CN117899010A - Preparation method of epinephrine hydrochloride injection and injection - Google Patents
Preparation method of epinephrine hydrochloride injection and injection Download PDFInfo
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- CN117899010A CN117899010A CN202311691529.8A CN202311691529A CN117899010A CN 117899010 A CN117899010 A CN 117899010A CN 202311691529 A CN202311691529 A CN 202311691529A CN 117899010 A CN117899010 A CN 117899010A
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- Prior art keywords
- epinephrine hydrochloride
- injection
- filling
- preparation
- liquid medicine
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- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 title claims abstract description 131
- 229960003072 epinephrine hydrochloride Drugs 0.000 title claims abstract description 129
- 238000002347 injection Methods 0.000 title claims abstract description 96
- 239000007924 injection Substances 0.000 title claims abstract description 96
- 238000002360 preparation method Methods 0.000 title claims abstract description 82
- 239000007788 liquid Substances 0.000 claims abstract description 141
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 120
- 238000011049 filling Methods 0.000 claims abstract description 116
- 239000003814 drug Substances 0.000 claims abstract description 94
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000008215 water for injection Substances 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 230000001954 sterilising effect Effects 0.000 claims abstract description 5
- 238000007789 sealing Methods 0.000 claims description 35
- 238000003780 insertion Methods 0.000 claims description 16
- 230000037431 insertion Effects 0.000 claims description 16
- 229940071643 prefilled syringe Drugs 0.000 claims description 13
- 239000012528 membrane Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 238000005538 encapsulation Methods 0.000 claims description 4
- 238000010926 purge Methods 0.000 claims description 4
- 229930182837 (R)-adrenaline Natural products 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 2
- 241000289690 Xenarthra Species 0.000 claims description 2
- 229960005139 epinephrine Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- 239000008155 medical solution Substances 0.000 claims 3
- 239000011148 porous material Substances 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 31
- 239000001301 oxygen Substances 0.000 description 31
- 229910052760 oxygen Inorganic materials 0.000 description 31
- 239000012535 impurity Substances 0.000 description 25
- 238000011835 investigation Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000005259 measurement Methods 0.000 description 5
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000012864 cross contamination Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B31/00—Packaging articles or materials under special atmospheric or gaseous conditions; Adding propellants to aerosol containers
- B65B31/04—Evacuating, pressurising or gasifying filled containers or wrappers by means of nozzles through which air or other gas, e.g. an inert gas, is withdrawn or supplied
Abstract
The application provides a preparation method of epinephrine hydrochloride injection and an injection, wherein the method comprises the steps of conveying a preset amount of water for injection into a liquid preparation tank; preparing epinephrine hydrochloride liquid medicine; and the steps of secondary conveying water for injection, introducing nitrogen and the like to prepare liquid, and combining with the steps of filtering, filling, sterilizing and the like. By strictly controlling each working procedure of the preparation process, the stability of the epinephrine hydrochloride pre-filled injection product is improved, and the product quality of the medicament injection product is ensured.
Description
Technical Field
The application relates to the field of pharmaceutical preparations, in particular to a preparation method of epinephrine hydrochloride injection and the injection.
Background
The pre-filling and sealing injection of the epinephrine hydrochloride is characterized in that the epinephrine hydrochloride is directly filled in the pre-filling and sealing injector, and can be directly injected when in use, thereby having the advantages of convenient and quick use, accurate dosage, no cross contamination or secondary pollution, and the like.
In the prior art, the epinephrine hydrochloride liquid medicine is stored in a pre-canned injector in a sealing way, the pre-canned injector has good sealing performance, but the existing epinephrine hydrochloride injection preparation method is difficult to ensure the liquid medicine stability of the epinephrine hydrochloride liquid medicine in the long-term storage process of the pre-canned injector, and the product quality of a medicament injection product is easily influenced by the fact that the impurity level of the liquid medicine with higher level is higher.
Disclosure of Invention
The embodiment of the application provides a preparation method of an epinephrine hydrochloride injection and the injection, which are used for solving the technical problem that the epinephrine hydrochloride pre-filled injection is easy to oxidize in the related technology.
In a first aspect, the invention provides a preparation method of an epinephrine hydrochloride pre-filled injection, comprising the following steps:
Vacuumizing the prefilled syringe;
filling epinephrine hydrochloride liquid medicine into the pre-filling injector after the vacuumization treatment through a plug plunger, wherein the filling speed is less than or equal to 50 bottles/min, and the insertion depth of the plunger filled with epinephrine hydrochloride liquid medicine is 16-20 mm;
And (3) filling nitrogen into the pre-filling and sealing syringe filled with the epinephrine hydrochloride liquid medicine to prepare the epinephrine hydrochloride pre-filling and sealing injection product.
Preferably, the pre-filled and sealed injector is vacuumized; before the step, the method further comprises the following steps:
the nitrogen is used for purging a liquid inlet pipeline, the liquid inlet pipeline is used for conveying water for injection into a liquid preparation tank, and the liquid preparation tank is used for preparing epinephrine hydrochloride injection;
Delivering a predetermined amount of water for injection into the dosing tank;
preparing epinephrine hydrochloride liquid medicine into a liquid preparation tank;
Delivering a predetermined preparation amount of the residual injection water to the preparation tank;
And (3) introducing nitrogen into the liquid preparation tank after the secondary injection water delivery to prepare the prepared epinephrine hydrochloride liquid medicine.
Preferably, the water for injection with the prescription amount of 90 percent and the temperature of 20-30 ℃ is delivered into the liquid preparation tank at one time;
preparing epinephrine hydrochloride liquid medicine into a liquid preparation tank;
secondarily delivering 10% of the injection water into the liquid preparation tank;
And (3) introducing nitrogen into the liquid preparation tank after the secondary injection water delivery to prepare the prepared epinephrine hydrochloride liquid medicine.
Preferably, the epinephrine hydrochloride liquid medicine is prepared into the liquid preparation tank; the method specifically comprises the following steps:
sequentially adding sodium metabisulfite, disodium edentate, L-tartaric acid and sodium hydroxide with the prescription amount, and stirring for 5 minutes; adding a proper amount of concentrated hydrochloric acid, and stirring for 2 minutes;
adding epinephrine in the prescribed amount, and stirring for 10 minutes;
Adding sodium chloride with a prescription amount, and stirring for 5 minutes; detecting the pH value, controlling the pH value to be 3.0-4.0, and adjusting the pH value by using hydrochloric acid solution with proper concentration or sodium hydroxide solution with proper concentration if the pH value is not in the specified range.
Preferably, the step of introducing nitrogen into the liquid preparation tank after the secondary injection water delivery to prepare the prepared epinephrine hydrochloride liquid medicine comprises the following steps of:
Introducing nitrogen into the liquid preparation tank after the secondary injection water delivery, wherein the time of introducing the nitrogen is 0-10 min;
Filling the epinephrine hydrochloride liquid medicine into a liquid preparation tank filled with nitrogen to fix the volume, and filtering to reduce the impurity content in the epinephrine hydrochloride liquid medicine, thus preparing the epinephrine hydrochloride liquid medicine with low residual oxygen content after preparation.
Preferably, the step of introducing nitrogen into the liquid preparation tank after the secondary injection water delivery to prepare the prepared epinephrine hydrochloride liquid medicine comprises the following steps of:
Introducing nitrogen into the liquid preparation tank after the secondary injection water delivery, wherein the time of introducing the nitrogen is 3-10 min;
Filling the epinephrine hydrochloride liquid medicine into a liquid preparation tank filled with nitrogen to fix the volume, and filtering to reduce the impurity content in the epinephrine hydrochloride liquid medicine, thus preparing the epinephrine hydrochloride liquid medicine with low residual oxygen content after preparation.
Preferably, the step of introducing nitrogen into the liquid preparation tank after the secondary injection water delivery to prepare the prepared epinephrine hydrochloride liquid medicine comprises the following steps of:
Introducing nitrogen into the liquid preparation tank after the secondary injection water delivery, wherein the time of introducing the nitrogen is 3-5 min;
Filling the epinephrine hydrochloride liquid medicine into a liquid preparation tank filled with nitrogen to fix the volume, and filtering to reduce the impurity content in the epinephrine hydrochloride liquid medicine, thus preparing the epinephrine hydrochloride liquid medicine with low residual oxygen content after preparation.
Preferably, the filtering specifically comprises the following steps:
forming a series loop by the liquid preparation tank and a group of cylindrical microporous filter membranes with the aperture of 0.45um, and circulating the epinephrine hydrochloride liquid medicine with the constant volume in the series loop;
Checking the circulating epinephrine hydrochloride liquid medicine;
Forming three groups of barrel-type microporous filter membranes with the aperture of 0.45um and two groups of barrel-type microporous filter membranes with the aperture of 0.22um into a series connection;
And filtering the qualified epinephrine hydrochloride liquid medicine through three groups of cylindrical microporous filter membranes connected in series until the epinephrine hydrochloride liquid medicine is filled.
Preferably, the filling speed value is less than or equal to 50 bottles/min, and the plunger insertion depth of the filling epinephrine hydrochloride liquid medicine is 16 mm-20 mm.
Preferably, the pre-filling and sealing injector which is vacuumized is filled with epinephrine hydrochloride liquid medicine; in the step, the filling speed value is 40 bottles/min, and the plunger insertion depth range for filling the epinephrine hydrochloride liquid medicine is 18mm.
Preferably, in the step of filling the epinephrine hydrochloride liquid medicine into the pre-filling syringe subjected to the vacuumizing treatment, the temperature range of the liquid medicine filled with the epinephrine hydrochloride liquid medicine is 20-30 ℃.
Preferably, in the step of filling the epinephrine hydrochloride liquid medicine into the pre-filling syringe subjected to the vacuumizing treatment, the liquid medicine temperature range of the epinephrine hydrochloride liquid medicine filling is 28 ℃.
Preferably, in the step of filling nitrogen into the prefilled syringe filled with the epinephrine hydrochloride liquid medicine, the flow rate of the filled nitrogen ranges from 8m/s to 20m/s.
Preferably, after the step of filling nitrogen into the pre-filled syringe filled with the epinephrine hydrochloride liquid medicine to prepare the epinephrine hydrochloride pre-filled injection product, the method further comprises the following steps:
Sterilizing the pre-encapsulated injection product with RFM-1.2 ventilating and drying sterilizer at 121deg.C for 12min, and sterilizing cabinet with steam pressure not less than 0.25Mpa.
Preferably, after the sterilization treatment step, manual light inspection is further included for quality inspection of the epinephrine hydrochloride pre-filled injection product.
In a second aspect, the invention provides an epinephrine hydrochloride injection prepared by the preparation method, which comprises the following components in parts by mass;
The technical scheme provided by the application has the beneficial effects that:
The embodiment of the application provides a preparation method of an epinephrine hydrochloride injection and an injection, wherein the method adopts the modes of vacuumizing a pre-filling injector, filling the epinephrine hydrochloride liquid medicine, filling nitrogen after filling the liquid medicine, and adjusting the insertion depth and the filling speed value of a plunger to reduce the residual oxygen content of the epinephrine hydrochloride injection product, thereby improving the stability of the epinephrine hydrochloride pre-filling injection product and guaranteeing the product quality of the medicament injection product.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present application more apparent, the technical solutions in the embodiments of the present application will be clearly and completely described in the following in conjunction with the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
Example 1
The preparation method of the epinephrine hydrochloride prefilled injection comprises the following steps: the nitrogen is used for purging a liquid inlet pipeline, the liquid inlet pipeline is used for conveying water for injection into a liquid preparation tank, and the liquid preparation tank is used for preparing epinephrine hydrochloride injection;
Delivering a predetermined amount of water for injection into the dosing tank;
Preparing epinephrine hydrochloride liquid medicine into a liquid preparation tank; delivering a predetermined preparation amount of the residual injection water to the preparation tank; preparing the prepared epinephrine hydrochloride liquid medicine.
Vacuumizing the prefilled syringe;
Filling nitrogen into the pre-filling and sealing injector after the vacuumization treatment;
Filling epinephrine hydrochloride liquid medicine into a pre-filling and sealing injector filled with nitrogen, wherein the insertion depth of a filling plunger is 18mm, the liquid medicine temperature is 28 ℃, and the filling speed is 40 bottles/min;
And (3) filling nitrogen into the pre-filling and sealing syringe filled with the epinephrine hydrochloride liquid medicine, wherein the nitrogen flow is 20m/s, and the epinephrine hydrochloride pre-filling and sealing injection product is prepared.
Example 2
The preparation method of the epinephrine hydrochloride prefilled injection is the same as that of example 1.
Filling nitrogen into the prefilled syringe;
Filling epinephrine hydrochloride liquid medicine into a pre-filling and sealing injector filled with nitrogen, wherein the insertion depth of a filling plunger is 18mm, the liquid medicine temperature is 28 ℃, and the filling speed is 40 bottles/min;
And (3) filling nitrogen into the pre-filling and sealing syringe filled with the epinephrine hydrochloride liquid medicine, wherein the nitrogen flow is 20m/s, and the epinephrine hydrochloride pre-filling and sealing injection product is prepared.
Example 3
Preparing an epinephrine hydrochloride prefilled injection; the preparation method is the same as in example 1.
Vacuumizing the prefilled syringe;
Filling epinephrine hydrochloride liquid medicine into the pre-filling injector which is vacuumized, wherein the insertion depth of a filling plunger is 18mm, the liquid medicine temperature is 28 ℃, and the filling speed is 40 bottles/min;
And (3) filling nitrogen into the pre-filling and sealing syringe filled with the epinephrine hydrochloride liquid medicine, wherein the nitrogen flow is 20m/s, and the epinephrine hydrochloride pre-filling and sealing injection product is prepared.
The preparation method comprises the steps of respectively preparing an epinephrine hydrochloride pre-encapsulation injection product by adopting the embodiment 1, the embodiment 2 and the embodiment 3, measuring the residual oxygen content of the epinephrine hydrochloride pre-encapsulation injection product, taking an average value of 12 samples measured by samples in each embodiment, and carrying out stability investigation on the samples, wherein the impurity content results are shown in the table 1:
Table 1 residual oxygen and stability of the injecta preparations of the examples of different filling modes examination of the results of the impurity contents at the same stage during the period
| Sample of | Average value of residual oxygen amount 2 | 3 Months of impurity content (%) |
| Example 1 | 3.5 | 11 |
| Example 2 | 2.6 | 10 |
| Example 3 | 1.7 | 5.0 |
The impurity of the pre-filled and encapsulated injection product of epinephrine hydrochloride is usually required to be controlled below 10%, and as can be seen from table 1, the residual oxygen amount in the pre-filled and encapsulated injector is accurately controlled by adjusting the filling and encapsulation process step, so that the impurity content of the pre-filled and encapsulated injection product after being placed for 3 months can be controlled within 5%, and the product stability is effectively improved. The pre-filling and sealing injector is vacuumized, then the pre-filling and sealing injector which is vacuumized is filled with the epinephrine hydrochloride, and finally the pre-filling and sealing injector filled with the epinephrine hydrochloride liquid is filled with nitrogen to prepare the epinephrine hydrochloride pre-filling and sealing injection product, the impurity content is the lowest after the pre-filling and sealing injection product is placed for 3 months, and the stability of the prepared epinephrine hydrochloride pre-filling and sealing injection product is the best.
Example 4
Preparing an epinephrine hydrochloride prefilled injection; the preparation method is the same as in example 1.
Vacuumizing the prefilled syringe;
Filling epinephrine hydrochloride liquid medicine into the pre-filling injector which is vacuumized, wherein the insertion depth of a filling plunger is 18mm, the liquid medicine temperature is 28 ℃, and the filling speed is 35 bottles/min, 45 bottles/min and 50 bottles/min respectively for three groups of tests;
And (3) filling nitrogen into the pre-filling and sealing syringe filled with the epinephrine hydrochloride liquid medicine, wherein the nitrogen flow is 20m/s, and the epinephrine hydrochloride pre-filling and sealing injection product is prepared.
Three groups of epinephrine hydrochloride pre-filled injection products are prepared by the method, the average value of residual oxygen measurement results of each group of 12 samples are shown in table 2, the samples are subjected to stability investigation, and the impurity content results are shown in table 2:
TABLE 2 residual oxygen content and stability of injection products of examples at different filling speeds examination of results of contemporaneous impurity content during period
| Sample of | Filling speed | Average value of residual oxygen amount | Stability investigation period contemporaneous impurity content (%) |
| Group 1 | 35 Bottle/min | 1.6 | 5.1 |
| Group 2 | 45 Bottle/min | 2.0 | 6.0 |
| Group 3 | 50 Bottle/min | 2.6 | 6.7 |
As can be seen from Table 2, the smaller the filling rate value, the lower the residual oxygen content of the injection product, and the lower the impurity level of the sample acceleration test. When the filling speed is 50 bottles/min, the residual oxygen content of the prepared medicine is relatively high compared with that of the medicine injection product under the conditions of 40 bottles/min and 45 bottles/min, and the condition of liquid medicine leakage is easy to occur. However, when the filling rate is lower than 40 bottles/min, the problem of too low production efficiency is considered, so that the above-mentioned 40 bottles/min filling rate is selected comprehensively to be optimal.
Example 5
Preparing an epinephrine hydrochloride prefilled injection; the preparation method is the same as in example 1.
Vacuumizing the prefilled syringe;
And filling the epinephrine hydrochloride liquid medicine into the pre-filling and sealing injector subjected to vacuumizing treatment, wherein the liquid medicine temperature is 28 ℃, the filling speed is 40 bottles/min, and the filling plunger insertion depths are 16mm, 20mm and 22mm respectively, so as to carry out three groups of tests.
And (3) filling nitrogen into the pre-filling and sealing syringe filled with the epinephrine hydrochloride liquid medicine, wherein the nitrogen flow is 20m/s, and the epinephrine hydrochloride pre-filling and sealing injection product is prepared.
Three groups of epinephrine hydrochloride pre-filled injection products are prepared by the method, the average value of residual oxygen measurement results of each group of 12 samples are shown in table 3, the samples are subjected to stability investigation, and the impurity content results are shown in table 3:
TABLE 3 results of examining residual oxygen content and stability of injection products of examples under different plunger depths
| Sample of | Depth of plunger insertion | Average value of residual oxygen amount | Stability investigation period contemporaneous impurity content (%) |
| Group 4 | 16mm | 2.8 | 8.3 |
| Group 5 | 20mm | 2.0 | 5.6 |
| Group 6 | 22mm | 4.6 | 11.8 |
From table 3, it can be seen that in the process of filling the epinephrine hydrochloride medicine liquid, the plunger insertion depth controls the size of top air bubbles in the injector, the deeper the plunger insertion depth is, the smaller the top air bubbles are, the smaller the residual oxygen amount is, but when the plunger depth exceeds a certain value, the medicine liquid can be extruded and oozed, the residual oxygen amount of the injection product is not controlled accurately, and the product stability is not obviously improved.
Example 6
Preparing an epinephrine hydrochloride prefilled injection; the preparation method is the same as in example 1.
Vacuumizing the prefilled syringe;
And filling the epinephrine hydrochloride liquid medicine into the pre-filling injector subjected to the vacuumizing treatment, wherein the insertion depth of a filling plunger is 18mm, the filling speed is 40 bottles/min, and the liquid medicine temperature is 24 ℃, 26 ℃ and 30 ℃ respectively, and three groups of tests are carried out.
And (3) filling nitrogen into the pre-filling and sealing syringe filled with the epinephrine hydrochloride liquid medicine, wherein the nitrogen flow is 20m/s, and the epinephrine hydrochloride pre-filling and sealing injection product is prepared.
Three groups of epinephrine hydrochloride pre-filled injection products are prepared by the method, the average value of residual oxygen measurement results of each group of 12 samples are shown in table 4, the samples are subjected to stability investigation, and the impurity content results are shown in table 4:
TABLE 4 residual oxygen content and stability of injection products of examples under different filling liquid temperature conditions results of examining impurity content
| Sample of | Filling liquid temperature | Average value of residual oxygen amount | Stability investigation period contemporaneous impurity content (%) |
| Group 7 | 24℃ | 6.2 | 11 |
| Group 8 | 26℃ | 2.6 | 7.8 |
| Group 9 | 30℃ | 2.0 | 6.0 |
As can be seen from Table 4, the residual oxygen content of the injection product filled with the epinephrine hydrochloride liquid medicine at 30 ℃ and 26 ℃ is higher than that of the injection product filled with the epinephrine hydrochloride liquid medicine at 28 ℃, and the residual oxygen content of the injection product is not reduced under the condition that the filling liquid medicine temperature is higher and lower, and the liquid medicine temperature of the filling liquid medicine is preferably set at 28 ℃.
Example 7
Preparing an epinephrine hydrochloride prefilled injection; the preparation method is the same as in example 1.
Vacuumizing the prefilled syringe;
And filling the epinephrine hydrochloride liquid medicine into the pre-filling injector subjected to vacuumizing treatment, wherein the insertion depth of a filling plunger is 18mm, the filling speed is 40 bottles/min, and the liquid medicine temperature is 28 ℃.
And (3) filling nitrogen into the pre-filling and sealing syringe filled with the epinephrine hydrochloride liquid medicine, and performing three groups of tests with the nitrogen flow of 8m/s, 15m/s and 25m/s respectively to obtain the epinephrine hydrochloride pre-filling and sealing injection product.
Three groups of epinephrine hydrochloride pre-filled injection products are prepared by the method, the average value of residual oxygen measurement results of each group of 12 samples are shown in table 5, the samples are subjected to stability investigation, and the impurity content results are shown in table 5:
TABLE 5 residual oxygen content and 3 months impurity content results for injection products prepared in each example under different nitrogen flow rates
| Sample of | Flow of nitrogen | Average value of residual oxygen amount | Stability investigation period contemporaneous impurity content (%) |
| Group 10 | 8m/s | 1.8 | 5.2 |
| Group 11 | 15m/s | 2.0 | 5.1 |
| Group 12 | 18m/s | 1.9 | 5.0 |
As can be seen from Table 5, the pre-filled injection product of the epinephrine hydrochloride solution has better stability by adjusting the nitrogen filling flow value in the pre-filled injection filled with the epinephrine hydrochloride solution.
Example 8
Preparing an epinephrine hydrochloride prefilled injection; the preparation method comprises the following steps: the nitrogen is used for purging a liquid inlet pipeline, the liquid inlet pipeline is used for conveying water for injection into a liquid preparation tank, and the liquid preparation tank is used for preparing epinephrine hydrochloride injection;
Delivering a predetermined amount of water for injection into the dosing tank;
Preparing epinephrine hydrochloride liquid medicine into a liquid preparation tank; delivering a predetermined preparation amount of the residual injection water to the preparation tank;
Introducing nitrogen into the liquid preparation tank after the secondary injection water delivery, and performing three groups of tests respectively for 3min, 5min and 10min to obtain the prepared epinephrine hydrochloride liquid medicine;
vacuumizing the prefilled syringe;
Filling epinephrine hydrochloride liquid medicine into the pre-filling injector which is vacuumized, wherein the insertion depth of a filling plunger is 18mm, the liquid medicine temperature is 28 ℃, and the filling speed is 40 bottles/min;
And (3) filling nitrogen into the pre-filling and sealing syringe filled with the epinephrine hydrochloride liquid medicine, wherein the nitrogen flow is 20m/s, and the epinephrine hydrochloride pre-filling and sealing injection product is prepared.
Three groups of epinephrine hydrochloride pre-filled injection products are prepared by the method, the average value of residual oxygen measurement results of each group of 12 samples are shown in table 6, the samples are subjected to stability investigation, and the impurity content results are shown in table 6:
TABLE 6 residual oxygen and stability examination of impurity content results for injection products prepared by introducing nitrogen into a liquid preparation tank at different time periods
| Sample of | Duration of nitrogen introduction | Average value of residual oxygen amount | Stability investigation period contemporaneous impurity content (%) |
| Group 13 | 3min | 1.6 | 5.3 |
| Group 14 | 5min | 1.3 | 4.3 |
| Group 15 | 10min | 1.3 | 5.1 |
As can be seen from Table 6, the nitrogen gas is introduced into the liquid preparation tank after the secondary injection water delivery, so that the stability of the product can be effectively improved, preferably, the nitrogen gas is introduced into the liquid preparation tank after the secondary injection water delivery for 5min, the residual oxygen content of the liquid medicine of the prepared injection product is obviously reduced, the stability of the product is optimal, and the continuous nitrogen charging time is prolonged after the nitrogen charging time reaches 5min, so that the residual oxygen content of the liquid medicine is not obviously reduced.
The foregoing is only a specific embodiment of the application to enable those skilled in the art to understand or practice the application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the application. Thus, the present application is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (11)
1. The preparation method of the epinephrine hydrochloride prefilled injection is characterized by comprising the following steps of:
the nitrogen is used for purging a liquid inlet pipeline, the liquid inlet pipeline is used for conveying water for injection into a liquid preparation tank, and the liquid preparation tank is used for preparing epinephrine hydrochloride injection;
Delivering a predetermined amount of water for injection into the dosing tank;
preparing epinephrine hydrochloride liquid medicine into a liquid preparation tank;
Delivering a predetermined preparation amount of the residual injection water to the preparation tank;
And (3) introducing nitrogen into the liquid preparation tank after the secondary injection water delivery to prepare the prepared epinephrine hydrochloride liquid medicine.
2. The preparation method according to claim 1, comprising the steps of:
Delivering 90% of the prescribed amount of water for injection into the dosing tank;
preparing epinephrine hydrochloride liquid medicine into a liquid preparation tank;
The injection water with the prescription amount of 10% is delivered into the liquid preparation tank.
3. The preparation method of claim 1, wherein the preparation of the epinephrine hydrochloride liquid medicine into the liquid preparation tank comprises the following steps:
Sequentially adding sodium metabisulfite, disodium edentate, L-tartaric acid and sodium hydroxide with the prescription amount, and stirring; adding concentrated hydrochloric acid and stirring; adding epinephrine in the prescribed amount, and stirring; adding sodium chloride with a prescription amount, and stirring; detecting the pH value and controlling the pH value range to be 3.0-4.0.
4. The preparation method according to claim 1, wherein the time for introducing nitrogen into the liquid preparation tank is 0-10 min.
5. The preparation method of claim 1, further comprising a step of filtering the filled epinephrine hydrochloride medical solution after introducing nitrogen into the liquid preparation tank, wherein the step of filtering comprises the steps of: the liquid preparation tank and a group of cylinder type microporous filter membranes with the aperture of 0.45 mu m form a series loop, and the epinephrine hydrochloride liquid medicine with the constant volume is circulated in the series loop.
6. The preparation method according to claim 1, further comprising the following steps after preparing the prepared epinephrine hydrochloride medical solution:
Filtering the epinephrine hydrochloride liquid medicine to be filled by three groups of cylinder type microporous filter membranes which are connected in series.
7. The method according to claim 6, wherein the three sets of cartridge type microporous filter membranes comprise three sets of cartridge type microporous filter membranes which are formed by connecting a set of cartridge type microporous filter membranes with a pore size of 0.45 μm and two sets of cartridge type microporous filter membranes with a pore size of 0.22 μm in series.
8. The preparation method according to claim 6, wherein the filling speed is less than or equal to 50 bottles/min, and the plunger insertion depth of the filling epinephrine hydrochloride liquid medicine is 16-20 mm.
9. The preparation method according to claim 1, wherein after preparing the prepared epinephrine hydrochloride medical solution, the preparation method further comprises the following steps:
Filling nitrogen into the prefilled syringe;
filling epinephrine hydrochloride liquid medicine into a prefilled syringe filled with nitrogen;
And (3) filling nitrogen into the pre-filling and sealing syringe filled with the epinephrine hydrochloride liquid medicine to prepare the epinephrine hydrochloride pre-filling and sealing injection product.
10. The method of manufacturing according to claim 9, comprising the steps of:
Sterilizing the pre-encapsulated injection product of epinephrine hydrochloride at 121deg.C for 12min.
11. An epinephrine hydrochloride injection prepared by the preparation method of the epinephrine hydrochloride pre-encapsulation injection as claimed in any one of claims 1 to 10, comprising the following components in parts by mass:
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| CN202011550454.8A CN114668714B (en) | 2020-12-24 | 2020-12-24 | Preparation method of epinephrine hydrochloride injection and injection |
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| CN102335125A (en) * | 2010-07-16 | 2012-02-01 | 上海禾丰制药有限公司 | Adrenaline hydrochloride injection and preparation process thereof |
| CN102525894A (en) * | 2012-01-04 | 2012-07-04 | 上海禾丰制药有限公司 | Isoproterenol hydrochloride injection and preparation process thereof |
| CN105982851A (en) * | 2015-03-06 | 2016-10-05 | 上海禾丰制药有限公司 | Adrenaline hydrochloride injection and preparation method thereof |
| US20170189352A1 (en) * | 2015-03-13 | 2017-07-06 | Par Pharmaceutical, Inc. | Epinephrine formulations |
| CN108078917A (en) * | 2017-12-20 | 2018-05-29 | 远大医药（中国）有限公司 | A kind of preparation method of adrenalin hydrochloride parenteral solution |
| WO2019150381A1 (en) * | 2018-02-01 | 2019-08-08 | Joshi Mahendra R | A stable pharmaceutical composition and process for production of isoproterenol hydrochloride injection |
| WO2019183416A1 (en) * | 2018-03-23 | 2019-09-26 | Nevakar Inc. | Epinephrine compositions and containers |
| CN109394683A (en) * | 2018-12-07 | 2019-03-01 | 远大医药（中国）有限公司 | A kind of preparation method of noradrenaline bitartrate injection |
| CN109528645A (en) * | 2018-12-29 | 2019-03-29 | 遂成药业股份有限公司 | A kind of children's adrenalin hydrochloride injection and preparation method thereof |
| CN109998990B (en) * | 2019-04-30 | 2021-12-03 | 遂成药业股份有限公司 | Small-size epinephrine hydrochloride injection and preparation method thereof |
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