An epinephrine co-amorphous composition and methods of making the same

Abstract

The present application relates to the technical field of pharmaceutical preparation, and specifically discloses an adrenaline co-amorphous composition and a preparation method thereof, which aims at the problems of existing adrenaline, such as easy oxidative degradation, slow dissolution rate, poor storage stability, difficulty in forming stable amorphous by binary compounding of adrenaline and dexamethasone sodium phosphate, and complicated operation of multiple drug administration in clinic, and the present application prepares a ternary single-phase co-amorphous system by mixing adrenaline, ascorbic acid and dexamethasone sodium phosphate according to a molar ratio of 1:(0.1-1):1, and ascorbic acid is used as a molecular bridge to construct intermolecular interaction with an antioxidant stabilizer; during preparation, the raw materials are dissolved in water, reacted through water bath reaction, and then crude products are obtained through vacuum rotary evaporation or freeze-drying, and the finished products are obtained through vacuum drying to remove residual solvents. The composition has no crystal characteristic diffraction peak, a glass transition temperature of 70-90 DEG C, and greatly improved dissolution rate, chemical and physical stability, and the pharmacological synergy of the three components can reduce the side effects of first aid.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to an adrenaline co-amorphous composition and its preparation method. Background Technology

[0002] Epinephrine, an important endogenous catecholamine, exerts a wide and complex range of pharmacological effects by activating α and β adrenergic receptors widely distributed throughout the body. Its main effects include enhancing myocardial contractility, increasing heart rate, regulating vascular tone (causing vasoconstriction), relaxing bronchial smooth muscle, promoting glycogenolysis and lipolysis, and regulating the nervous and immune systems. These effects make it a key drug for treating various acute and critical illnesses such as anaphylactic shock, cardiac arrest, and as an adjunct to local anesthesia. However, epinephrine is a highly oxidizable and unstable drug, capable of rapid oxidation and discoloration even in solution and in the solid state. Furthermore, its limited solubility and slow dissolution rate affect its effectiveness in scenarios requiring rapid onset of action (such as the resuscitation of anaphylactic shock). Therefore, improving the dissolution rate and storage stability of epinephrine has been a long-standing technical need in the field of pharmaceutical formulation.

[0003] In the clinical treatment of severe allergic reactions and other diseases, adrenaline can be used in combination with drugs that have potent anti-inflammatory and anti-allergic effects, such as dexamethasone sodium phosphate. As an adrenocortical hormone, dexamethasone sodium phosphate can alleviate the pathological damage of allergic reactions through its powerful anti-inflammatory and immunosuppressive effects, and is widely used in the comprehensive treatment of allergic diseases, autoimmune diseases, and severe infections. It forms a synergistic and complementary relationship with adrenaline in terms of its mechanism of action. Based on this, the initial consideration was to combine adrenaline and dexamethasone sodium phosphate to simultaneously address the formulation defects of adrenaline by constructing a co-amorphous system. However, studies have shown that directly mixing dexamethasone sodium phosphate and adrenaline cannot improve the stability of adrenaline, and the two drug molecules lack sufficiently strong interactions to spontaneously form a stable co-amorphous compound, nor can they effectively inhibit the oxidative degradation of adrenaline, indicating that this binary system cannot achieve the expected goals. Therefore, to overcome this bottleneck, ascorbic acid was further introduced as a third component.

[0004] Ascorbic acid, also known as vitamin C, is an essential nutrient for the human body. At normal physiological concentrations, it possesses redox activity, with its core characteristic being its powerful antioxidant function. It can significantly reduce the oxidation rate of adrenaline, providing a crucial foundation for its role in the prevention and treatment of various diseases. Simultaneously, ascorbic acid can alleviate the severity of allergic reactions and has an auxiliary effect on the body's resistance to infection. More importantly, ascorbic acid can act as a "bridge" for the formation of co-amorphous systems. Through its molecular structure, it can form stable intermolecular interactions with adrenaline and dexamethasone sodium phosphate, promoting the formation of a ternary co-amorphous system. Therefore, ascorbic acid can act as both an antioxidant stabilizer and a co-amorphous promoter in ternary co-amorphous systems. This ternary composition provides a novel approach for the optimization of adrenaline preparations.

[0005]

[0006] Adrenaline, dexamethasone, sodium phosphate, ascorbic acid Coamorphous drug systems (CAS) are special solid forms in which molecules lack regularity and order, yet remain a single phase. Weak but discrete intermolecular interactions exist between the components forming the CAS. Compared to individual amorphous substances, CAS can significantly improve drug solubility and dissolution rate, and also exhibit stronger physical stability and improved bioavailability. However, it is unpredictable which substances will form CAS under what conditions, and current research on the CAS system of adrenaline is not publicly available. In summary, existing adrenaline preparations suffer from drawbacks such as easy drug oxidation, slow dissolution rate, and poor storage stability; the binary combination of adrenaline and dexamethasone sodium phosphate cannot form a stable amorphous composition and has insufficient antioxidant effect; the simple physical mixing of the three active ingredients lacks synergistic formulation advantages, and the operation of multiple drug combinations in clinical practice is complicated. There is an urgent need to develop a novel ternary co-amorphous composition that takes into account the stability and rapid dissolution characteristics of adrenaline, while achieving pharmacological synergy of the three active ingredients and simplifying the emergency administration process. Summary of the Invention

[0007] The purpose of this invention is to address the deficiencies of the prior art by providing an adrenaline co-amorphous composition and its preparation method, thereby resolving the problems raised in the background art.

[0008] To achieve the above objectives, the present invention provides the following technical solution: an adrenaline co-amorphous composition, wherein the adrenaline co-amorphous composition is composed of adrenaline, ascorbic acid and dexamethasone sodium phosphate, wherein the molar ratio of adrenaline, ascorbic acid and dexamethasone sodium phosphate is 1:(0.1~1):1.

[0009] As a preferred embodiment of the present invention, the molar ratio of adrenaline, ascorbic acid and dexamethasone sodium phosphate is 1:0.8 to 1:1.

[0010] As a preferred embodiment of the present invention, the composition is a ternary single-phase co-amorphous system, in which the three components are bound together by intermolecular interactions; the X-ray powder diffraction pattern of the composition has no sharp crystal characteristic diffraction peaks, and the glass transition temperature of the composition is 70℃~90℃.

[0011] As a preferred embodiment of the present invention, the Fourier transform infrared spectrum of the composition after KBr tablet preparation is at 3423.83 cm⁻¹. -l 1719.73cm -l 1661.02cm -l 1605.07cm -l 1523.22cm -l 1391.33cm -l 1289.94cm -l 1241.12cm -l 1109.63cm -l 1069.97cm -l 978.49cm -l 882.89cm -l 818.41cm -l 758.19cm -l 539.04cm -l A characteristic absorption peak exists at this location.

[0012] A method for preparing the adrenaline co-amorphous composition as described above includes the following steps: S1. Weigh out adrenaline, ascorbic acid and dexamethasone sodium phosphate in a molar ratio of 1:(0.1~1):1; S2. Dissolve the three raw materials from step S1 in water and react them in a water bath for 60–180 min to obtain a clear mixed solution; the water bath temperature is 25–40 °C. S3. The mixed solution is treated by solvent evaporation or freeze-drying to obtain a co-amorphous crude product; S4. The co-amorphous crude product obtained in step S3 is subjected to vacuum drying to remove residual solvent, and adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous product is obtained.

[0013] As a preferred technical solution of the present invention, in step S3, the solvent evaporation method is as follows: the mixed solution is subjected to reduced pressure rotary evaporation at 40-55°C for 30-120 min to obtain a co-amorphous crude product.

[0014] As a preferred technical solution of the present invention, in step S3, the freeze-drying method is as follows: after the mixed solution is pre-frozen, it is freeze-dried under vacuum for 12-24 hours to obtain amorphous crude product.

[0015] As a preferred embodiment of the present invention, the vacuum drying time in step S4 is 12-24 hours.

[0016] The use of an adrenaline co-amorphous composition as described above in the preparation of a medicament for the treatment and / or prevention of anaphylactic shock, cardiac arrest, or chronic inflammatory diseases.

[0017] As a preferred embodiment of the present invention, the drug is an injection, a lyophilized powder injection, or an oral preparation.

[0018] Compared with the prior art, the beneficial effects of the present invention are: 1. Construct a stable ternary co-amorphous single-phase system, distinct from monomers and physical mixtures, to address the inherent defects of adrenaline preparations at the solid-state level. This invention uses a 1:(0.1-1):1 molar ratio of adrenaline, ascorbic acid, and dexamethasone sodium phosphate. Utilizing the polyhydroxy structure of ascorbic acid as a molecular bridge, the regular crystal structures of the three active pharmaceutical ingredients are disrupted through intermolecular hydrogen bonds and other interactions, forming a homogeneous single-phase ternary amorphous system. The PXRD pattern shows no sharp diffraction peaks characteristic of each monomer, the DSC shows only a single glass transition temperature, and the infrared characteristic peaks show a significant shift, proving that the product is a novel solid form, not a simple physical mixture. Compared to binary systems, this invention overcomes the technical bottleneck of the adrenaline-dexamethasone sodium phosphate binary system's inability to spontaneously form a stable amorphous structure.

[0019] 2. Significantly increases the rate of adrenaline dissolution, meeting the need for rapid onset of action in emergency treatment of anaphylactic shock. The disordered dispersion structure of the co-amorphous molecules eliminates the lattice energy barrier to crystal dissolution. Comparing the three physical mixtures: in a pure water system, the ternary co-amorphous compound dissolves completely in 25 seconds, while the physical mixture still cannot be completely dissolved after 300 seconds; in a physiological saline system, the ternary co-amorphous compound dissolves completely in 57 seconds, and the physical mixture dissolves very poorly. This significantly accelerates the dissolution rate, and in emergency situations requiring rapid onset of action, such as shock and cardiac arrest, it can quickly increase the drug concentration in the body and shorten the time to treatment effectiveness.

[0020] 3. Dual antioxidant protection significantly reduces adrenaline oxidative degradation impurities and improves chemical storage stability. Ascorbic acid exerts a strong antioxidant effect within the system, blocking the oxidation pathway of the catechol group in adrenaline and inhibiting the formation of adrenaline, the main degradation impurity. Stability test data shows that after 15 days of accelerated oxidation at 40℃ / 75%RH, the total impurities of adrenaline monomers reached as high as 14.9%, and adrenaline impurities reached 12.7%; while the total impurities of the ternary co-amorphous composition of this invention were only 2.9%, and adrenaline only 1.8%, effectively delaying drug oxidation and discoloration, and reducing efficacy.

[0021] 4. Excellent long-term physical stability; not prone to recrystallization during storage; wider range of formulation applications. The ternary intermolecular forces bind the molecular rearrangement. After being placed in high humidity (25℃ / 92.5%RH), accelerated humidity (40℃ / 75%RH), and long-term (25℃ / 60%RH) (90 days), the sample PXRD pattern showed no crystal diffraction peaks and no recrystallization. The hygroscopicity test showed a weight gain of only 0.62%, classifying it as a slightly hygroscopic material. It is not prone to moisture absorption and deterioration during storage, dispensing, and formulation processing, and can be stored stably for a long time. It is suitable for the development of various dosage forms such as lyophilized powder injections, injections, and oral preparations.

[0022] 5. The three active components exhibit synergistic pharmacological effects, resulting in superior emergency treatment efficacy compared to single drugs and physical mixtures. Epinephrine rapidly corrects shock circulation and respiratory failure; dexamethasone sodium phosphate provides long-lasting anti-inflammatory effects and inhibits the inflammatory cascade of allergic reactions; ascorbic acid provides antioxidant effects and reduces tissue oxidative damage. All three are released and act simultaneously in a homogeneous amorphous molecular system. A rat anaphylactic shock model confirmed that, compared to the single-apinephrine group, this combination resulted in faster recovery of blood oxygen saturation and a more stable return of heart rate to baseline after administration, without the excessive tachycardia side effect caused by epinephrine alone. Compared to physical mixtures, there was no significant therapeutic advantage, demonstrating that only the ternary amorphous system can achieve synergistic pharmacological effects, reducing mortality and improving prognosis in shock animals.

[0023] 6. Simplify clinical emergency drug administration procedures and reduce operational risks. Traditional emergency treatment requires multiple intravenous injections of three medications: adrenaline, dexamethasone, and vitamin C. Multiple punctures and multi-line infusions can increase the circulatory burden on shock patients, making the procedure cumbersome and time-consuming. The ternary co-amorphous composition of this invention can be formulated into a single injection / lyophilized powder, providing three therapeutically active ingredients simultaneously with a single dose. This simplifies emergency procedures, shortens rescue time, and reduces the clinical risks associated with multiple administrations.

[0024] 7. The preparation process is simple and controllable, and the two preparation routes are suitable for industrial production. This invention provides two preparation routes: aqueous phase reaction + vacuum rotary evaporation and aqueous phase reaction + vacuum freeze-drying. Only pure water is used as the solvent, eliminating the risk of residual organic solvents. Water bath reaction, evaporation, freeze-drying, and vacuum drying are all mature and conventional equipment in the pharmaceutical industry. The process parameters have a wide range (water bath 25-40℃ reaction 60-180 min, rotary evaporation 40-55℃, freeze-drying 12-24 h), mild conditions, easy scale-up, stable product yield, no complicated purification steps, and low production cost, making it suitable for large-scale pharmaceutical production.

[0025] 8. Adjustable grouping ratio, flexible application scenarios. The molar ratio of ascorbic acid can be adjusted in the range of 0.1 to 1, with 0.8 being preferred. The proportion of antioxidant components can be adjusted according to the formulation, storage period, and clinical needs. The product can be processed into injections, lyophilized powder injections, and oral preparations. It can be used for emergency rescue of anaphylactic shock and cardiac arrest, as well as for long-term adjuvant treatment of chronic inflammatory diseases, with a wide range of applications. Attached Figure Description

[0026] Figure 1 X-ray diffraction pattern of the adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous compound prepared in Example 1; Figure 2 The DSC spectrum of the adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous compound prepared in Example 1; Figure 3 Fourier transform infrared spectrum of the adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous compound prepared in Example 1; Figure 4 X-ray diffraction patterns of the adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous compound prepared in Example 1 under different conditions; Figure 5 Comparison of powder X-ray diffraction patterns of adrenaline, ascorbic acid, dexamethasone sodium phosphate, and the ternary amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate prepared in Example 1; Figure 6Comparison of DSC spectra of adrenaline, ascorbic acid, dexamethasone sodium phosphate, and the ternary amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate prepared in Example 1; Figure 7 Comparison of infrared spectra of adrenaline, ascorbic acid, dexamethasone sodium phosphate, physical mixture of adrenaline-ascorbic acid-dexamethasone sodium phosphate, and the ternary amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate prepared in Example 1. Detailed Implementation

[0027] The preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby providing a clearer and more explicit definition of the scope of protection of the present invention.

[0028] Based on the embodiments disclosed in this invention, reasonable variations, equivalent substitutions, or further applications that can be conceived by those skilled in the art without creative effort should all be considered to fall within the scope of protection of this invention as defined by the appended claims.

[0029] Any numerical range (including endpoint values ​​or specific numerical points) disclosed in the specification should be understood to include the acceptable tolerance range in the vicinity of that range. Furthermore, different endpoint values ​​and individual numerical points can be combined to form new numerical ranges that are not explicitly listed in the text but are logically valid. These derived ranges should also be considered as having been disclosed in this invention.

[0030] Based on the issue of the need to improve the stability of adrenaline, the present invention discovered during the research process that when adrenaline, ascorbic acid and dexamethasone sodium phosphate are mixed in a specific molar ratio and under the action of a specific type of solvent, a co-amorphous compound can be formed. Therefore, the present invention provides an adrenaline co-amorphous composition and its preparation method.

[0031] The instruments used in this invention for detecting the co-amorphous structure and properties of drugs are as follows: (1) X-ray powder diffractometer, manufactured by Panaco GmbH, Netherlands, model X' Pert PRO MPD, Cu-K(α), tube voltage 40kV, tube current 40mA, scanning speed 2° / min, 2θ range 3-60℃; (2) Differential scanning calorimeter, Netzsch GmbH, Germany, model DSC 3500 Sirius. This invention uses a nitrogen atmosphere, with a heating rate of 10 K / min; range: 30-250 ℃; (3) Fourier transform infrared spectrometer, manufactured by Bruker GmbH, Germany, model Vertex 70, with an absorption wavelength of 4000–500 cm⁻¹. -lKBr tablets.

[0032] A method for preparing an adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous compound, the specific steps of which are as follows: S1. Weigh out adrenaline, ascorbic acid and dexamethasone sodium phosphate in a molar ratio of 1:(0.1~1):1; S2. Dissolve the three raw materials from step S1 in water and react them in a water bath for 60–180 min to obtain a clear mixed solution; the water bath temperature is 25–40°C. The freeze-drying method includes: dissolving the adrenaline, ascorbic acid and dexamethasone sodium phosphate weighed in step S1 in a suitable aqueous solvent, pre-freezing, and then freeze-drying under vacuum for 12-24 h to obtain a co-amorphous crude product. The solvent evaporation method includes: dissolving the adrenaline, ascorbic acid and dexamethasone sodium phosphate weighed in step S1 in a solvent, and rotary evaporating the mixed solution under reduced pressure at 40-55°C for 30-120 min to obtain a co-amorphous crude product; S3. The co-amorphous crude product is freeze-dried or vacuum-dried to remove the solvent and obtain adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous product. The freeze-drying method includes: dissolving adrenaline, ascorbic acid and dexamethasone sodium phosphate in a solvent, reacting them in a water bath at 30-40°C for 60-180 min, pre-freezing them, placing them in a freeze dryer, and freeze-drying them under vacuum for 12-24 h to obtain a co-amorphous crude product.

[0033] The solvent evaporation method includes: dissolving the adrenaline and dexamethasone sodium phosphate weighed in step S1 in an aqueous solution, reacting them in a water bath at 30-40 °C for 60-180 min, evaporating the solvent under reduced pressure at 50-55 °C, and then vacuum drying for 12-24 h to obtain a co-amorphous crude product.

[0034] The preferred molar ratio of adrenaline, ascorbic acid, and dexamethasone sodium phosphate is 1:0.8:1.

[0035] The following detailed description, with reference to specific embodiments, illustrates the adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous compound and its preparation method provided by the present invention: Example 1: A method for preparing an adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous compound, comprising the following steps: S1. Weigh out 36.64 mg (0.2 mmol) of adrenaline, 35.22 mg (0.2 mmol) of ascorbic acid, and 103.282 mg (0.2 mmol) of dexamethasone sodium phosphate according to the molar ratio of adrenaline:ascorbic acid:dexamethasone sodium phosphate 1:1:1. S2. After completely dissolving the adrenaline, ascorbic acid, and dexamethasone sodium phosphate weighed in S1 in water, the mixture was reacted in a 40 ℃ water bath for 3 hours to obtain a co-amorphous crude product. S3. The co-amorphous crude product obtained in step S2 is subjected to rotary evaporation under reduced pressure at 50°C for 120 min, and then placed in a vacuum drying oven at 40°C for 24 h to remove the solvent, resulting in a solid powder, thus obtaining the ternary co-amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate.

[0036] The X-ray powder diffraction pattern of the amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate obtained in Example 1 is as follows: Figure 1 As shown, there are no sharp crystal diffraction peaks; The DSC spectrum of the amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate obtained in Example 1 is as follows: Figure 2 As shown, the glass transition temperature of this co-amorphous material is 79.7 °C. The Fourier transform infrared spectrum of the amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate obtained in Example 1 is shown below. Figure 3 As shown, at 3423.83 cm -l 1719.73 cm -l 1661.02 cm -l 1605.07 cm -l 1523.22 cm -l 1391.33 cm -l 1289.94 cm -l 1241.12 cm -l 1109.63 cm -l 1069.97 cm -l 978.49 cm -l 882.89 cm -l 818.41 cm -l 758.19 cm -l 539.04 cm -l It has a characteristic peak.

[0037] Example 2: A method for preparing an adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous compound, comprising the following steps: S1. Weigh out 36.64 mg (0.2 mmol) of adrenaline, 35.22 mg (0.2 mmol) of ascorbic acid, and 103.282 mg (0.2 mmol) of dexamethasone sodium phosphate according to the molar ratio of adrenaline:ascorbic acid:dexamethasone sodium phosphate 1:1:1. S2. After completely dissolving the adrenaline, ascorbic acid, and dexamethasone sodium phosphate weighed in S1 in water, the mixture was reacted in a 40 ℃ water bath for 3 hours to obtain a co-amorphous crude product. S3. The co-amorphous crude product obtained in step S2 is subjected to rotary evaporation under reduced pressure at 55°C for 100 min, and then placed in a vacuum drying oven at 40°C for 24 h to remove the solvent, resulting in a solid powder, thus obtaining the ternary co-amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate.

[0038] Upon testing, the X-ray powder diffraction pattern, DSC pattern, and Fourier transform infrared spectrum of the ternary co-amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate obtained in Example 2 were found to be basically consistent with those of Example 1.

[0039] Example 3: A method for preparing an adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous compound, comprising the following steps: S1. According to the molar ratio of adrenaline: ascorbic acid: dexamethasone sodium phosphate 1:1:1, weigh out 36.64 mg (0.2 mmol) of adrenaline, 35.22 mg (0.2 mmol) of ascorbic acid and 103.282 mg (0.2 mmol) of dexamethasone sodium phosphate. S2. After completely dissolving the adrenaline, ascorbic acid, and dexamethasone sodium phosphate weighed in S1 in water, the mixture was reacted in a water bath at 40°C for 3 hours to obtain a co-amorphous crude product. S3. The co-amorphous crude product obtained in step S2 is first pre-frozen in a freezer at -80°C, and then freeze-dried in a freeze dryer for 24 hours to remove the solvent, and then formed into a solid powder to obtain the ternary co-amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate.

[0040] Upon testing, the X-ray powder diffraction pattern, DSC pattern, and Fourier transform infrared spectrum of the ternary co-amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate obtained in Example 3 were found to be basically consistent with those of Example 1.

[0041] Examples 4-5:

[0042] Upon testing, the X-ray powder diffraction pattern, DSC pattern, and Fourier transform infrared spectrum of the ternary co-amorphous compounds of adrenaline-ascorbic acid-dexamethasone sodium phosphate obtained in Examples 4 and 5 were found to be basically consistent with those in Example 1.

[0043] Comparative Example 1: It provides adrenaline monomers.

[0044] Comparative Example 2: Ascorbic acid monomers are provided.

[0045] Comparative Example 3: Dexamethasone sodium phosphate monomer is provided.

[0046] To compare the ternary co-amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate prepared in Example 1 with the adrenaline monomer, ascorbic acid monomer, and dexamethasone sodium phosphate monomer, X-ray diffraction patterns and DSC spectra of the adrenaline monomer, ascorbic acid monomer, and dexamethasone sodium phosphate monomer were measured according to the test methods provided in the examples, and compared with the ternary co-amorphous compound of adrenaline-ascorbic acid-dexamethasone sodium phosphate prepared in Example 1. The results are as follows: Figure 5 , Figure 6 As shown.

[0047] Comparative Example 4: Preparation method of adrenaline-ascorbic acid-dexamethasone sodium phosphate mixture: adrenaline, ascorbic acid and dexamethasone sodium phosphate are simply physically mixed in a molar ratio of 1:1:1 to obtain the mixture.

[0048] The physical mixture of adrenaline-ascorbic acid-dexamethasone sodium phosphate provided in this comparative example and the monomers provided in comparative examples 1-3 were subjected to infrared spectroscopy according to the test methods provided in the examples, and compared with the amorphous product of adrenaline-ascorbic acid-dexamethasone sodium phosphate prepared in example 1. The results are as follows: Figure 7 As shown.

[0049] Depend on Figure 7 It can be seen that the infrared spectra of the ternary amorphous compounds of adrenaline-ascorbic acid-dexamethasone sodium phosphate prepared in Examples 1 and 2 are significantly different from those of adrenaline monomer, ascorbic acid monomer, dexamethasone sodium phosphate monomer, and the physical mixture of adrenaline-dexamethasone sodium phosphate. This indicates that the amorphous compounds of adrenaline-ascorbic acid-dexamethasone sodium phosphate prepared in Example 1 and the physical mixture of adrenaline-ascorbic acid-dexamethasone sodium phosphate belong to different solid forms.

[0050] To examine the difference in solubility between the physical mixture of adrenaline-ascorbic acid-dexamethasone sodium phosphate provided in Comparative Example 4 and the amorphous co-amorphous product of adrenaline-dexamethasone sodium phosphate prepared in Example 1, the physical mixture of adrenaline-ascorbic acid-dexamethasone sodium phosphate provided in Comparative Example 3 was dissolved in 1 mL of pure water and physiological saline, respectively, and the time required for complete dissolution was tested. Under the same conditions, the ternary amorphous co-amorphous product of adrenaline-ascorbic acid-dexamethasone sodium phosphate prepared in Example 1 was dissolved in 1 mL of pure water and physiological saline, respectively, and the time required for complete dissolution was tested. The results are shown in Table 1.

[0051] Table 1: Comparison of solubility of substances provided in Example 1 and Comparative Example 4

[0052] As can be seen from Table 1, the solubility of the adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous compound prepared in Example 1 in pure water and physiological saline was significantly improved compared with that of the physical mixture.

[0053] Example 6: Chemical Stability Study To verify the significant effect of the adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous composition provided by this invention in improving the chemical stability of adrenaline, especially its antioxidant capacity, the ternary co-amorphous composition and a reference standard were placed under the following conditions: long-term conditions: 25°C / 60%RH; accelerated conditions: 40°C / 75%RH. High-performance liquid chromatography (HPLC) was used to determine the content of the main adrenaline component and related substances in the samples. The method used is a validated stability indication method capable of effectively separating adrenaline from its main degradation products (such as adrenaline ketone). Adrenaline ketone is the main product of the oxidative degradation of adrenaline; the catecholamines in the adrenaline structure are readily oxidized by air, light, etc., to generate red adrenaline ketone.

[0054] Table 2: Study on the content of adrenaline monomers and co-amorphous impurities

[0055] The experimental data in Table 2 fully demonstrate that by introducing ascorbic acid to form a ternary co-amorphous system with adrenaline and dexamethasone sodium phosphate, the antioxidant effect of ascorbic acid is exerted, the content of the main impurities of adrenaline oxidation degradation products is reduced, and the stability of adrenaline is greatly improved.

[0056] Example 7: Stability Study To test the storage stability of the adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous composition prepared in this embodiment, it was aliquoted into different clean petri dishes and subjected to stability studies under different conditions. Specifically, it was placed under high humidity conditions (25°C / 92.5%RH) for 15 days, under accelerated stability study conditions (40°C / 75%RH) for 15 days, and under long-term stability study conditions (25°C / 60%RH) for 90 days. X-ray diffraction patterns were measured under different conditions, as shown below. Figure 4 As shown.

[0057] Depend on Figure 4 It can be seen that the X-ray diffraction patterns of the adrenaline-ascorbic acid-dexamethasone sodium phosphate amorphous composition under different conditions are not significantly different, indicating that the adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous composition has good storage stability.

[0058] Example 8: Hygroscopicity Study To evaluate the hygroscopicity of the adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous composition prepared in this invention, the ternary co-amorphous composition, along with the adrenaline monomer, ascorbic acid monomer, and dexamethasone sodium phosphate monomer, were placed in clean, dry vials, and the sample weights were accurately measured. Subsequently, each sample was placed in a constant temperature and humidity chamber at 25°C / 80%RH for 24 hours. After removal, the samples were weighed again, and the weight gain percentage was calculated using the following formula: Percentage of weight gain Where M1 is the weight of the empty vial, M2 is the weight after adding the sample, and M3 is the total weight of the vial and sample after moisture absorption. The test results are shown in Table 3. By comparing the weight changes of each sample before and after moisture absorption, the differences in moisture absorption behavior between the co-amorphous composition and each monomer under the same humidity environment are evaluated, thereby determining its physical stability and suitability under actual storage conditions.

[0059] Table 3: Results of Hygroscopicity Study

[0060] As shown in Table 3, according to the hygroscopicity classification criteria (weight gain ≥15% is highly hygroscopic, 2%~15% is hygroscopic, 0.2%~2% is slightly hygroscopic, and <0.2% is non-hygroscopic or almost non-hygroscopic), all tested samples fall into the "slightly hygroscopic" category. The hygroscopicity of the ternary co-amorphous composition (0.62%) is similar to that of the adrenaline and dexamethasone sodium phosphate monomers, and slightly higher than that of the ascorbic acid monomer, but the overall weight gain is low, indicating that the co-amorphous composition does not exhibit a significant tendency to absorb moisture under high humidity conditions. This result proves that the ternary co-amorphous composition has good physical stability, and its hygroscopicity will not adversely affect storage and use, further supporting its feasibility and reliability in pharmaceutical applications.

[0061] Example 9: Therapeutic effect of a rat model of anaphylactic shock The therapeutic effect of the optimal epinephrine-ascorbic acid-dexamethasone sodium phosphate co-amorphous formulation prepared in Example 1 was evaluated using a rat anaphylactic shock model.

[0062] The method is as follows: The therapeutic effect and synergistic effect of the adrenaline-ascorbic acid-dexamethasone sodium phosphate ternary co-amorphous composition of the present invention on anaphylactic shock were evaluated using an ovalbumin-induced rat anaphylactic shock model (n=5). Active sensitization was performed by subcutaneous injection of ovalbumin (OVA, 1 mg / rat) and aluminum hydroxide adjuvant (10 mg / rat) on days 0, 4, and 14. On day 21, anaphylactic shock was induced by intravenous injection of ovalbumin (1 mg / 500 μL saline, administered within 1 min) via the external jugular vein. Five minutes after OVA challenge, the animals were randomly divided into four groups (n=5): a blank group (anaphylactic shock without drug administration, i.e., model control group), an adrenaline monomer group (commercially available adrenaline hydrochloride injection), a physical mixture group (simple mixture of adrenaline + ascorbic acid + dexamethasone sodium phosphate in a 1:1:1 molar ratio), and a ternary co-amorphous group (prepared in Example 1 of the present invention).

[0063] Accurately weigh the ternary amorphous composition of adrenaline-ascorbic acid-dexamethasone sodium phosphate prepared in Example 1 of this invention, add physiological saline, gently shake to completely dissolve, filter through a 0.22 μm microporous membrane for sterilization, and use immediately after preparation. The dosage is calculated based on the adrenaline content, and injection should be completed within 30 minutes after preparation. For the adrenaline monomer group, commercially available adrenaline hydrochloride injection solution is diluted with physiological saline to the required concentration. For the physical mixture group, adrenaline, ascorbic acid, and dexamethasone sodium phosphate are physically mixed in a 1:1:1 molar ratio and prepared into a solution using the same method (ultrasonic dissolution is required for approximately 3-5 minutes until complete dissolution).

[0064] Dosing began 5 minutes after OVA stimulation (T0+5 min), via external jugular vein. The foot sensor of a small animal pulse oximeter was clipped to the rat's hind paw pad for continuous monitoring of heart rate and oxygen saturation. In the adrenaline monomer group, the initial dose was 0.02 mg / kg (diluted to 0.1 mL with normal saline). A second dose of 0.02 mg / kg was administered when a further decrease in heart rate was detected by the pulse oximeter, with the infusion rate titrated according to heart rate changes. In the physical mixture group and the ternary co-amorphous group, the adrenaline was administered at an equimolar dose, with ascorbic acid and dexamethasone sodium phosphate administered proportionally, following the same administration method and titration principles. The control group received an equal volume of normal saline at a matched infusion rate.

[0065] Heart rate and blood oxygen saturation were continuously monitored using a small animal pulse oximeter before administration and at 10, 30, and 60 minutes after administration, as well as at subsequent time points. Changes in heart rate and mean survival time were observed and recorded. The anti-anaphylactic shock effect of the composition of this invention was evaluated using heart rate changes in rats.

[0066] Table 4: Changes in heart rate and blood oxygen saturation (SpO2) at different time points in each group of rats (n=5)

[0067] Note: T0 is the time of ovalbumin injection; T0+5 min is the time of the first administration. The blank group is the anaphylactic shock group that did not receive the drug (model control group). "—" indicates that all animals have died or there is no data.

[0068] Model validation: In the control group (anaphylactic shock without drug administration), after ovalbumin stimulation, blood oxygen saturation (SpO2) rapidly dropped below 70%, followed by initial cardiac fluctuations and a sharp decline, resulting in death within 30 minutes, demonstrating the successful establishment of the anaphylactic shock model. In the adrenaline monomer group: after administration, the heart rate significantly increased, peaking at 470 beats / min, while SpO2 slowly recovered to approximately 90%, confirming that adrenaline can partially correct hypoxemia, but with the side effect of excessive tachycardia. In the ternary physical mixture group: changes in heart rate and SpO2 were not significantly different from the adrenaline monomer group (P>0.05), indicating that simple physical mixing does not provide synergistic effects. The ternary co-amorphous composition (of this invention): After administration, the heart rate recovered steadily, reaching 408 beats / min within 10 minutes, and subsequently maintained at 415-422 beats / min, with no significant difference from the baseline level of the blank group, thus avoiding excessive tachycardia caused by adrenaline alone; SpO2 rapidly recovered, reaching 88% at 10 minutes, 92% at 15 minutes, and 94% at 30 minutes after administration, significantly superior to the adrenaline monotherapy group. These results indicate that the ternary co-amorphous composition of this invention, in a co-amorphous system, allows the anti-inflammatory effect of dexamethasone (improving lung oxygenation) and the antioxidant effect of ascorbic acid (protecting microcirculation) to be fully utilized, achieving a rapid, stable, and high-quality recovery effect.

[0069] In summary, the present invention provides an adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous composition. This co-amorphous composition is a solid form of adrenaline, ascorbic acid, and dexamethasone sodium phosphate monomers and their physical mixtures that are completely different from each other. Furthermore, the combined use of adrenaline, ascorbic acid, and dexamethasone sodium phosphate can produce a synergistic effect, which has good application prospects.

[0070] The above embodiments merely illustrate implementation methods of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. An adrenaline co-amorphous composition, characterized in that: The adrenaline co-amorphous composition comprises adrenaline, ascorbic acid, and dexamethasone sodium phosphate, wherein the molar ratio of adrenaline, ascorbic acid, and dexamethasone sodium phosphate is 1:(0.1-1):

1.

2. The adrenaline co-amorphous composition according to claim 1, characterized in that: The molar ratio of adrenaline, ascorbic acid, and dexamethasone sodium phosphate is 1:0.8 to 1:

1.

3. The adrenaline co-amorphous composition according to claim 2, characterized in that: The composition is a ternary single-phase co-amorphous system, in which the three components are bound together by intermolecular interactions; the X-ray powder diffraction pattern of the composition has no sharp crystal characteristic diffraction peaks, and the glass transition temperature of the composition is 70℃~90℃.

4. The adrenaline co-amorphous composition according to claim 3, characterized in that: The Fourier transform infrared spectrum of the composition after KBr pellet preparation was at 3423.83 cm⁻¹. -l 1719.73cm -l 1661.02cm -l 1605.07cm -l 1523.22cm -l 1391.33cm -l 1289.94cm -l 1241.12cm -l 1109.63cm -l 1069.97cm -l 978.49cm -l 882.89cm -l 818.41cm -l 758.19cm -l 539.04cm -l A characteristic absorption peak exists at this location.

5. A method for preparing the adrenaline co-amorphous composition according to any one of claims 1-4, characterized in that: Includes the following steps: S1. Weigh out adrenaline, ascorbic acid and dexamethasone sodium phosphate in a molar ratio of 1:(0.1~1):1; S2. Dissolve the three raw materials from step S1 in water and react them in a water bath for 60–180 min to obtain a clear mixed solution; the water bath temperature is 25–40 °C. S3. The mixed solution is treated by solvent evaporation or freeze-drying to obtain a co-amorphous crude product; S4. The co-amorphous crude product obtained in step S3 is subjected to vacuum drying to remove residual solvent, and adrenaline-ascorbic acid-dexamethasone sodium phosphate co-amorphous product is obtained.

6. The method for preparing the adrenaline co-amorphous composition according to claim 5, characterized in that: In step S3, the solvent evaporation method involves: rotary evaporating the mixed solution under reduced pressure at 40–55°C for 30–120 min to obtain a co-amorphous crude product.

7. The method for preparing the adrenaline co-amorphous composition according to claim 5, characterized in that: In step S3, the freeze-drying method involves pre-freezing the mixed solution and then freeze-drying it under vacuum for 12–24 hours to obtain a co-amorphous crude product.

8. The method for preparing the adrenaline co-amorphous composition according to claim 1, characterized in that: The vacuum drying time for step S4 is 12–24 hours.

9. The use of the adrenaline co-amorphous composition according to any one of claims 1-4 in the preparation of a medicament for the treatment and / or prevention of anaphylactic shock, cardiac arrest or chronic inflammatory diseases.

10. The application according to claim 9, characterized in that, The drug is an injection, a lyophilized powder injection, or an oral preparation.

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