added, stirred for 2, glacial acetic acid is added to adjust the pH value to 5.5-6.5, stirred for 3, cysteine ​​hydrochloride and an antioxidant are added, water is added to make up the volume, and an amino acid injection is obtained.

8. The preparation method according to claim 7, characterized in that: The temperature of the temperature 1 is 70-80°C, and the temperature of the temperature 2 is 40-50°C.

9. The preparation method according to claim 7, characterized in that: The rotation speeds of stirring 1, stirring 2 and stirring 3 are independently selected from 50 to 400 rpm.

10. The preparation method according to claim 6, characterized in that: The preparation method of the glucose injection comprises: dissolving glucose in water under a nitrogen atmosphere, adding dilute hydrochloric acid to adjust the pH value to 3.2-6.8, and adding water to make up the volume to obtain the glucose injection.

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