Antioxidant-free epinephrine hydrochloride injection and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a prescription composition of an antioxidant-free epinephrine hydrochloride injection and a preparation method of the antioxidant-free epinephrine hydrochloride injection. The formula of the injection comprises epinephrine, sodium chloride, acetic acid, sodium acetate, hydrochloric acid and water for injection, and the pH value of the injection is 3.0-4.0. The preparation is simple in prescription composition, good in stability and higher in safety. The invention further provides a preparation method of the antioxidant-free epinephrine hydrochloride injection. The method is easy to operate, the residual oxygen content is controlled to be 2.0%-3.0%, terminal sterilization can be tolerated, the production cost is low, the requirements for equipment and preparation conditions are not high, and the antioxidant-free epinephrine hydrochloride injection is suitable for large-scale production.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical preparations, and mainly relates to a prescription composition of an antioxidant-free adrenaline hydrochloride injection and a preparation method thereof. Background Art

[0002] Epinephrine is 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]-1,2-benzenediol, an active ingredient of the adrenal medulla and endogenous catecholamines that acts directly on alpha and beta adrenergic receptors. When used in the form of a pharmaceutical composition, epinephrine can act as a non-selective alpha and beta adrenergic agonist and can act rapidly to accelerate breathing, stimulate the heart, increase low blood pressure, reverse urticaria, and reduce swelling of the face, lips, and throat. Epinephrine is mainly used to increase mean arterial blood pressure in hypotensive adult patients with septic shock, emergency treatment of type 1 allergic reactions, and to induce and maintain pupil dilation during intraocular surgery. It belongs to the cardiovascular drugs. Epinephrine can also be used to increase blood flow in ACLS during CPR, as an adjunct to local anesthesia, and for radiographic purposes. The following is the structural formula of epinephrine:

[0003]

[0004] Molecular formula: C 9 H 13 NO 3

[0005] Molecular weight: 183.21

[0006] Epinephrine hydrochloride injection was developed by Macarthys Laboratonies Ltd T / AMartindale Pharma and launched in the UK in 1990. It has been widely used in clinical practice and has achieved good therapeutic effects.

[0007] In the prior art, most prescriptions for epinephrine hydrochloride injection contain antioxidants. This is because epinephrine contains phenolic hydroxyl groups in its structure, which are very easy to be oxidized. Light, heat, metal ions, etc. can promote its oxidative degradation. In order to delay the oxidation of the active ingredient, antioxidants are usually added to the preparations. However, at the same time, the sulfate contained in the antioxidants is easy to react with epinephrine to form epinephrine sulfonate, causing a decrease in content and allergic reactions. If antioxidants are not added to the prescription, when preparing the preparation, the headspace residual oxygen content needs to be controlled at a very low level during the filling stage, which places extremely high requirements on equipment performance, and therefore the production cost is relatively high. Summary of the invention

[0008] In order to solve the above technical problems, the present application provides a prescription composition of epinephrine hydrochloride injection and a preparation method thereof. The injection has a simple prescription composition, no epinephrine sulfonate impurities are detected, can withstand terminal sterilization, has high safety, few adverse reactions and good stability.

[0009] The present application provides an epinephrine hydrochloride injection, which comprises epinephrine, sodium chloride, acetic acid, sodium acetate, hydrochloric acid and water for injection, and the pH value of the injection is 3.0-4.0.

[0010] In some embodiments, the injection of the present application comprises the following components (by weight):

[0011]

[0012] In some embodiments, the concentration of the hydrochloric acid is 4% (w / w) hydrochloric acid solution.

[0013] In some embodiments, the pH value of the injection solution is 3.0-4.0.

[0014] In some embodiments, the injection of the present application comprises the following components (by weight):

[0015]

[0016] The present application also provides a method for preparing the above injection, which comprises the following steps:

[0017] (1) Add 80% of the prepared amount of water for injection into the preparation container, add sodium chloride, acetic acid, sodium acetate, and an appropriate amount of 4% hydrochloric acid solution in sequence, stir until completely dissolved, add the prescribed amount of epinephrine, and stir until completely dissolved;

[0018] (2) Use 4% (w / w) hydrochloric acid solution to adjust the pH to 3.0-4.0 and add water for injection to the full amount;

[0019] (3) Filtration, filling and sterilization.

[0020] In some embodiments, the liquid preparation temperature of step (1) is 40°C; the filtration is performed using a folded filter element, the filter element material is polyethersulfone, and the filter element pore size is 0.45μm and 0.22μm; the filling volume is controlled at 1.10-1.20mL / vial; the packaging material is 2mL medium borosilicate glass ampoule; the sterilization temperature is 121°C, and the sterilization time is 12 minutes.

[0021] Compared with the prior art, the beneficial effects of this application include but are not limited to the following:

[0022] (1) According to the injection of the present application, the raw material of the epinephrine hydrochloride injection is easily affected by metal elements, which accelerates the formation of degradation products in the preparation. After adding acetic acid and sodium acetate, the generation of related substances in the composition is significantly improved, and the safety is higher.

[0023] (2) According to the injection of the present application, the use of excipients with good water solubility and compatibility, such as sodium chloride, acetic acid, sodium acetate, and hydrochloric acid, can reduce the irritation of the preparation; in addition, acetic acid and sodium acetate can form a buffering effect, making the preparation more stable.

[0024] (3) According to the injection of the present application, the excipients in the prescription do not contain sulfur element, and adrenaline sulfonate is not detected, so it can withstand terminal sterilization, with a higher level of sterility assurance and higher safety.

[0025] (4) The preparation method of the injection solution according to the present application is simple to operate, easy to control, has low production cost, does not require high equipment and preparation conditions, is suitable for large-scale production, and is conducive to industrialization. DETAILED DESCRIPTION

[0026] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present invention more clearly understood, the present invention is further described below in conjunction with embodiments. It should be noted that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0027] Example 1

[0028] The prescribing information for epinephrine hydrochloride injection is as follows:

[0029]

[0030] Preparation method of epinephrine hydrochloride injection:

[0031] (1) Add 800 g of water for injection into a preparation container, heat the water for injection to 40°C, add the prescribed amount of sodium chloride, acetic acid, sodium acetate, and an appropriate amount of 4% hydrochloric acid solution in sequence, stir until completely dissolved, then add the prescribed amount of epinephrine and stir until completely dissolved;

[0032] (2) Use 4% (w / w) hydrochloric acid solution to adjust the pH value to 3.0-4.0, add water for injection to the full amount, and stir for 10 minutes;

[0033] (3) Filter with 0.45 μm and 0.22 μm folded cartridge polyethersulfone filters. Fill the filtered solution into 2 mL medium borosilicate glass ampoules, with a theoretical filling volume of 1.10 to 1.20 mL per ampoule, and control the residual oxygen content below 2.0%.

[0034] (4) Sterilize at 121°C for 12 minutes.

[0035] Example 2

[0036] The prescribing information for epinephrine hydrochloride injection is as follows:

[0037]

[0038] The preparation method of epinephrine hydrochloride injection is the same as that of Example 1.

[0039] Example 3

[0040] The prescribing information for epinephrine hydrochloride injection is as follows:

[0041]

[0042] The preparation method of epinephrine hydrochloride injection is the same as that of Example 1.

[0043] Example 4

[0044] The prescribing information for epinephrine hydrochloride injection is as follows:

[0045]

[0046]

[0047] Preparation method of epinephrine hydrochloride injection:

[0048] (1) Add 800 g of water for injection into a preparation container, heat the water for injection to 40°C, add the prescribed amount of sodium chloride, acetic acid, sodium acetate, and an appropriate amount of 4% hydrochloric acid solution in sequence, stir until completely dissolved, then add the prescribed amount of epinephrine and stir until completely dissolved;

[0049] (2) Use 4% (w / w) hydrochloric acid solution to adjust the pH value to 3.0-4.0, add water for injection to the full amount, and stir for 10 minutes;

[0050] (3) Filter with 0.45 μm and 0.22 μm folded cartridge polyethersulfone filters. Fill the filtered solution into 2 mL medium borosilicate glass ampoules, with a theoretical filling volume of 1.10 to 1.20 mL per ampoule, and control the residual oxygen content below 3.0%.

[0051] (4) Sterilize at 121°C for 12 minutes.

[0052] Comparative Example 1

[0053] The prescription was prepared with reference to patent US9119876.

[0054]

[0055] Preparation method of epinephrine hydrochloride injection:

[0056] (1) Liquid preparation tank ①: pressurize with nitrogen, add deoxygenated water for injection, and add the prescribed amount of sodium chloride, sodium hydroxide, tartaric acid, disodium edetate, and sodium metabisulfite in sequence, and stir to dissolve;

[0057] (2) Liquid preparation tank ②: Add the prescribed amount of hydrochloric acid and epinephrine and stir to dissolve;

[0058] (3) Add the Chinese medicine solution in preparation tank ② to preparation tank ①, rinse the remaining medicine solution in preparation tank ② 1-3 times with deoxygenated injection water, and transfer to preparation tank ①, stirring evenly;

[0059] (4) pH adjustment: Use a pH adjuster to adjust the pH to 4.0 ± 0.1 and add water for injection to the full amount;

[0060] (5) Filter using a 0.22 μm pleated cartridge polyethersulfone filter;

[0061] (6) The filtered drug solution is filled into 2 mL medium borosilicate glass ampoules, with the theoretical filling volume of each ampoule being 1.10 to 1.20 mL and the residual oxygen content being less than 5%.

[0062] (7) Sterilize at 121°C for 12 minutes.

[0063] Comparative Example 2

[0064] The prescribing information for epinephrine hydrochloride injection is as follows:

[0065]

[0066] Preparation method of epinephrine hydrochloride injection:

[0067] Add 80% water for injection to the preparation container, fill with nitrogen as protective gas, add the prescribed amount of sodium chloride and appropriate amount of hydrochloric acid in turn, stir until completely dissolved, add the prescribed amount of epinephrine, stir until completely dissolved, use 0.1mol / L hydrochloric acid solution to adjust the pH value to 3.2, add water for injection to the full amount, and stir for 10 minutes. Filter with a 0.22μm folded cartridge polypropylene filter. Fill the filtered liquid into 2mL medium borosilicate glass ampoules, each with a theoretical filling volume of 1.10~1.20mL and a residual oxygen content of less than 0.3%. Sterilize at 121℃ for 12min.

[0068] Comparative Example 3

[0069] The prescribing information for epinephrine hydrochloride injection is as follows:

[0070]

[0071] Preparation method of epinephrine hydrochloride injection:

[0072] Add 80% water for injection to the preparation container, fill with nitrogen as protective gas, add the prescribed amount of sodium chloride and appropriate amount of hydrochloric acid in turn, stir until completely dissolved, add the prescribed amount of epinephrine, stir until completely dissolved, use 0.1mol / L hydrochloric acid solution to adjust the pH value to 3.2, add water for injection to the full amount, and stir for 10 minutes. Filter with a 0.22μm folded cartridge polypropylene filter. Fill the filtered liquid into 2mL medium borosilicate glass ampoules, each with a theoretical filling volume of 1.10~1.20mL and a residual oxygen content of less than 0.6%. Sterilize at 121℃ for 12min.

[0073] Comparative Example 4

[0074] The prescribing information for epinephrine hydrochloride injection is as follows:

[0075]

[0076] Preparation method of epinephrine hydrochloride injection:

[0077] Add 80% water for injection to the preparation container, fill with nitrogen as protective gas, add the prescribed amount of sodium chloride, appropriate amount of hydrochloric acid in turn, stir until completely dissolved, add the prescribed amount of epinephrine, stir until completely dissolved, add sodium metabisulfite, stir until completely dissolved, use 0.1mol / L hydrochloric acid solution to adjust the pH value to 3.2, add water for injection to the full amount, and stir for 15 minutes. Filter with a 0.22μm folded cartridge polypropylene filter. Fill the filtered liquid into 2mL medium borosilicate glass ampoules, each with a theoretical filling volume of 1.0mL and a residual oxygen content of less than 5.0%. Sterilize at 121℃ for 12min.

[0078] Test Example 1 Study on the dosage of key excipients in preparations

[0079] Table 1 Preparation quality

[0080]

[0081]

[0082] According to the data in the above table, there is no significant difference in the effect of different amounts of acetic acid and sodium acetate on the quality of the preparation in Example 1, Example 2, and Example 3. Therefore, the amount of acetic acid and sodium acetate added in the prescription of the epinephrine hydrochloride injection of the present application can be formulated as 0.14 mg / ml to 0.18 mg / ml.

[0083] Test Example 2 Comparison of the quality of the preparations in Example 1 and Comparative Example 1

[0084] Table 2 Preparation quality

[0085]

[0086] According to the data in the above table, there is no significant change in each test item before and after sterilization in Example 1. After sterilization, the impurity F in Comparative Example 1 increases significantly and the detected amount is larger than that before sterilization, indicating that Comparative Example 1 cannot tolerate terminal sterilization. Impurity F is adrenaline sulfonate, which is produced by the reaction of adrenaline and sodium pyrosulfite. Comparative Example 1 contains sodium pyrosulfite, which accelerates the formation of adrenaline sulfonate after high-temperature sterilization, while Example 1 does not contain sodium pyrosulfite, so there is no significant difference in quality before and after sterilization, indicating that the epinephrine hydrochloride injection of the present application has a simple prescription composition, can tolerate terminal sterilization, has a lower detection amount of related substances, a higher sterility assurance level, and higher safety.

[0087] Comparison of the quality of the preparations in Example 3 and Example 2

[0088] According to the "ICH Guidelines" published by the International Council for Harmonization of Technical Requirements for Pharmaceuticals and the "Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations)" published by the State Drug Administration, an accelerated stability study was conducted. The sample placement conditions were 40±2℃ / 75%±5%RH, and the relevant results are shown in the following table.

[0089] Table 3 Preparation quality

[0090]

[0091] The prescription compositions of Comparative Examples 2 and 3 are the same, and no antioxidant is added. The residual oxygen content of Comparative Example 2 is controlled below 0.3%, and the residual oxygen content of Comparative Example 3 is controlled below 0.6%. The color of the solution of Comparative Example 2 did not change under the accelerated 3-month condition, and the color of Comparative Example 3 changed from colorless to yellow under the accelerated 3-month condition, which exceeded the acceptable standard. This indicates that when the preparation prescription does not add antioxidants, and only has cosolvents, osmotic pressure regulators and active ingredients, the residual oxygen content needs to be strictly controlled, which places high requirements on equipment performance and preparation conditions during production, and the production cost is also high.

[0092] Test Example 4 Comparison of quality before and after sterilization in different embodiments

[0093] Example 1, Comparative Example 1 and Comparative Example 4 were sterilized at 121° C. for 12 min, and the product quality before and after sterilization was tested and compared. The relevant results are detailed in the table below.

[0094] Table 4 Preparation quality

[0095]

[0096]

[0097] No antioxidant was added in Example 1, the amount of antioxidant added in Comparative Example 1 was 0.457 mg / ml, and the amount of antioxidant added in Comparative Example 4 was 0.75 mg / ml. After sterilization, the impurity F (epinephrine sulfonate) in Comparative Example 1 and Comparative Example 4 increased significantly, and the detected amount also increased with the increase in the amount of antioxidant added. There was no significant change in all items before and after sterilization in Example 1, indicating that when the preparation prescription contains an antioxidant, the preparation cannot withstand terminal sterilization while meeting the requirements of the impurity limit, indicating that the epinephrine hydrochloride injection of the present application can withstand terminal sterilization, with a higher level of sterility assurance and higher safety.

[0098] Experimental Example 5 Comparison of related properties between different embodiments and comparative examples

[0099] Table 5 Preparation quality

[0100]

[0101] According to the above results, Comparative Examples 1 and 4 contain antioxidants, and the impurity F (epinephrine sulfonate) in the related substances increases significantly after sterilization; Comparative Example 2 does not contain an antioxidant, and the residual oxygen content control requirements during its preparation are very strict, and the isomer detection amount is large; therefore, it can be compared that the advantages of the adrenaline hydrochloride injection (Examples 1 and 4) of the present application are simple prescription composition, can withstand terminal sterilization, low related substance detection amount, higher sterility assurance level, and better safety; during preparation, the residual oxygen level control does not need to be very strict, and during production, the requirements for equipment performance are lower, and it is easier to produce.

[0102] Test Example 6 Preparation Full Inspection Test and Stability Study

[0103] According to the "ICH Guidelines" published by the International Council for Harmonization of Technical Requirements for Pharmaceuticals and the "Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations)" published by the State Drug Administration, accelerated stability studies and influencing factor studies were conducted. The sample placement conditions were accelerated (40±2℃ / 75%±5%RH), illumination (illuminance of 5000Lx, and the total illumination of the light source should not be less than 1.2×10 6 lux˙hr, near-ultraviolet lamp energy not less than 200W˙hr / m 2 , naked), low temperature (2-8℃ for two days, 40±2℃ for two days, three cycles) and freeze-thaw (-20--10℃ for two days, 40±2℃ for two days, three cycles).

[0104] The testing standards refer to the requirements for injection in the 2020 edition of the "Chinese Pharmacopoeia", and also refer to the requirements for epinephrine hydrochloride-related preparations in pharmacopoeias of various countries. The relevant standards for epinephrine hydrochloride injection are formulated on the basis of the ChP2020 standard. The preparation stability study is detailed in the table below.

[0105] Table 6 Preparation stability

[0106]

[0107]

[0108] Table 7 Preparation stability

[0109]

[0110]

[0111] According to the above data, it can be seen that all test items of the adrenaline hydrochloride injection obtained in Example 1 meet the preparation standards. Under the conditions of acceleration and light exposure, the related substances increased slightly, but all met the regulations. There was no obvious change in other test items. In the low-temperature freeze-thaw test, there was no obvious change in each test item, indicating that the preparation has good stability.

[0112] Test Example 7 Irritation Study

[0113] With reference to the "Technical Guidance for Drug Irritation, Allergy and Hemolysis Research" published by the Drug Review Center of the State Drug Administration, the experiment was designed, and the hydrochloride injection obtained from Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 4 was set up for rabbit muscle administration irritation study. Muscle irritation test method: 24 New Zealand rabbits, half male and half female, were designed by the same body left and right side self-comparison method. The left quadriceps of each group was given Example 1 or Comparative Example 1 or Comparative Example 2 or Comparative Example 4, and the right side was given a negative control substance (0.9% sodium chloride injection). The drug was administered once a day, and each time it was administered at the same site for 3 consecutive days. After each administration, 24h, 48h and 72h after the last administration, and during the recovery period of 21 days, the general signs of the animals and the skin injection site were observed with the naked eye every day. After 72h of drug withdrawal and 21 days of recovery, 4 and 2 animals were dissected in each group, respectively, and the administration site was observed with the naked eye and histopathological examination was performed. The research data are shown in Tables 8 to 10 below.

[0114] Table 8 Score standard for rabbit muscle irritation test

[0115] Points Stimulus Response 0 No significant changes 1 Mild congestion, less than 0.5 × 1.0 cm 2 Moderate congestion, with an area of ​​0.5 × 1.0 cm or more 3 Severe congestion with muscle degeneration 4 Necrosis and brown degeneration 5 Extensive necrosis

[0116] Table 9 Average scores and grades

[0117]

[0118]

[0119] Table 10 Irritation evaluation

[0120]

[0121] According to the data in the above table, Example 1 and Comparative Example 2 are mildly irritating to rabbit muscles, and Comparative Example 1 and Comparative Example 4 are moderately irritating to rabbit muscles. No antioxidant is added to the formulations of Example 1 and Comparative Example 2. Therefore, it can be shown that the epinephrine hydrochloride injection (Example 1) disclosed in the present invention has good tolerance and mild irritation.

[0122] In the description of the above embodiments, specific features, structures, materials or characteristics may be combined in a suitable manner in any one or more embodiments or examples.

[0123] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. An epinephrine hydrochloride injection, characterized in that: The prescription contains epinephrine, sodium chloride, acetic acid, sodium acetate, hydrochloric acid and water for injection, and the pH value of the injection is 3.0-4.

0.

2. The injection according to claim 1, characterized in that: Contains the following components (by weight):

3. The injection according to claim 2, characterized in that: The hydrochloric acid solution should be prepared to a concentration of 4% (w / w).

4. The injection according to claim 1, characterized in that: Contains the following components (by weight):

5. A method for preparing the injection according to any one of claims 1 to 4, characterized in that: The following steps are included: (1) Add 80% of the prepared amount of water for injection into a preparation container, add sodium chloride, acetic acid, sodium acetate, and an appropriate amount of 4% (w / w) hydrochloric acid solution in sequence, stir until completely dissolved, add epinephrine, and stir until completely dissolved; (2) Use 4% (w / w) hydrochloric acid solution to adjust the pH to 3.0-4.0 and add water for injection to the full amount; (3) Filtration, filling and sterilization.

6. The preparation method according to claim 5, characterized in that: The liquid preparation temperature in step (1) is below 40°C.

7. The preparation method according to claim 5, characterized in that: The filtration in step (3) is performed using a folded filter element, the filter element material is polyethersulfone, and the filter element pore size is 0.45 μm and 0.22 μm.

8. The preparation method according to claim 5, characterized in that: The sterilization parameter in step (3) is sterilization at 121° C. for 12 minutes.

Images