Pre-filled device containing epinephrine medicine liquid, and composition and preparation method therefor

Abstract

The present invention relates to the pharmaceutical field of epinephrine. Provided in the present invention are a pre-filled device containing epinephrine medicine liquid, and a composition and a preparation method therefor. The pre-filled device of the present invention comprises a syringe for pre-filling and the epinephrine medicine liquid filled therein. The change value range of the pH of a piston of the syringe is ≤0.5 and the change value range of the pH of a protective cap of a needle is ≤0.5. The epinephrine medicine liquid comprises an epinephrine active agent with a content of 1.0-1.2 mg / ml and sodium pyrosulfite with a content of 0.1-0.35 mg / ml. The pre-filled device of the present invention is capable of effectively maintaining the efficacy and quality of the medicine, has a relatively low content of sodium metabisulfite, and has relatively high levels of safety and quality stability.

Description

Pre-filled device containing epinephrine liquid, composition and preparation method thereof Technical Field

[0001] The present application relates to the field of adrenaline pharmaceutical manufacturing, in particular to a pre-filled device containing adrenaline liquid and a preparation method thereof. Background Art

[0002] Epinephrine is a key medication in the medical and biopharmaceutical fields. It is primarily indicated for treating severe respiratory distress caused by bronchospasm, rapidly relieving anaphylactic shock induced by drugs, and prolonging the duration of action of infiltration anesthetics. It is also a primary rescue medication for cardiopulmonary resuscitation following cardiac arrest from various causes. Prefilled syringes of epinephrine save time compared to ampoule or penicillin packaging, making them particularly suitable for emergency patients. They also reduce drug absorption and waste, minimizing the risk of secondary contamination.

[0003] Currently available epinephrine preparations are primarily packaged in vials or ampoules, which do not allow for rapid injection. While autoinjector pens can achieve rapid injection, they are expensive and have yet to be widely adopted in China. Due to epinephrine's oxidative sensitivity, it is highly susceptible to oxidative degradation impurities. Currently available epinephrine injections include those containing and those without antioxidants.

[0004] Products that do not contain antioxidants require extremely strict oxygen control during the production process. Any slight fluctuation in the process will have a significant impact on product quality and safety. Products that do contain antioxidants generally use sodium metabisulfite as an antioxidant or contain the preservative chlorobutanol to improve the stability of epinephrine. Due to the risks of using chlorobutanol, its addition to injectables is strictly restricted according to the strict technical requirements for drug registration review and approval. The high proportion of sodium metabisulfite in the preparation can easily lead to the production of excessive impurity F, namely sulfonic acid impurities, especially under high temperature conditions. Moreover, in certain susceptible populations, sulfites can cause allergic reactions, such as allergic symptoms and life-threatening or less severe asthma attacks.

[0005] Currently available products contain high levels of antioxidants or preservatives, posing certain risks. Furthermore, compared to vials or ampoules, prefilled syringes have more components that come into direct contact with the drug solution, making quality control more complex. Existing research on prefilled products is lacking.

[0006] Summary of the Invention

[0007] To address the shortcomings of existing technologies, the present invention, through extensive experimental research, provides a pre-filled epinephrine device with reduced antioxidant content and improved stability. The composition of the drug solution and the syringe in which it is stored have a significant impact on the drug. Compared to vials and ampoules, the packaging material of the present invention is a pre-filled syringe.

[0008] According to a first aspect of the present invention, there is provided a pre-filled device containing an adrenaline solution, comprising a pre-filled syringe and an adrenaline solution filled therein, wherein the pre-filled syringe is selected from syringe 1 or syringe 2;

[0009] The syringe 1 includes a first needle tube 101, a first piston 102, a first injection needle 103, a first needle cap 104, and a first push rod 105. The first needle tube 101, the first piston 102, the first injection needle 103, and the first needle cap 104 constitute a first sealing system, and the first sealing system is used to encapsulate the adrenaline solution 106.

[0010] The syringe 2 includes a second needle tube 201, a second piston 202, a second retaining ring 203, a second protective cap 204, and a second push rod 205. The second needle tube 201, the second piston 202, and the second protective cap 204 constitute a second sealing system, and the interior of the second sealing system is used to encapsulate the adrenaline solution 206.

[0011] The epinephrine solution includes an epinephrine active agent at a concentration of 1.0 to 1.2 mg / ml and sodium metabisulfite at a concentration of 0.1 to 0.35 mg / ml. Taking into account the characteristics of the prefilled packaging material, the sodium metabisulfite content in the device of the present invention does not exceed 0.35 mg / ml, which can control the impurity F, i.e., sulfonic acid impurities, to less than 10%. Furthermore, controlling the sodium metabisulfite content to no less than 0.1 mg / ml effectively controls isomers and other impurities, ensuring product stability.

[0012] According to a preferred embodiment of the present invention, when the device of the present invention is stored under long-term storage conditions for 9 months, the adrenaline solution has a sodium metabisulfite content of not less than 0.1 mg / ml and not more than 0.3 mg / ml.

[0013] According to a preferred embodiment of the present invention, when the device of the present invention is stored under long-term storage conditions for 6 months, the adrenaline solution has a sodium metabisulfite content of not less than 0.1 mg / ml and not more than 0.3 mg / ml.

[0014] The "long-term storage conditions" of the present invention refer to the storage conditions indicated on the drug label, including but not limited to a temperature of 25±2°C and a relative humidity of 60%±5%.

[0015] The "adrenaline active agent" of the present invention refers to adrenaline and / or its salts. Examples of adrenaline salts include but are not limited to acetate, carbonate, citrate, hydrochloride, hydrocyanate, hydrofluoride, nitrate, nitrite, phosphate and sulfate, preferably hydrochloride.

[0016] According to one embodiment of the present invention, the adrenaline active agent is epinephrine. The liquid medicine encapsulated in the prefilled device of the present invention contains epinephrine and sodium metabisulfite. Sodium metabisulfite acts as an antioxidant in the liquid medicine, and its antioxidant effect is to protect epinephrine from oxidation by molecular oxygen through preferential oxidation. Although sodium metabisulfite can protect epinephrine from oxidation, it reacts with epinephrine to form a pharmacologically inactive impurity F. Excessive sodium metabisulfite content in the prefilled device will not only lead to an excess of impurity F, but may also pose a risk of sodium metabisulfite sensitization; if the sodium metabisulfite content in the device is too low, it will not be sufficient to maintain the efficacy of the drug within the shelf life.

[0017] According to one embodiment of the present invention, the mass ratio of sodium metabisulfite to epinephrine in the device is ≤0.3, and the mass of epinephrine in this ratio refers to the labeled amount of epinephrine in the prefilled device; this ratio is much lower than that of other injections, which can ensure product stability. In addition, the present invention does not add preservatives to maintain the quality of the drug. Even if a small amount of preservatives, including chlorobutanol, are present, they are usually present as impurities. The preservative content does not exceed 0.005 mg / ml, and more preferably does not exceed 0.001 mg / ml, thereby improving the safety of the prefilled device.

[0018] Epinephrine is present in different amounts for different uses. According to an embodiment of the present invention, the epinephrine content is preferably 1 to 1.2 mg / mL. In some embodiments, epinephrine is present in a concentration range of any one of 0.9 mg / mL, 1 mg / mL, 1.1 mg / mL, 1.15 mg / mL, and 1.2 mg / mL, or any two thereof.

[0019] According to one embodiment of the present invention, the epinephrine solution includes a metal ion complexing agent. The epinephrine composition of the present invention may include one or more metal ion complexing agents. The metal ion complexing agent can chelate trace metals in the solution that would otherwise increase and / or accelerate the formation of degradation products. In some embodiments, the metal ion complexing agent can inhibit the formation of degradation products formed by the interaction of epinephrine, sodium metabisulfite, and oxygen.

[0020] Suitable metal ion complexing agents include disodium edetate, N-(2-hydroxyethyl)iminodiacetic acid, iminodiacetic acid citrate, nitrilotriacetic acid, nitrilotripropionic acid, nitrilotris(methylenephosphonic acid) trisodium salt, triethylenetetraaminehexaacetic acid, salicylic acid and / or malic acid, including analogs, derivatives and pharmaceutically acceptable salts thereof.

[0021] According to one embodiment of the present invention, the metal ion complexing agent comprises edetate disodium. The edetate disodium content is 0.1-0.3 mg / ml, optionally present in a concentration range of any one of 0.1 mg / ml, 0.15 mg / ml, 0.2 mg / ml, 0.25 mg / ml, and 0.3 mg / ml, or between any two of these values, preferably 0.15-0.3 mg / ml, and more preferably 0.15-0.25 mg / ml.

[0022] According to one embodiment of the present invention, the adrenaline solution includes a pH regulator, and the pH value of the adrenaline solution ranges from 2.5 to 5.0. According to one embodiment of the present invention, the pH regulator includes hydrochloric acid. The pH value of the adrenaline solution ranges from 2.5 to 5.0. In some embodiments, the pH value of the adrenaline solution ranges from 3.0 to 5.0, 3.5 to 5.0, or 4.0 to 5.0; in some embodiments, the pH value of the adrenaline solution ranges from 2.5 to 4.5, 3.0 to 4.5, or 3.5 to 4.5.

[0023] According to one embodiment of the present invention, the epinephrine solution contains a buffer. "Buffer" herein refers to a component present in a solution that can resist significant changes in pH caused by strong acids or bases. Suitable buffers include, but are not limited to, acetic acid, glutamic acid, citric acid, tartaric acid, benzoic acid, lactic acid, histidine or other amino acids; sodium hydroxide, potassium hydroxide, sodium citrate, potassium citrate, sodium bicarbonate, potassium bicarbonate, ethanolamine, and the like.

[0024] According to one embodiment of the present invention, the buffer includes tartaric acid and sodium hydroxide. In some embodiments, the pH value of the adrenaline solution ranges from 3.0 to 5.0, 3.5 to 5.0, or 4.0 to 5.0; in some embodiments, the pH value of the adrenaline solution ranges from 2.5 to 4.5, 3.0 to 4.5, or 3.5 to 4.5.

[0025] According to one embodiment of the present invention, the adrenaline solution includes a pH regulator and a buffer, and the pH value of the adrenaline solution ranges from 2.9 to 4.5, optionally, any one of 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.1, 4.2, 4.3, 4.4, and 4.5, or a range between any two values; preferably, 3.0 to 4.0.

[0026] According to one embodiment of the present invention, the prefilled device of the present invention may include an osmotic pressure regulator, including but not limited to anhydrous or aqueous sodium chloride, sucrose, glycerol, potassium chloride, magnesium chloride and the like.

[0027] The device of the present invention may be hypotonic, isotonic or hypertonic. According to one embodiment of the present invention, the osmotic pressure concentration of the pre-filled device is 257-315 mOsmol / kg, preferably 270-310 mOsmol / kg.

[0028] According to one embodiment of the present invention, the prefilled syringe includes a first needle tube, a first piston, a first injection needle, a first needle cap and a first push rod, wherein the first needle tube, the first piston, the first injection needle and the first needle cap constitute a first sealing system, and the interior of the first sealing system is used to fill the epinephrine solution;

[0029] Alternatively, the prefilled syringe includes a second needle tube, a second piston, a second retaining ring, a second protective cap and a second push rod. The second needle tube, the second piston and the second protective cap constitute a second sealing system, and the interior of the second sealing system is used to fill the epinephrine solution.

[0030] The syringe storing the epinephrine solution also has a significant impact on the drug and needs to meet a series of special requirements to ensure the stability and safety of the drug. Compared with vials and ampoules, the packaging material of the present invention is a pre-filled syringe.

[0031] The prefilled syringe of the present invention includes a syringe with a needle and a syringe without a needle, which will be described with reference to the accompanying drawings.

[0032] Referring to Figure 1 , the prefilled device utilizes a syringe 1 with a needle. The syringe 1 comprises a first needle tube 101, a first piston 102, a first injection needle 103, a first needle cap 104, and a first push rod 105. The first needle tube 101, first piston 102, first injection needle 103, and first needle cap 104 constitute a first sealing system, which contains an epinephrine solution 106.

[0033] Referring to FIG. 2 , the pre-filled device uses a syringe 2 without a needle. The syringe 2 includes a second needle tube 201 , a second piston 202 , a second retaining ring 203 , a second protective cap 204 , and a second push rod 205 . The second needle tube 201 , the second piston 202 , and the second protective cap 204 constitute a second sealing system, and the second sealing system is filled with epinephrine solution 206 .

[0034] Compared to other packaging, prefilled syringes have more components in contact with the drug solution, and each component is made of a variety of materials. The performance of each component in the sealing system has a significant impact on the quality and stability of the drug solution. In particular, pH changes, absorbance, and oxidizable substances are all tested in drug packaging material dissolution tests.

[0035] According to one embodiment of the present invention, the pH change range of the first piston of the prefilled syringe is ≤0.5 and the pH change range of the first needle cap is ≤0.5.

[0036] According to one embodiment of the present invention, the pH change range of the second piston of the prefilled syringe is ≤0.5 and the pH change range of the second protective cap is ≤0.5.

[0037] According to one embodiment of the present invention, the absorbance of the first needle cap of the prefilled syringe does not exceed 0.3; and / or the absorbance of the first piston does not exceed 0.1.

[0038] According to one embodiment of the present invention, the absorbance of the second protective cap of the prefilled syringe does not exceed 0.3; and / or the absorbance of the second piston does not exceed 0.1.

[0039] According to one embodiment of the present invention, the volume of easily oxidized substances in the first needle cap of the prefilled syringe does not exceed 7 ml, and the volume of easily oxidized substances in the first piston does not exceed 3 ml.

[0040] According to one embodiment of the present invention, the second protective cap of the prefilled syringe is not more than 7 ml of easily oxidizable substances, and the second piston is not more than 3 ml of easily oxidizable substances.

[0041] According to one embodiment of the present invention, the pH change range of the first piston of the prefilled syringe is ≤0.5 and the pH change range of the first needle cap is ≤0.5;

[0042] Alternatively, the pH change range of the second piston is ≤0.5 and the pH change range of the second protective cap is ≤0.5.

[0043] According to a second aspect of the present invention, a composition is provided for preparing a pre-filled device containing an adrenaline solution.

[0044] After the composition is filled into the filling syringe, it needs to be sterilized to obtain the pre-filled device of the present invention. Conventional sterilization methods include aseptic production and terminal sterilization: aseptic production refers to ensuring the sterility level through sterilization filtration or aseptic operation methods in a sterile system environment; terminal sterilization refers to sterilization by moist heat steam.

[0045] If the encapsulated liquid is sterilized terminally, due to the sensitivity of epinephrine to high temperatures and oxygen, the hot and humid conditions will cause instantaneous changes in epinephrine, sodium metabisulfite, and impurity F, resulting in a higher content of impurity F than in aseptic processes. Therefore, controlling the content of sodium metabisulfite is the key point of the present invention.

[0046] According to one embodiment of the present invention, the composition includes epinephrine and sodium metabisulfite, wherein the epinephrine content is 1.0 to 1.2 mg / ml and the sodium metabisulfite content is 0.1 to 0.35 mg / ml. After sterilization, the epinephrine content in the liquid within the device is 1.0 to 1.2 mg / ml, and the sodium metabisulfite content is 0.1 to 0.35 mg / ml, with impurity levels remaining within controlled ranges, thereby ensuring product stability.

[0047] According to one embodiment of the present invention, sodium metabisulfite is present in an amount of 0.1 to 0.35 mg / mL, and is present in a concentration range of any one of 0.10 mg / ml, 0.12 mg / ml, 0.13 mg / ml, 0.14 mg / ml, 0.15 mg / ml, 0.16 mg / ml, 0.17 mg / ml, 0.18 mg / ml, 0.19 mg / ml, 0.20 mg / ml, 0.21 mg / ml, 0.22 mg / ml, 0.23 mg / ml, 0.24 mg / ml, 0.25 mg / mL, 0.26 mg / mL, 0.27 mg / mL, 0.28 mg / mL, 0.29 mg / mL, 0.3 mg / mL, 0.31 mg / mL, 0.32 mg / mL, 0.33 mg / mL, 0.34 mg / mL, and 0.35 mg / mL, or a concentration range between any two of the values.

[0048] According to one embodiment of the present invention, the sodium metabisulfite of the composition is greater than 0.2 mg / ml and ≤ 0.35 mg / ml; preferably, it is present in a concentration range between any one of 0.21 mg / ml, 0.22 mg / ml, 0.23 mg / ml, 0.24 mg / ml, 0.25 mg / mL, 0.26 mg / mL, 0.27 mg / mL, 0.28 mg / mL, 0.29 mg / mL, 0.3 mg / mL, 0.31 mg / mL, 0.32 mg / mL, 0.33 mg / mL, 0.34 mg / mL, and 0.35 mg / mL, or any two of the values.

[0049] According to one embodiment of the present invention, the composition further comprises a buffer comprising tartaric acid and sodium hydroxide; the content of the buffer is 0.5 to 3.0 mg / ml. Optionally, the content is any one of 0.5 mg / ml, 0.8 mg / ml, 1.0 mg / ml, 1.2 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, 2.0 mg / ml, 2.1 mg / ml, 2.2 mg / ml, 2.3 mg / ml, 2.4 mg / ml, 2.5 mg / ml, 2.6 mg / ml, 2.7 mg / ml, 2.8 mg / ml, 2.9 mg / ml, and 3.0 mg / ml, or a range between any two of the values.

[0050] According to one embodiment of the present invention, the composition buffer comprises sodium hydroxide and tartaric acid. The sodium hydroxide content is 0.1-1 mg / ml, optionally, any one of 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, and 1.0 mg / ml, or a range between any two values. The tartaric acid is optionally L-tartaric acid, D-tartaric acid, DL-tartaric acid, or a mixture of different isomers. The tartaric acid content is 0.5-2 mg / ml, optionally, any one of 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.1 mg / ml, 1.2 mg / ml, 1.3 mg / ml, 1.4 mg / ml, 1.5 mg / ml, 1.6 mg / ml, 1.7 mg / ml, 1.8 mg / ml, 1.9 mg / ml, and 2.0 mg / ml, or a range between any two of the values.

[0051] According to one embodiment of the present invention, the composition comprises a pH adjuster and a buffer, and the mass ratio of the buffer to the sodium metabisulfite is in the range of 7.0 to 15. Optionally, the mass ratio is any one of 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, and 15, or a range between any two of the values. The pH adjuster comprises hydrochloric acid.

[0052] According to one embodiment of the present invention, the composition comprises edetate disodium, and the edetate disodium content is 0.1-0.3 mg / ml, optionally, present in a concentration range of any one of 0.1 mg / ml, 0.15 mg / ml, 0.2 mg / ml, 0.25 mg / ml, 0.3 mg / ml or between any two values, preferably 0.15-0.3 mg / ml, preferably 0.15-0.25 mg / ml.

[0053] According to one embodiment of the present invention, the composition includes sodium chloride to adjust the osmotic pressure molar concentration of the drug solution in the device, and the sodium chloride content is 7.0-9.0 mg / ml, optionally, any one of 7.1 mg / ml, 7.2 mg / ml, 7.3 mg / ml, 7.4 mg / ml, 7.5 mg / ml, 7.6 mg / ml, 7.7 mg / ml, 7.8 mg / ml, 7.9 mg / ml, 8.0 mg / ml, 8.1 mg / ml, 8.2 mg / ml, 8.3 mg / ml, 8.4 mg / ml, 8.5 mg / ml, 8.6 mg / ml, 8.7 mg / ml, 8.8 mg / ml, 8.9 mg / ml, and 9.0 mg / ml, or a range between any two values.

[0054] According to a preferred example of the present invention, the composition includes the following components:

[0055] hydrochloric acid;

[0056] The pH value of the composition ranges from 2.5 to 5.0.

[0057] According to a preferred example of the present invention, the composition includes the following components:

[0058] Epinephrine 1–1.2 mg / ml

[0059] Sodium metabisulfite 0.1~0.35mg / ml

[0060] Sodium chloride 7.3-9.0 mg / ml

[0061] Edetate disodium 0.1-0.3 mg / ml

[0062] Tartaric acid 0.5-2 mg / ml

[0063] Sodium oxide 0.1~1.0mg / ml

[0064] hydrochloric acid;

[0065] The pH value of the composition ranges from 2.0 to 5.0.

[0066] According to a third aspect of the present invention, there is provided a method for preparing a prefilled device, comprising the following steps:

[0067] Liquid preparation: preparation of composition;

[0068] Filling: filling the composition into a prefilled syringe;

[0069] Sterilization: sterilize the prefilled syringe containing the composition to obtain the prefilled device containing the adrenaline solution.

[0070] According to one embodiment of the present invention, the filling specifically includes the following steps:

[0071] The composition is filled into a syringe under a nitrogen atmosphere, and a piston is installed, and the concentration of residual oxygen in the headspace of the pre-filled syringe is controlled to be ≤10%.

[0072] According to one embodiment of the present invention, the filling specifically includes the following steps:

[0073] The composition is filled into a syringe under a nitrogen atmosphere, and a piston is installed, and the concentration of residual oxygen in the headspace of the pre-filled syringe is controlled to be ≤5%.

[0074] According to one embodiment of the present invention, the sterilization of the present invention is steam sterilization. Compared with the high environmental requirements of aseptic production, steam sterilization has a relatively higher sterility assurance level, relatively lower cost and higher safety.

[0075] According to one embodiment of the present invention, the sterilization is steam sterilization, the sterilization temperature is 121° C., and the sterilization time is 8 to 15 minutes.

[0076] According to one embodiment of the present invention, the sterilization is steam sterilization, the sterilization temperature is 121° C., and the sterilization time is 9 minutes, 10 minutes, 11 minutes, 12 minutes or 13 minutes, which has a reliable sterilization effect.

[0077] According to one embodiment of the present invention, the pre-filled device is obtained by filling the composition into a filling syringe and then sterilizing the syringe. The sterilization is steam sterilization at a temperature of 121° C. and a sterilization time of 12 minutes.

[0078] The beneficial effects of the present invention are as follows: the present invention provides a pre-filled device containing an epinephrine solution, which has a lower sodium metabisulfite content while effectively maintaining the drug efficacy and quality, has a wider range for controlling headspace residual oxygen, and has higher safety and quality stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0080] FIG1 shows a prefilled device according to one embodiment of the present invention;

[0081] FIG2 shows a pre-filled device according to another embodiment of the present invention;

[0082] FIG3 shows the effect of different pH values ​​on the quality of the medical solution in the device according to one embodiment of the present invention.

[0083] Reference Signs List

[0084] 101: first needle tube, 102: first piston, 103: first injection needle, 104: first needle cap, 105: first push rod, 106: adrenaline solution encapsulated in the first sealing system;

[0085] 201: second needle tube, 202: second piston, 203: second retaining ring, 204: second protective cap, 205: second push rod, 206: adrenaline solution encapsulated inside the second sealing system. DETAILED DESCRIPTION

[0086] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0087] The present invention will be further described in detail below with reference to Figures 1-2.

[0088] 1-2 illustrate a pre-filled device containing an adrenaline solution according to some embodiments of the present invention, including a pre-filled syringe and the adrenaline solution filled therein.

[0089] Referring to Figure 1 , the prefilled device utilizes a syringe 1 with a needle. Syringe 1 comprises a first needle tube 101, a first piston 102, a first injection needle 103, a first needle cap 104, and a first push rod 105. These first needle tube 101, first piston 102, first injection needle 103, and first needle cap 104 form a first sealing system, which contains epinephrine solution 106. The prefilled device is already filled with epinephrine solution, and injection is achieved by simply pushing first push rod 105.

[0090] Referring to Figure 2 , this prefilled device utilizes a needleless syringe 2 comprising a second needle tube 201, a second piston 202, a second retaining ring 203, a second protective cap 204, and a second push rod 205. The second needle tube 201, second piston 202, and second protective cap 204 form a second sealing system, which contains an epinephrine solution 206. The prefilled device is already filled with epinephrine solution. To inject, the second protective cap 204 is removed, and the needle is installed at the second retaining ring 203 before injection.

[0091] The epinephrine of the present invention has a chemical name: (R)-4-[2-(methylamino)-1-hydroxyethyl]-1,2-benzenediol.

[0092] The isomer of the present invention is the optical isomer of adrenaline, D-adrenaline.

[0093] The impurities of the present invention are described as follows:

[0094] Impurity F, adrenaline sulfonic acid

[0095] Impurity B, norepinephrine

[0096] Impurity C, adrenaline

[0097] Other total impurities, impurities other than impurity F and impurity B.

[0098] Example 1

[0099] The contents of the components of the prepared epinephrine pharmaceutical composition are as follows (based on 1 ml):

[0100] According to the above composition, an epinephrine pre-filled device is prepared according to the following preparation method:

[0101] Step 1: Prepare the liquid

[0102] According to the above prescription, the raw materials and auxiliary materials are weighed to prepare the adrenaline composition. After mixing and dissolving the raw materials and auxiliary materials with water for injection, an appropriate amount of dilute hydrochloric acid is added to adjust the pH of the solution to about 3.5, and finally the volume is made up to the full amount with water for injection.

[0103] Step 2: Filling

[0104] The prepared epinephrine pharmaceutical composition is filled into the barrel of a prefilled syringe. During the filling process, ensure that it is carried out under a nitrogen atmosphere to reduce the presence of oxygen, install the piston, and ensure that the composition is sealed in the syringe.

[0105] Step 3: Sterilization

[0106] After the filling is completed, the pre-filled syringe is sterilized using terminal sterilization at 121° C. for 12 minutes to obtain Preparation 1, with a detected pH value of 3.6.

[0107] The parameters related to the preparation 1 of the present invention were analyzed, including properties, pH, isomer content, sodium metabisulfite content, epinephrine content and related substances, and compared with the commercially available product PAR Company's A quality comparison study was conducted between the preparation (specification 1 ml: 1 mg) and the EPINEPHRINE preparation of BELCHER PHARMACEUTIC ALS LLC.

[0108] 1. Sample Source

[0109] Table 1 Sample information

[0110] 2. Comparison of the quality of the preparation of the present invention and commercially available preparations

[0111] The formulations were evaluated for potency and impurity levels using high performance liquid chromatography with UV detection. All impurities are expressed as area percentage. "ND" indicates not detected.

[0112] Table 2 Comparison of test data of different samples

[0113] The content of epinephrine in the present invention refers to the percentage compared to the labeled amount of epinephrine; the content of isomers or related substances refers to the percentage compared to the labeled amount of epinephrine.

[0114] 3. Quality comparison under stability test conditions

[0115] Further stability data of the present invention and PAR preparations were tested. Table 3 lists the stability test results of different samples at 40±2°C and 75±5% relative humidity, as well as the long-term test results of 3 months and 6 months at 25°C and 60% relative humidity.

[0116] Table 3 Comparison of stability data between formulation 1 and PAR formulation

[0117] The impurity contents of both the formulation 1 of the present invention and the commercially available PAR formulation were within the quality standards. However, based on the accelerated 3-month data, the impurity F in the PAR formulation was 11.1%, exceeding the limit of impurity F ≤ 10%. The formulation of the present invention is more effective in controlling the growth of impurity F under extreme conditions. Moreover, compared with the vial formulation of the prior art, the prefilled device of the present invention can reduce the adsorption and waste of the drug solution, achieve rapid injection, and is particularly suitable for emergency patient rescue.

[0118] Example 2-8 Study on the content of sodium metabisulfite

[0119] 1. Preparation

[0120] Using the composition listed in Table 4 below, an epinephrine prefilled device was prepared according to the method of Example 1.

[0121] Table 4 Different epinephrine compositions and devices

[0122] 2. Stability test

[0123] Formulations 2 to 8 prepared in accordance with Examples 2 to 8 were placed at high temperature (60° C.) for 10 days, and at 25° C. and 60% relative humidity for 3 months and 6 months, respectively. The isomer and impurity F data for the accelerated and long-term tests were tested.

[0124] Test results:

[0125] Table 5 Results of investigation on different preparations

[0126] The above results show that the higher the sodium metabisulfite content, the higher the initial content of impurity F after high-temperature sterilization. The sodium metabisulfite content in the apparatus for preparations 7 and 8 exceeded 0.35 mg / ml, and the impurity F content was as high as 4.61% and 7.16%. Moreover, after 10 days of high-temperature acceleration, the impurity F content in preparations 7 and 8 increased significantly, with its content far exceeding 10%, not meeting quality control requirements. The present invention effectively controls the content of impurity F by controlling the sodium metabisulfite content to ≤ 0.35 mg / ml. However, too low a sodium metabisulfite content will lead to an increase in the content of isomers. The present invention limits the sodium metabisulfite content to a range of 0.1 to 0.35 mg / ml, which effectively controls the content of impurity F.

[0127] Example 9-10 Study on Dosage of Tension Regulator

[0128] Using the compositions listed in Table 6 below, epinephrine pre-filled devices were prepared according to the method of Example 1, and the properties and osmotic pressure molar concentrations of different preparations were tested.

[0129] Table 6 Different epinephrine compositions and devices

[0130] The molar osmotic pressure concentration of the prefilled device of the present invention is 257-315 mOsmol / kg, and the amount of sodium chloride in the composition is preferably within 9 mg / ml.

[0131] Effect of pH value of drug solution in the device on drug solution quality in Examples 11-17

[0132] The difference between Examples 11-17 and Example 1 is that the pH value of the drug solution in the device is different.

[0133] The pH value of the liquid in the device was adjusted by adding different amounts of dilute hydrochloric acid. The other components and preparation process were consistent with Example 1. The dilute hydrochloric acid of the present invention is used to adjust the pH value, and its concentration is adjusted as needed. As an example, the concentration of dilute hydrochloric acid used in the present invention is 2-8%.

[0134] For the prepared preparations 1 and 11-17, samples were taken to test their properties, pH, isomers and impurity F content.

[0135] Preparation quality inspection results:

[0136] Table 7 Results of investigation on different preparations

[0137] As can be seen from the above results, preparations 11-17 are all colorless or nearly colorless clear liquids, and the pH value of the liquid in the device has a significant impact on the content of impurity F and isomers. According to one embodiment of the present invention, the pH value is preferably 2.9 to 4.3, which can control the content of impurity F and isomers at a low level. As shown in Figure 3, the impurity F / isomer and pH change curve shows that the most preferred pH range is 3.3 to 3.7, which has the best control effect on impurities and isomers.

[0138] Example 18 Prefilled Syringe

[0139] The filling syringe prepared in Example 1 of the present invention is syringe 1#. In order to investigate the quality of preparations in different pre-filled syringes, research experiments were conducted on different syringe properties and the quality of the drug solution after filling.

[0140] 1. Preparation

[0141] The contents of the components of the prepared epinephrine pharmaceutical composition are as follows (based on 1 ml):

[0142] According to the above composition, an epinephrine pre-filled device is prepared according to the following preparation method:

[0143] Step 1: Prepare the liquid

[0144] According to the above prescription, the raw materials and auxiliary materials are weighed to prepare the adrenaline composition. After mixing and dissolving the raw materials and auxiliary materials with water for injection, an appropriate amount of dilute hydrochloric acid is added to adjust the pH of the solution to about 3.5, and finally the volume is made up to the full amount with water for injection.

[0145] Step 2: Filling

[0146] The prepared epinephrine pharmaceutical composition was filled into the prefilled syringes #1 to #5 shown in Table 8. During the filling process, ensure that the process is carried out under a nitrogen atmosphere to reduce the presence of oxygen. The stopcock was installed to ensure that the drug solution was completely sealed in the container.

[0147] Step 3: Sterilization

[0148] After the filling is completed, the filling syringe is sterilized using terminal sterilization at 121° C. for 12 minutes to prepare preparations 18-22, respectively.

[0149] Table 8 Different prefilled syringes

[0150] The above test items, such as pH change, absorbance and oxidizable substances, are carried out according to the following standards:

[0151] Preparation for test:

[0152] Take the equivalent surface area of ​​200cm 2 Several complete pistons / protective caps, according to the sample surface area (cm 2 ) and water (ml) in a ratio of 1:2, add to immersion, boil for 5 minutes, let cool, and rinse with the same volume of water five times. Transfer to a conical flask, add the same volume of water, place in a high-pressure steam sterilizer at 121±2℃, maintain for 30 minutes, cool to room temperature, remove, and obtain the test solution. Prepare a blank solution in the same manner for testing.

[0153] pH change test

[0154] Take 20 ml of the test solution and blank solution, add 1 ml of potassium chloride solution (1→1000) respectively, and determine according to the general rules 0631 of Part IV of the 2015 edition of the Chinese Pharmacopoeia.

[0155] absorbance

[0156] Take an appropriate amount of the test solution and use the blank solution as the control. According to the general rule 0401 of Part IV of the 2015 edition of the Chinese Pharmacopoeia, test the absorbance in the wavelength range of 220-360 nm according to the UV-visible spectrophotometry method.

[0157] Oxidizable substances

[0158] Accurately measure 20 ml of the test solution, accurately add 20 ml of 0.002 mol / L potassium permanganate solution and 2 ml of dilute sulfuric acid, boil for 3 minutes, cool rapidly, add 0.1 g of potassium iodide, place in a dark place for 5 minutes, titrate with sodium thiosulfate titrant (0.01 mol / L) until it turns light brown, then add 5 drops of starch indicator solution and titrate until it is colorless, collect a blank solution and operate in the same way, the difference between the consumption of sodium thiosulfate titrant (0.01 mol / L) of the two is the measured value.

[0159] 2. Performance Testing

[0160] Preparations 18 to 22 were subjected to accelerated testing at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5%. Samples were taken at 0 and 3 months to test properties, pH, isomers, and related substances.

[0161] Table 9 Accelerated test data of different syringe filling preparations

[0162] Experimental studies have shown that absorbance and oxidizable substances primarily influence the clarity and color of the finished formulation, while pH fluctuations at the cap and piston significantly impact the formulation's quality stability. Accelerated data show a slightly elevated impurity F content in Formulation 21, with the fastest impurity growth rate after three months of accelerated testing. Further research in the present invention, by limiting the pH fluctuations at the cap and piston to no more than 0.5, can control the impurity F content to around 9% or less after three months of accelerated testing, resulting in significantly improved long-term stability.

[0163] Example 19 Investigation of residual oxygen control in filling process

[0164] 1. Preparation

[0165] The contents of the components of the prepared epinephrine pharmaceutical composition are as follows (based on 1 ml):

[0166] Step 1: Prepare the liquid

[0167] According to the above prescription, the raw materials and auxiliary materials are weighed to prepare the adrenaline composition. After mixing and dissolving the raw materials and auxiliary materials with water for injection, an appropriate amount of dilute hydrochloric acid is added to adjust the pH of the solution to about 3.5, and finally the volume is made up to the full amount with water for injection.

[0168] Step 2: Filling

[0169] The prepared epinephrine pharmaceutical composition was filled into the syringe used for Preparation 1. During the filling process, the residual oxygen concentration was controlled according to the amount of nitrogen injection, and Preparations 23 to 26 were prepared without nitrogen injection: that is, the headspace residual oxygen concentration was controlled at 3% with nitrogen injection, 5% with nitrogen injection, 10% with nitrogen injection, and 0% without nitrogen injection, respectively. The stopcock was installed to ensure that the drug solution was completely sealed in the container.

[0170] Step 3: Sterilization

[0171] After filling is completed, the filling syringe is sterilized using terminal sterilization at a temperature of 121°C for 12 minutes.

[0172] The sterilized product was stored at 40°C for 30 days and then stored for 3 months under long-term conditions. Samples were taken to determine properties, pH, isomers, and related substances. The results are shown in Table 10.

[0173] Table 10 Test results of influencing factors under nitrogen filling and non-nitrogen filling conditions

[0174] From the above tests, it can be seen that the pre-filled device for residual oxygen control, under long-term conditions of 3 months and accelerated conditions of 40°C for 1 month, the total impurities (the sum of impurities F, impurity B, impurity C and other total impurities) are all controlled at around 6.5% or less; significantly better than the conditions without nitrogen filling. On the other hand, the present invention has a wide process range for controlling the amount of residual oxygen in the headspace by nitrogen filling, and the concentration of residual oxygen in the headspace is controlled within the range of 3% to 5%, and the difference in total impurities is within the limit of 1%. The present invention can have a better impurity control effect through chemical component content and pH control, and its residual oxygen content has a wide process range.

[0175] Example 20 Preparation 27 and Comparative Example 1

[0176] 1. Preparation

[0177] Using the composition listed in Table 11 below, an epinephrine prefilled device 27 was prepared according to the method of Example 1.

[0178] Table 11 Different epinephrine compositions

[0179] 2. Accelerated testing of different packaging

[0180] The preparation was placed under the conditions of temperature 40°C ± 2°C and RH 75 ± 5% for accelerated testing. For Preparation 1 and Comparative Example 1, the test data of accelerated testing for 1 month, 2 months, and 3 months were tested to examine the effects of different packaging on the device.

[0181] Test results:

[0182] Table 12 Comparison of stability test data of different samples

[0183] Formulation 1 and Comparative Example 1 share identical compositions, yet their devices exhibit distinct impurity growth trends. The prefilled packaging material is a slow-oxygen permeable container, resulting in a higher oxygen permeability than ampoules, which provide a permanent barrier. Experimental data indicate that the impurity F content in Comparative Example 1 increased significantly, reaching 11.7% after three months of accelerated growth, exceeding the 10% control requirement. Quality control of the present device is closely linked to the properties of the packaging material and the controlled content of each component. The prefilled device containing the drug solution provided by the present invention exhibits excellent stability and enables rapid injection.

[0184] 3. Long-term stability test of formulation 1 and formulation 27

[0185] Formulation 1 and Formulation 27 were placed under long-term storage conditions (25±2°C, relative humidity 60%±5%), and the results of the storage for 0 months, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months were respectively observed, as shown in Tables 13 and 14.

[0186] Test results:

[0187] Table 13 Long-term stability test data of preparation 1

[0188] Table 14 Long-term stability test data of formulation 27

[0189] In long-term experiments, Formulations 1 and 27 of the present invention maintained impurity F ≤ 10%, isomer content ≤ 10%, and epinephrine content at 90-110% of the labeled amount over 24 months of storage, meeting formulation requirements. Compared to existing technologies, the sodium metabisulfite content of the present invention was ≤ 0.35 mg / ml, significantly reducing sodium metabisulfite usage while maintaining a shelf life of up to 24 months.

[0190] Formulation 1 exhibits superior isomer control compared to Formulation 27, maintaining an isomer content of ≤5% even after 24 months of storage. Therefore, the sodium metabisulfite content in the composition used to prepare the prefilled device is >0.2 mg / ml, ensuring a sodium metabisulfite content of no less than 0.1 mg / ml after 6 months of storage, demonstrating extended drug solution stability and a shelf life of ≥24 months.

[0191] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0192] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A pre-filled device containing adrenaline solution, characterized in that: It comprises a pre-filled syringe and an epinephrine solution filled therein; the pre-filled syringe is selected from syringe 1 or syringe 2; The syringe 1 includes a first needle tube 101, a first piston 102, a first injection needle 103, a first needle cap 104, and a first push rod 105; the first needle tube 101, the first piston 102, the first injection needle 103, and the first needle cap 104 constitute a first sealing system, and the first sealing system is used to encapsulate an epinephrine solution 106; The syringe 2 includes a second needle tube 201, a second piston 202, a second retaining ring 203, a second protective cap 204 and a second push rod 205; the second needle tube 201, the second piston 202 and the second protective cap 204 constitute a second sealing system, and the interior of the second sealing system is used to encapsulate the adrenaline solution 206; The pH value variation range of the first piston is ≤0.5 and the pH value variation range of the first needle cap is ≤0.5; Alternatively, the pH variation range of the second piston is ≤0.5 and the pH variation range of the second protective cap is ≤0.5; The adrenaline liquid comprises an adrenaline active agent with a content of 1.0 to 1.2 mg / ml and sodium metabisulfite with a content of 0.1 to 0.35 mg / ml.

2. The pre-filled device according to claim 1, characterized in that: The adrenaline solution comprises a metal ion complexing agent, and the content of the metal ion complexing agent is 0.1-0.3 mg / ml.

3. The pre-filled device according to claim 1, characterized in that: The adrenaline solution includes a pH regulator, and the pH value of the adrenaline solution ranges from 2.5 to 5.

0.

4. The prefilled device according to claim 1, characterized in that: The adrenaline solution includes a buffer, and the pH value of the adrenaline solution ranges from 3.0 to 4.

5.

5. The pre-filled device according to claim 1, characterized in that: The adrenaline solution comprises a pH regulator and a buffer, and the pH value of the adrenaline solution ranges from 3.0 to 4.

0.

6. A composition for preparing the prefilled device according to any one of claims 1 to 5, characterized in that: The composition comprises the following components: The pH value of the composition ranges from 2.5 to 5.

0.

7. A method for preparing a prefilled device according to any one of claims 1 to 5, characterized in that: The following steps are involved: Liquid preparation: Prepare a composition comprising the following components: The pH value of the composition ranges from 2.5 to 5.0; Filling: filling the composition into a prefilled syringe; Sterilization: sterilize the prefilled syringe containing the composition to obtain the prefilled device containing the adrenaline solution.

8. The preparation method according to claim 7, characterized in that The filling comprises the following steps: The composition is filled into a syringe under a nitrogen atmosphere, and a piston is installed, and the concentration of residual oxygen in the headspace of the pre-filled syringe is controlled to be ≤5%.

9. The preparation method according to claim 7, characterized in that The sterilization comprises the following steps: The sterilization is steam sterilization, the sterilization temperature is 121° C., and the sterilization time is 8 to 15 minutes.

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