Injection composition for treating pancreatitis and preparation method thereof

Abstract

The invention provides an ulinastatin water injection composition, which contains ulinastatin, sodium chloride and a buffer salt, and the ulinastatin water injection also contains cysteine, praeruptorin A and dimethyl sulfoxide. According to the ulinastatin water injection composition disclosed by the invention, the praeruptorin A is added, so that the influence of temperature on the preparation is obviously improved, and the stability of the ulinastatin water injection composition under high-temperature and accelerated conditions is improved; a cysteine and dimethyl sulfoxide system improves the stability of the ulinastatin water injection composition under an illumination condition. The ulinastatin water injection composition is good in stability, simple in preparation process and suitable for commercial production, and an excellent medicine is provided for treatment of pancreatitis.

Description

Technical Field

[0001] The invention belongs to the field of drug preparation, and specifically relates to the preparation of an aqueous injection composition for treating pancreatitis. Background Art

[0002] Acute pancreatitis is a common acute inflammatory disease of the pancreas characterized by rapid onset, severe symptoms, and a high mortality rate. If left untreated, it can lead to coagulation disorders, damage to multiple organs including the liver and kidneys, and even death in severe cases.

[0003] Ulinastatin, a 143-amino acid glycoprotein, is a urinary trypsin inhibitor and a naturally occurring serine protease inhibitor in humans. It is a glycoprotein isolated and purified from male urine and is an endogenous inflammatory response regulator and hydrolase inhibitor. Ulinastatin inhibits multiple enzymes, including trypsin, hyaluronidase, and plasmin, and has a significant stabilizing effect on cell and lysosomal membranes. It is commonly used clinically to treat acute pancreatitis and acute organ failure.

[0004] Chinese patent application number 201610069990.3 provides an ulinastatin injection and a preparation method thereof. The disclosed process conditions are all prepared under low temperature conditions, with high process requirements. Activated carbon is used in the preparation process, and the process is relatively complicated. Chinese patent application number 202111451459.X provides an anti-inflammatory pharmaceutical composition and a preparation method thereof. The disclosed preparation has poor stability under high temperature and light conditions. Summary of the Invention

[0005] The purpose of the present invention is to overcome the deficiencies in the prior art. The present invention provides a novel aqueous ulinastatin injection, which has the advantages of good stability, simple preparation process, and suitability for commercial production.

[0006] In order to achieve the above object, the present invention provides an ulinastatin aqueous injection, which contains ulinastatin, sodium chloride, and buffer salt. The ulinastatin aqueous injection also contains cysteine, praeruptorin A, and dimethyl sulfoxide.

[0007] Preferably, the buffer salt is acetate or citrate.

[0008] Preferably, in any of the above items, the content of cysteine ​​in each 100 ml of ulinastatin aqueous injection is 0.5-1.5 g, preferably 0.5, 0.7, 1.0, 1.2, 1.5 g and ranges therebetween.

[0009] Preferably, in any of the above items, the content of praeruptorin A in every 100 ml of ulinastatin aqueous injection is 0.3 to 0.8 g, preferably 0.3, 0.5, 0.8 g and the ranges therebetween.

[0010] Preferably, in any of the above items, the content of dimethyl sulfoxide in every 100 ml of ulinastatin aqueous injection is 1 to 3 g, preferably 1, 2, 3 g and the range therebetween.

[0011] Preferably, any of the above items has a pH value of 4.5 to 5.5, preferably 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5 and ranges therebetween.

[0012] Preferably, any of the above items is that each 100 ml of ulinastatin aqueous injection contains the following ingredients in the following mass ratio: 50,000 to 300,000 units / g of ulinastatin, 0.3 to 1.0 g of sodium chloride, 0.5 to 1.5 g of cysteine, 0.3 to 0.8 g of praeruptorin A, 1 to 3 g of dimethyl sulfoxide, and 1.0 to 2.6 g of buffer salt, and the amount is made up to 100 ml with water for injection. Among them, ulinastatin is preferably 5, 10, 15, 20, 25, 300,000 units / g and ranges therebetween, sodium chloride is preferably 0.3, 0.5, 0.8, 1.0 g and ranges therebetween, cysteine ​​is preferably 0.5, 0.7, 1.0, 1.2, 1.5 g and ranges therebetween, praeruptorin is preferably 0.3, 0.5, 0.8 g and ranges therebetween, dimethyl sulfoxide is preferably 1, 2, 3 g and ranges therebetween, and buffer salt is preferably 1.0, 1.5, 2.0, 2.6 g and ranges therebetween.

[0013] The present invention also provides a method for preparing the ulinastatin aqueous injection composition described in any one of the above items, wherein the preparation of each 100 mL of ulinastatin aqueous injection comprises the following steps:

[0014] Step 1: Add the prescribed amount of sodium chloride, cysteine, and buffer salt to 70 ml of water for injection to obtain Solution I;

[0015] Step 2: dissolving the prescribed amount of praeruptolide A in dimethyl sulfoxide to obtain solution II;

[0016] Step 3: Add solution II to solution I and mix well;

[0017] Step 4: Adjust the pH value of the solution to 4.5-5.5; the pH value is preferably 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5 and ranges therebetween.

[0018] Step 5: Add water for injection to 100 ml;

[0019] Step 6: Filter twice with a 0.22 μm filter membrane; the filter membrane is preferably a polyethersulfone filter membrane;

[0020] Step 7: Packaging, nitrogen filling, and sealing.

[0021] Preferably, in step 4, acetate or citrate is used to adjust the pH value of the solution to 5.0±0.15.

[0022] The beneficial technical effects of the present invention are:

[0023] 1. The addition of praeruptolide A in the present invention can significantly improve the effect of temperature on the preparation and improve the stability of the ulinastatin aqueous injection composition under high temperature and accelerated conditions.

[0024] 2. In the present invention, praeruptolide A is insoluble in water, so it is dissolved in dimethyl sulfoxide and added. Surprisingly, the cysteine ​​and dimethyl sulfoxide system improves the stability of the ulinastatin aqueous injection composition under light conditions.

[0025] 3. The ulinastatin aqueous injection composition of the present invention has good stability, simple preparation process, is suitable for commercial production, and provides an excellent drug for the treatment of pancreatitis.

[0026] In a preferred embodiment of the present invention, the ulinastatin aqueous injection contains ulinastatin, sodium chloride, cysteine, praeruptorin A, dimethyl sulfoxide, and a buffer salt, which may be acetate or citrate.

[0027] The preferred formula is: ulinastatin 50,000-300,000 units / g; sodium chloride 0.3-1.0g; cysteine ​​0.5-1.5g;

[0028] Peucedanum praeruptorum A 0.3-0.8g; dimethyl sulfoxide 1-3g, buffer salt 1.0-2.6g, make up to 100ml with water for injection. pH range: 4.5-5.5.

[0029] The preferred preparation process is:

[0030] (1) Add the prescribed amount of sodium chloride, cysteine, and buffer salt to 70 ml of water for injection to obtain Solution I;

[0031] (2) dissolving the prescribed amount of praeruptorin A in dimethyl sulfoxide to obtain solution II;

[0032] (3) Add solution II to solution I and mix well;

[0033] (4) Adjust the pH of the solution to 5.0 ± 0.1 with acetate or citrate;

[0034] (5) Dilute to 100 ml with water for injection;

[0035] (6) Filter twice with a 0.22 μm polyethersulfone membrane;

[0036] (7) Packaging, nitrogen filling, and sealing. DETAILED DESCRIPTION

[0037] The present invention is further described in detail below through specific embodiments.

[0038] Example 1

[0039] Ulinastatin 50,000 units / ml; sodium chloride 0.4g; cysteine ​​0.7g; praeruptorin A 0.4g; dimethyl sulfoxide 1.0g, citric acid 0.4g, sodium citrate 0.8g, make up to 100ml with water for injection.

[0040] Process:

[0041] (1) Add the prescribed amount of sodium chloride, cysteine, citric acid, and sodium citrate to 70 ml of water for injection to obtain Solution I;

[0042] (2) dissolving the prescribed amount of praeruptorin A in dimethyl sulfoxide to obtain solution II;

[0043] (3) Add solution II to solution I and mix well;

[0044] (4) Adjust the pH value of the solution to 5.0 ± 0.1 with citric acid or sodium citrate solution;

[0045] (5) Make up to the full volume with water for injection;

[0046] (6) Filter twice with a 0.22 μm polyethersulfone membrane;

[0047] (7) Packaging, nitrogen filling, and sealing.

[0048] The pH in step (4) in Example 1 may also preferably be 4.5 to 5.5, i.e., 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5 and ranges therebetween.

[0049] Example 2

[0050] Ulinastatin 100,000 units / ml; sodium chloride 0.6g; cysteine ​​0.9g; praeruptorin A 0.4g; dimethyl sulfoxide 1.5g, acetic acid 0.6g, sodium acetate 1.1g, make up to 100ml with water for injection.

[0051] Process:

[0052] (1) Add the prescribed amount of sodium chloride, cysteine, acetic acid, and sodium acetate to 70 ml of water for injection to obtain Solution I;

[0053] (2) dissolving the prescribed amount of praeruptorin A in dimethyl sulfoxide to obtain solution II;

[0054] (3) Add solution II to solution I and mix well;

[0055] (4) Adjust the pH value of the solution to 5.0 ± 0.1 with acetic acid or sodium acetate solution;

[0056] (5) Make up to the full volume with water for injection;

[0057] (6) Filter twice with a 0.22 μm polyethersulfone membrane;

[0058] (7) Packaging, nitrogen filling, and sealing.

[0059] Example 3

[0060] Ulinastatin 200,000 units / ml; sodium chloride 0.6g; cysteine ​​1.1g; praeruptorin A 0.6g; dimethyl sulfoxide 2.0g, citric acid 0.8g, sodium citrate 1.2g, make up to 100ml with water for injection.

[0061] The process steps are the same as in Example 1.

[0062] Example 4

[0063] Ulinastatin 300,000 units / ml; sodium chloride 0.8g; cysteine ​​1.3g; praeruptorin A 0.8g; dimethyl sulfoxide 3.0g, acetic acid 0.9g, sodium acetate 1.3g, make up to 100ml with water for injection.

[0064] The process steps are the same as in Example 2.

[0065] Comparative Example 1

[0066] Ulinastatin 100,000 units / ml; sodium chloride 0.6g; cysteine ​​1.3g; dimethyl sulfoxide 1.9g, acetic acid 0.6g, sodium acetate 1.1g, make up to 100ml with water for injection.

[0067] (1) Add the prescribed amount of sodium chloride, cysteine, acetic acid, and sodium acetate to 70 ml of water for injection to obtain Solution I;

[0068] (2) adding the prescribed amount of dimethyl sulfoxide;

[0069] (3) Adjust the pH value of the solution to 5.0 ± 0.1 with acetic acid or sodium acetate solution;

[0070] (4) Make up to the full volume with water for injection;

[0071] (5) Filter twice with a 0.22 μm polyethersulfone membrane;

[0072] (6) Packaging, nitrogen filling, and sealing.

[0073] Comparative Example 2

[0074] Ulinastatin 100,000 units / ml; sodium chloride 0.6g; praeruptorin A 1.5g; dimethyl sulfoxide 2.4g, acetic acid 0.6g, sodium acetate 1.1g, make up to 100ml with water for injection.

[0075] Process:

[0076] (1) Add the prescribed amount of sodium chloride, acetic acid, and sodium acetate to 70 ml of water for injection to obtain Solution I;

[0077] (2) dissolving the prescribed amount of praeruptorin A in dimethyl sulfoxide to obtain solution II;

[0078] (3) Add solution II to solution I and mix well;

[0079] (4) Adjust the pH value of the solution to 5.0 ± 0.1 with acetic acid or sodium acetate solution;

[0080] (5) Make up to the full volume with water for injection;

[0081] (6) Filter twice with a 0.22 μm polyethersulfone membrane;

[0082] (7) Packaging, nitrogen filling, and sealing.

[0083] Comparative Example 3

[0084] Ulinastatin 100,000 units / ml; sodium chloride 0.6g; cysteine ​​2.8g; acetic acid 0.6g, sodium acetate 1.1g, make up to 100ml with water for injection.

[0085] Process:

[0086] (1) Add the prescribed amount of sodium chloride, cysteine, acetic acid, and sodium acetate to 70 ml of water for injection

[0087] (2) Adjust the pH value of the solution to 5.0 ± 0.1 with acetic acid or sodium acetate solution;

[0088] (3) Make up the volume with water for injection;

[0089] (4) Filter twice with a 0.22 μm polyethersulfone membrane;

[0090] (5) Packaging, nitrogen filling, and sealing.

[0091] Comparative Example 4

[0092] Ulinastatin 100,000 units / ml; sodium chloride 0.6g; cysteine ​​0.9g; praeruptorin A 0.4g; acetone 1.5g, acetic acid 0.6g, sodium acetate 1.1g, make up to 100ml with water for injection.

[0093] Process:

[0094] (1) Add the prescribed amount of sodium chloride, cysteine, acetic acid, and sodium acetate to 70 ml of water for injection to obtain Solution I;

[0095] (2) dissolving the prescribed amount of praeruptorin A in acetone to obtain solution II;

[0096] (3) Add solution II to solution I and mix well;

[0097] (4) Adjust the pH value of the solution to 5.0 ± 0.1 with acetic acid or sodium acetate solution;

[0098] (5) Make up to the full volume with water for injection;

[0099] (6) Filter twice with a 0.22 μm polyethersulfone membrane;

[0100] (7) Packaging, nitrogen filling, and sealing.

[0101] Stability test:

[0102] Examples 1 to 4 and comparative examples 1 to 4 were respectively subjected to high temperature (60°C), strong light irradiation (4500±500lx, 10d total illumination ≥1.2×10 6 lx·h, near-ultraviolet lamp energy ≥200W·h / m 2 The stability was investigated under the conditions of 200 ℃ and 400 ℃, 75% ± 5% and the test results are shown in Table 1 and Table 2 respectively.

[0103] Table 1 Test results of influencing factors

[0104]

[0105]

[0106] Table 2 Accelerated test results (inspection time: month)

[0107]

[0108]

[0109] As can be seen from Table 1 and Table 2, Examples 1 to 4 were tested under high temperature, light and accelerated conditions, and the stability was good. Comparative Example 1 and Comparative Example 3 do not contain white flower peucedanum A, and are unstable under high temperature and accelerated conditions; Comparative Example 2, Comparative Example 4 and Example 2 all contain white flower peucedanum A, and have good stability under high temperature and accelerated conditions. It can be seen that white flower peucedanum A can improve the effect of temperature on the preparation and improve its stability under high temperature and accelerated conditions. Compared with Example 2, Comparative Example 2 does not contain cysteine, Comparative Example 3 does not contain dimethyl sulfoxide, and Comparative Example 4 replaces dimethyl sulfoxide with acetone. These three comparative examples are unstable under light conditions. It can be seen that the cysteine ​​and dimethyl sulfoxide system can increase the light stability of the preparation.

[0110] The above embodiments are provided for illustrative purposes only and are not intended to limit the scope of implementation. Those skilled in the art will readily appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to provide an exhaustive list of all implementations. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. An ulinastatin aqueous injection composition comprising ulinastatin, sodium chloride, and buffer salt, characterized in that: The ulinastatin aqueous injection also contains cysteine, praeruptorin A and dimethyl sulfoxide.

2. The ulinastatin aqueous injection composition according to claim 1, characterized in that: The buffer salt is acetate or citrate.

3. The ulinastatin aqueous injection composition according to claim 2, characterized in that: The content of cysteine ​​in each 100 ml of ulinastatin aqueous injection is 0.5-1.5 g.

4. The ulinastatin aqueous injection composition according to claim 2, characterized in that: The content of praeruptorin A in every 100 ml of ulinastatin aqueous injection is 0.3-0.8 g.

5. The ulinastatin aqueous injection composition according to claim 2, characterized in that: The content of dimethyl sulfoxide in each 100 ml of ulinastatin aqueous injection is 1 to 3 g.

6. The ulinastatin aqueous injection composition according to claim 2, characterized in that: The pH value of the ulinastatin aqueous injection ranges from 4.5 to 5.

5.

7. The ulinastatin aqueous injection composition according to any one of claims 1 to 6, characterized in that: Each 100 ml of ulinastatin aqueous injection contains the following ingredients in the following mass ratio: 50,000 to 300,000 units / g of ulinastatin, 0.3 to 1.0 g of sodium chloride, 0.5 to 1.5 g of cysteine, 0.3 to 0.8 g of praeruptorin A, 1 to 3 g of dimethyl sulfoxide, and 1.0 to 2.6 g of buffer salt. The amount is made up to 100 ml with water for injection.

8. The method for preparing the ulinastatin aqueous injection composition according to any one of claims 1 to 7, wherein the preparation of each 100 mL of ulinastatin aqueous injection comprises the following steps: Step 1: Add the prescribed amount of sodium chloride, cysteine ​​and buffer salt into 70 ml of water for injection to obtain solution I; Step 2: dissolving the prescribed amount of praeruptorin A in dimethyl sulfoxide to obtain solution II; Step 3: Add solution II to solution I and mix well; Step 4: Adjust the pH value of the solution to 4.5-5.5; Step 5: Make up to 100 ml with water for injection; Step 6: Filter twice with a 0.22 μm filter membrane; Step 7: Packaging, nitrogen filling, and sealing.

9. The method for preparing the ulinastatin aqueous injection composition according to claim 8, characterized in that: In step 4, the pH value of the solution is adjusted to 5.0±0.15 with acetate or citrate.

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