Urapidil hydrochloride injection and a preparation method thereof

Abstract

The application provides an urapidil hydrochloride injection, and belongs to the field of chemical medicine preparation.The injection comprises urapidil hydrochloride, tromethamine and water for injection, and the pH value of the injection is 6.8-7.5.The application uses tromethamine to improve the pH value of the urapidil hydrochloride injection, greatly enhances the stability of urapidil hydrochloride, and still maintains the good solubility of urapidil hydrochloride at the higher pH value, the clarity of the injection is stable, the performance is excellent, and the product quality is obviously improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical medicine preparation, and particularly relates to an urapidil hydrochloride injection and a preparation method thereof. BACKGROUND

[0002] The urapidil hydrochloride injection is an antihypertensive drug, and has a central and peripheral double action mechanism. In the periphery, it can block the post-synaptic alpha 1 receptor and inhibit the vasoconstrictor effect of catecholamine, thereby reducing the peripheral vascular resistance and cardiac load; in the central nervous system, it can adjust the activity of the circulation center by exciting the 5-hydroxytryptamine-1A receptor, and prevent the blood pressure from rising and the heart rate from increasing due to sympathetic reflex. The indications of the urapidil hydrochloride injection are: (1) used for treating hypertensive crisis (such as acute blood pressure rise), severe and extremely severe hypertension and refractory hypertension; (2) used for controlling the perioperative hypertension. The urapidil hydrochloride injection can be intravenously injected, continuously intravenously dripped or used with an infusion pump. The urapidil hydrochloride injection can be single, repeated intravenously injected and long-time intravenously inputted, and can also be continuously intravenously inputted after intravenous injection to maintain the stability of the blood pressure.

[0003] The urapidil hydrochloride has a chemical name of 6-{[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl]amino}-1,3-dimethyl-2,4-(1H,3H)-pyrimidinedione hydrochloride, a molecular formula of C 20 H 30 ClN5O3, a molecular weight of 423.94, and a structural formula as follows:

[0004]

[0005] The urapidil hydrochloride injection is a small-volume injection developed by Takeda GmbH Company, and was first marketed in Germany in 1988. The marketed specifications are 5ml:25mg and 10ml:50mg, and the trade name is Ebrantil. The 5ml:25mg specification was approved for registration in China in June 1992, and the trade name is Yaningding.

[0006] The urapidil hydrochloride injection in the prior art has the following conditions:

[0007] (1) The original research product is the urapidil hydrochloride injection produced by Takeda GmbH Company, and the prescription is: urapidil hydrochloride, propylene glycol, sodium dihydrogen phosphate, disodium hydrogen phosphate, water for injection. In the preparation of the product, inert gas is filled, but it is not terminally sterilized. The product has a low sterility guarantee level, and has a certain safety risk.

[0008] (2)CN114344255A discloses a preparation method of urapidil hydrochloride injection, which needs nitrogen protection and terminal sterilization. The process needs to control the range of dissolved oxygen and residual oxygen during preparation, which is complex and requires a high production line. The pH of the injection is 5.9-6.5.

[0009] (3)CN104173281A discloses a urapidil hydrochloride injection and its preparation method. The injection contains urapidil hydrochloride, amino acid complex salt and 2-hydroxypropyl-beta-cyclodextrin, with a pH of 5.0-7.5. The preparation method is complex and needs to add activated carbon for decolorization. Due to the diversity of raw materials and production process, the uncertainty of activation mechanism, and the limitations of quality control, the use of activated carbon has the risk of introducing elemental impurities, mixing particulate impurities, and affecting the stability of the main drug content. Therefore, there is a potential quality risk.

[0010] (4)CN115645360A discloses a urapidil hydrochloride injection, which includes A component (an aqueous solution of urapidil hydrochloride and pH adjuster, with a pH of 6.1-6.3) and B component (basic infusion), which are packaged separately and prepared on demand during use, thereby reducing the risk of introducing impurities. Because the product contains two separate packages, it is not conducive to storage and transportation, and there is a risk of contamination when used on demand in clinical use. At the same time, the stability of urapidil hydrochloride in the product still has some defects.

[0011] (5)CN115770215A discloses a urapidil hydrochloride injection and its preparation method. The injection is obtained by filtering and diluting urapidil hydrochloride sterilization solution with sterile water. The urapidil hydrochloride sterilization solution is obtained by stirring the acid-treated urapidil hydrochloride base solution for 3-4 hours. The urapidil hydrochloride base solution contains urapidil hydrochloride, sterilizing agent and antioxidant, and the remaining part is supplemented by sodium chloride solution. The sterilizing agent is modified zeolite particles with a tacky layer on the surface. The components of the tacky layer include amino clay, and the amino clay is clay with amino groups grafted on the surface of the particles. The injection replaces high-temperature sterilization with normal-temperature sterilization by adding a sterilizing agent and using protonated amino groups, thereby increasing the content of effective ingredients in the urapidil hydrochloride injection. The sterilizing agent in the invention needs special preparation, and the technical process is complex, which has low practicality.

[0012] (6) CN113876705A discloses a urapidil hydrochloride injection and a preparation method thereof. The injection contains urapidil hydrochloride, an osmotic pressure regulator, and an acid-base buffer pair (such as citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate, or phosphoric acid-sodium phosphate), with a pH of 5.9-6.5. By adjusting the addition and mixing order of the main drug urapidil hydrochloride and other excipients, and controlling the temperature below 60°C during preparation, and using filtration to sterilize, the probability of deterioration of urapidil hydrochloride is reduced. However, the impurity increase is still very obvious in the stability study.

[0013] It is recorded in the instruction manual of urapidil hydrochloride injection that urapidil injection cannot be mixed with alkaline liquid, as its acidic nature may cause the solution to become turbid or form flocculation.

[0014] During the preparation of urapidil hydrochloride injection, there is also a phenomenon that urapidil hydrochloride is more easily oxidized and hydrolyzed in an acidic environment, and its two main impurities are impurity A and impurity C. Therefore, generally the higher the pH, the better the stability of urapidil. However, the higher the pH, the more likely urapidil is to precipitate. How to find a balance between the two and not introduce too many other excipients is a problem that needs to be solved for this product.

[0015]

[0016] The inventors accidentally discovered during long-term research on urapidil hydrochloride injection that the addition of a certain amount of tromethamine to the urapidil hydrochloride aqueous solution can greatly improve the stability of urapidil hydrochloride. The pH of the injection can be increased to 6.8-7.5, and urapidil hydrochloride can still be well dissolved without the formation of flocculation. The clarity of the injection is stable, thereby completing the present application. SUMMARY

[0017] The technical solution of the present application is as follows:

[0018] The present application provides a urapidil hydrochloride injection, which comprises urapidil hydrochloride, tromethamine, and water for injection, and the pH of the injection is 6.8-7.5.

[0019] Further, the concentration of urapidil hydrochloride is 3-8 mg / ml, preferably 5.47 mg / ml.

[0020] In some embodiments, the concentration of tromethamine is 3-5 mg / ml.

[0021] In other embodiments, the injection further comprises an appropriate amount of a pH adjuster, which is 5 wt% sodium bicarbonate, and the pH of the injection is adjusted to 7.0-7.5.

[0022] The present application also discloses a preparation method of urapidil hydrochloride injection, comprising the following steps:

[0023] Step 1: Weigh the prescribed amount of urapidil hydrochloride and add it to part of the water for injection (pH 5.0-6.8) and stir until it is completely dissolved; further, the temperature of the water for injection in Step 1 is controlled to be no higher than 40℃.

[0024] Step 2: Add tromethamine to the solution obtained in Step 1 at 3-5 mg / ml to adjust the pH to 6.8-7.5.

[0025] In other embodiments, after adding tromethamine, an appropriate amount of pH adjuster (5wt% sodium bicarbonate) is also added. Specifically, first adjust the pH of the solution to 6.8-7.0 with 3-3.6 mg / ml of tromethamine, and then adjust the pH to 7.0-7.5 with 5wt% sodium bicarbonate.

[0026] Step 3: The solution obtained in Step 2 is diluted to the full amount with water for injection, stirred to mix uniformly, and then filtered, filled, sealed and terminally sterilized to obtain the urapidil hydrochloride injection. Further, two-stage filtering is used, with the first stage being a 0.45 μm PTFE filter and the second stage being a 0.22 μm PTFE filter. Further, the sterilization conditions are 121℃ for 15 minutes.

[0027] Compared with the prior art, the application has the following beneficial effects:

[0028] (1) In the research process, it was unexpectedly found that the addition of tromethamine not only adjusts the pH of the urapidil injection to a higher value (6.8-7.5), but also improves the solubility of urapidil, solving the problem of precipitation due to high pH.

[0029] (2) The application also uses sodium bicarbonate as a pH adjuster, and by adjusting the addition order and process parameters of tromethamine and sodium bicarbonate, the sustained stability of the pH of the urapidil injection is further ensured.

[0030] (3) Since urapidil is not easily oxidized and hydrolyzed in a high-pH environment, the application does not need to control the residual oxygen rate by nitrogen flushing to maintain the stability of the product performance, saving the nitrogen flushing time, simplifying the process flow and greatly reducing the manufacturing cost of the product. DETAILED DESCRIPTION

[0031] The application will be further described in the following Embodiments. It should be understood that the Embodiments of the application are only used for illustrating the application, but not limiting the application. The experimental methods not specified in the following Embodiments are usually carried out according to the conventional conditions, or the conditions suggested by the manufacturers. The raw and auxiliary materials not specified in the following Embodiments are usually the conventional products in the market. The technical solutions obtained by simple improvement of the technical solutions of the application, or equivalent replacement of the conventional means or components, are also within the protection scope of the application.

[0032] Embodiment 1

[0033] The preparation of Urapidil Hydrochloride Injection includes the following steps:

[0034] Step 1: weigh 5.47g of Urapidil Hydrochloride, and add it into about 700ml of water for injection, and stir until completely dissolved, wherein the temperature of the water for injection is not higher than 40℃;

[0035] Step 2: add 3g of tromethamine into the solution obtained in Step 1, and adjust the pH to 6.8;

[0036] Step 3: use water for injection to make the solution obtained in Step 2 to 1000ml, and stir to mix uniformly, and then filter, fill and seal, and sterilize (121℃, 15min), and finally obtain Urapidil Hydrochloride Injection. The filtration uses two-stage filter cores, the first-stage filtration uses 0.45μm PTFE filter core, and the second-stage filtration uses 0.22μm PTFE filter core.

[0037] Embodiment 2

[0038] This embodiment is basically the same as Embodiment 1, except that in Step 2, 4.5g of tromethamine is added to adjust the pH to 7.3.

[0039] Embodiment 3

[0040] This embodiment is basically the same as Embodiment 1, except that in Step 2, 5g of tromethamine is added to adjust the pH to 7.5.

[0041] Embodiment 4

[0042] This embodiment is basically the same as Embodiment 1, except that in Step 2, after adding tromethamine, an appropriate amount of pH adjusting agent (5wt% sodium bicarbonate) is also added. The specific operation is: first add 3g of tromethamine to adjust the pH of the solution to 6.8, and then use 5wt% sodium bicarbonate to adjust the pH to 7.0.

[0043] Embodiment 5

[0044] This example is substantially the same as Example 1, except that 3.3 g tromethamine is first added to adjust the pH of the solution obtained in Step 1 to 6.9, and then 5 wt% sodium bicarbonate is used to continue adjusting the pH to 7.3.

[0045] Example 6

[0046] This example is substantially the same as Example 1, except that 3.6 g tromethamine is first added to adjust the pH of the solution obtained in Step 1 to 7.0, and then 5 wt% sodium bicarbonate is used to continue adjusting the pH to 7.5.

[0047] Comparative Example 1

[0048] The original preparation is used as Comparative Example 1, and the information of the original preparation is shown in Table 1.

[0049] Table 1 Information of the original preparation

[0050]

[0051] Comparative Example 2

[0052] This comparative example is substantially the same as Example 1, except that 2.1 g tromethamine is added in Step 2 to adjust the pH to 6.5.

[0053] Comparative Example 3

[0054] This comparative example is substantially the same as Example 1, except that 5.9 g tromethamine is added in Step 2 to adjust the pH to 7.8.

[0055] Comparative Example 4

[0056] This comparative example is substantially the same as Example 3, except that 5 wt% sodium bicarbonate is used in Step 2 to replace tromethamine to adjust the pH to 7.3.

[0057] Comparative Example 5

[0058] The prescription of urapidil hydrochloride injection is shown in Table 2:

[0059] Table 2 Prescription of urapidil injection in Comparative Example 5

[0060] Material Name Prescribed Amount / g Urapidil Hydrochloride 5.47 Antioxidant (Sodium Metabisulfite) 0.10 Trometamol 4.5 g, adjust pH to 7.3 Water for Injection q.s. to 1000 mL

[0061] Preparation method:

[0062] Step 1: 5.47 g of urapidil hydrochloride and 0.1 g of antioxidant (sodium pyrosulfite) are weighed and added to part of the water for injection to be stirred until completely dissolved, wherein the temperature of the water for injection is not higher than 40℃;

[0063] Step 2: 4.5 g of tromethamine is added to the solution obtained in Step 1 to adjust the pH to 7.3;

[0064] Step 3: The solution obtained in step 2 was diluted with water for injection to 1000 mL, and stirred to mix well, then filtered, filled and sealed under nitrogen, and sterilized (121℃, 15 min) to obtain the final Urapidil Hydrochloride Injection. The filtration was performed by two-stage filter cartridges, the first stage was 0.45 μm PTFE filter cartridge, and the second stage was 0.22 μm PTFE filter cartridge. Nitrogen was passed through the whole process of steps 1-3.

[0065] Comparative Example 6

[0066] This comparative example was basically the same as Comparative Example 5, except that in step 2, after the addition of tromethamine, an appropriate amount of pH adjuster (5wt% sodium bicarbonate) was also added. The specific operation was as follows: first, 3.3 g of tromethamine was added to adjust the pH of the solution to 6.9, and then 5wt% sodium bicarbonate was used to adjust the pH to 7.3.

[0067] Test Example 1: Stability Test

[0068] Examples 1-6 and Comparative Examples 1-6 were placed in a 40℃±2℃, 75%±5% RH environment for stability testing. The stability examination and related substance test results are shown in Table 3:

[0069] Table 3: Stability Examination and Related Substance Test Results of Examples and Comparative Examples

[0070]

[0071]

[0072] From Table 3, it can be seen that:

[0073] (1) By comparing Examples 1-6 and Comparative Examples 1-3, it can be seen that whether the pH is controlled by tromethamine alone or by tromethamine and 5wt% sodium bicarbonate together, when the pH is controlled at 6.8-7.5, the impurity of the injection is obviously better than that of Comparative Example 1 (original research formulation), and the optimal pH is 7.3.

[0074] (2) In order to study the influence of different pH buffers on the stability of urapidil injection, the results of Example 2 (tromethamine, pH adjusted to 7.3), Example 5 (tromethamine + 5wt% sodium bicarbonate, first adjust the pH to 6.9 with tromethamine, then adjust the pH to 7.3 with 5wt% sodium bicarbonate), and Comparative Example 4 (5wt% sodium bicarbonate, pH adjusted to 7.3) were compared. The stability of Example 5 was the best, the stability of Example 2 was slightly worse than that of Example 5, and the stability of Comparative Example 4 was the worst. The applicant found in the research process that although the higher the pH value, the higher the stability of urapidil in theory, it is also more likely to precipitate, which will cause urapidil to be more easily decomposed, so the stability of Comparative Example 4 is actually reduced. In Example 2, tromethamine not only can adjust the pH, but also can improve the solubility of urapidil because it is an organic solvent, which solves the problem of precipitation due to high pH. On this basis, we also unexpectedly found that by using tromethamine and 5wt% sodium bicarbonate in combination, the pH is adjusted in stages, and the stability of urapidil injection can be further improved, and the scheme of Example 5 is the best.

[0075] (3) In order to investigate whether the application needs to add an antioxidant and control oxygen, Example 2 (tromethamine, without adding an antioxidant, without passing nitrogen gas) and Comparative Example 5 (tromethamine, with adding an antioxidant and passing nitrogen gas) were taken as Experimental Group 1; Example 5 (tromethamine + 5wt% sodium bicarbonate, without adding an antioxidant, without passing nitrogen gas) and Comparative Example 6 (tromethamine + 5wt% sodium bicarbonate, with adding an antioxidant and passing nitrogen gas) were taken as Experimental Group 2 for grouping comparison. The results showed that the urapidil injection prepared by Example 2 and Example 5 of the application can achieve the same stability as Comparative Example 5 and Comparative Example 6 without adding an antioxidant and passing nitrogen gas.

[0076] Test Example 2: Vascular irritation test

[0077] Vascular irritation test: 32 rabbits were randomly divided into 8 groups, half male and half female. Test group: rabbits were injected with drugs of Examples 1-6 in the left auricular vein; control group: rabbits were injected with drugs of Comparative Example 1 in the left auricular vein; blank group: rabbits were injected with the same volume of normal saline in the left auricular vein. Each group was given drugs once a day for 5 consecutive days, and the injection site and surrounding tissues were observed for redness, congestion and other irritation phenomena.

[0078] Examples 1-6 and Comparative Example 1 (original research reagent) were subjected to irritation test, and the results are shown in Table 4:

[0079] Table 4 Irritation test results of Examples 1-6 and Comparative Example 1 (original research reagent)

[0080]

[0081] As is apparent from Table 4, the irritation of Examples 1 to 6 is less than that of Comparative Example 1.

[0082] The above detailed description merely illustrates the technical solutions of the present application and is not limiting. Although the present application has been described in detail with reference to the examples, it should be understood by those skilled in the art that the technical solutions of the present application can be modified or substituted equivalently without departing from the scope of the technical solutions of the present application, and all such modifications and substitutions should be encompassed in the scope of the claims of the present application.

Claims

1. An injection solution of urapidil hydrochloride, characterized in that, The injection liquid comprises urapidil hydrochloride, tromethamine and water for injection, and the pH value of the injection liquid is 6.8-7.

5.

2. The injectable solution according to claim 1, characterized in that, The concentration of the urapidil hydrochloride is 3-8 mg / ml; and the concentration of the tromethamine is 3-5 mg / ml.

3. The injectable solution according to claim 2, characterized in that, The concentration of the urapidil hydrochloride is 5.47 mg / ml.

4. The injection fluid according to any one of claims 1 to 3, characterized in that, The injection liquid further comprises a pH adjusting agent in an appropriate amount to adjust the pH value of the injection liquid to 7.0-7.5, and the pH adjusting agent is 5 wt% sodium bicarbonate.

5. A method for the preparation of the injection solution according to any one of claims 1-4, characterized in that, The method comprises the following steps: Step 1: weigh the prescription amount of urapidil hydrochloride, and add it into part of the water for injection to stir until completely dissolved; Step 2: add the prescription amount of tromethamine into the solution obtained in Step 1 to make the pH value of the injection liquid 6.8-7.5; Step 3: use water for injection to make the solution obtained in Step 2 to the full amount, and stir to mix uniformly, and then filter, fill and seal and terminal sterilization to finally obtain the urapidil hydrochloride injection liquid.

6. The method of claim 5, wherein the injection solution is prepared by, In Step 1, the temperature of the water for injection is controlled to be not higher than 40℃.

7. The preparation method according to claim 5, characterized in that, In Step 2, an appropriate amount of pH adjusting agent is further added to adjust the pH value of the injection liquid to 7.0-7.5, and the pH adjusting agent is 5 wt% sodium bicarbonate.

8. The method of claim 7, wherein, In Step 2, the specific operation is: first use the tromethamine to adjust the pH value of the solution to 6.8-7.0, and then use the 5 wt% sodium bicarbonate to adjust the pH value of the solution to 7.0-7.

5.

9. The production method according to any one of claims 5 to 8, characterized by, In Step 3, the filtration adopts two-stage filter cores, the first-stage filtration is 0.45 μm PTFE filter core, and the second-stage filtration is 0.22 μm PTFE filter core.

10. The production method according to any one of claims 5 to 8, characterized by, In Step 3, the sterilization condition is 121℃ for 15 min.

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