WO2023087578A1 - Urapidil hydrochloride injection and preparation method therefor - Google Patents

Abstract

The present application relates to the technical field of pharmaceutical preparations, and specifically disclosed are a urapidil hydrochloride injection and a preparation method therefor. According to the injection, every 1000 mL of urapidil hydrochloride injection contains the following raw materials: 5 g of urapidil hydrochloride, 100 g of an osmotic pressure regulator, and an acid-base buffer pair, wherein the pH value of the urapidil hydrochloride injection is 5.9-6.5. According to the present application, citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate is used as the acid-base buffer pair, and the pH value of the injection is adjusted to 5.9-6.5, which significantly improves the stability of the injection. In the process of preparing the injection, by means of adjusting the adding and mixing sequence of the main drug urapidil hydrochloride and other auxiliary materials and controlling the temperature in the preparation process to be lower than 60°C, the probability of the deterioration of urapidil hydrochloride is effectively reduced, and the stability of the injection is significantly improved.

Description

A kind of urapidil hydrochloride injection and preparation method thereof

This patent application claims priority to Chinese Patent Application No. CN202111363419.X filed on November 17, 2021. The disclosure of the prior application is incorporated by reference in its entirety into this application.

technical field

The application relates to the technical field of pharmaceutical preparations, in particular to an urapidil hydrochloride injection and a preparation method thereof.

Background technique

Urapidil hydrochloride is a uracil derivative substituted by phenylpiperazine, English name Urapidil Hydrochloride, chemical name: 6-[[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl ]-amino]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione hydrochloride. It is currently a safe and effective vasodilator for treating hypertensive crisis, severe hypertension, controlling hypertension during surgery, and treating congestive heart failure, and belongs to the national essential medicine. In addition, urapidil hydrochloride generally does not cause reflex tachycardia while lowering blood pressure.

At present, the types of pharmaceutical preparations mainly include injections, freeze-dried powder injections, tablets, capsules, etc. Among them, tablets and capsules are oral preparations, and the efficacy of oral preparations is reduced due to the unavoidable first-pass effect; freeze-dried powder injections require It is inconvenient to use clinically after reconstitution, and there is a risk of cross-contamination. In order to improve the curative effect, urapidil hydrochloride can be made into injections, thereby avoiding the problems of first-pass effect and clinical use inconvenience, but urapidil hydrochloride has problems such as poor stability and easy decomposition and deterioration in injection solutions, which seriously limit the Wide application of urapidil hydrochloride injection.

technical problem

The purpose of this application is to provide a kind of urapidil hydrochloride injection and preparation method thereof, adopt the acid-base buffer pair such as citric acid and sodium citrate to adjust the pH value of the injection to be 5.9~6.5, make its injection preparation have High stability, not easy to deteriorate, and more convenient for clinical application and other characteristics.

technical solution

In order to achieve the purpose of the above application, the embodiment of the present application adopts the following technical solutions:

The first aspect of the present application provides a kind of urapidil hydrochloride injection, and every 1000mL of urapidil hydrochloride injection contains the following raw materials: 5 g of uradil hydrochloride, 100 g of osmotic pressure regulator and acid-base buffer pair, the acid-base The buffer pair is citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate, and the pH value of the urapidil hydrochloride injection is 5.9-6.5.

The setting of the pH value of injection in this application, at first refer to the scope of pH value in the quality standard of injection, then select the scope of optimal pH value therefrom, improved the stability of injection; According to the pH value setting of injection The specific usage of the acid-base buffer pair.

In one of the embodiments, the pH value of the urapidil hydrochloride injection is 6.2.

In one of the embodiments, the osmotic pressure regulator is polyethylene glycol or glycerin.

Specifically, the osmotic pressure regulator is polyethylene glycol, and the acid-base buffer pair is citric acid-sodium citrate.

Compared with inorganic osmotic pressure regulators, polyethylene glycol not only has good water solubility, but also has good compatibility with many organic components, which is more conducive to the absorption and distribution of medicinal liquid in the body, so as to play a fast role. The effect of regulating osmotic pressure. Citric acid can be ionized in three steps according to the acidity of the liquid, and the buffering capacity is stronger.

In one embodiment, each 1000 mL of urapidil hydrochloride injection contains the following raw materials: 5 g of urapidil hydrochloride, 100 g of polyethylene glycol, 0.2 g to 0.6 g of citric acid, and 1.8 g to 6 g of sodium citrate.

The preferred prescription amount of urapidil hydrochloride injection significantly improves the stability of the main drug urapidil hydrochloride, making the injection have excellent stability.

The second aspect of the present application provides a method for preparing urapidil hydrochloride injection, at least including the following steps:

Step 1: weighing each component according to the ratio of the above-mentioned raw materials;

Step 2: Under the protection of inert gas, add the acid-base buffer pair, osmotic pressure regulator and urapidil hydrochloride to part of the water for injection at 20°C~60°C. Adjust the pH value of the solution to 5.9 to 6.5 with the remaining water for injection at 60°C, and filter to obtain the filtrate;

Step 3: filling, sterilizing, and cooling the filtrate to 40° C. to 60° C. to obtain the urapidil hydrochloride injection.

The acid-base buffer pair is citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate.

In this application, the specific addition sequence of the main drug urapidil hydrochloride and other auxiliary materials mainly considers the material effect of the main drug and each auxiliary material. The acid-base buffer pair is used to adjust the pH value of the injection, so the acid-base buffer pair is first added, and after the pH value is adjusted to a stable state, an osmotic pressure regulator is added to prevent the local overacidity or overalkaline of the medicinal solution; hydrochloric acid Urapidil is the main active ingredient and is sensitive to temperature, so Urapidil hydrochloride is added at the end to improve the stability of the injection.

In one of the embodiments, the osmotic pressure regulator is polyethylene glycol or glycerin.

Specifically, the osmotic pressure regulator is polyethylene glycol, and the acid-base buffer pair is citric acid-sodium citrate.

In one of the embodiments, the inert gas is nitrogen, and the inert gas is filled in the process of preparing urapidil hydrochloride injection, which can reduce the content of dissolved oxygen and effectively avoid the influence of oxygen on urapidil hydrochloride injection , improving the stability of urapidil hydrochloride injection.

In one embodiment, in step 2, the filtration is a two-stage filtration in which the pore diameter of the filter element decreases successively, wherein the pore diameter of the filter element of the first stage of filtration is 0.45 μm, and the pore size of the filter element of the second stage of filtration is 0.2 μm.

In one embodiment, the filter elements of the first-stage filtration and the second-stage filtration are both polyethersulfone filter elements.

This application adopts secondary filtration with a specific pore size and a specific filter element, and uses a polyethersulfone filter element with a pore size of 0.45 μm to filter to remove heat sources and impurities in the injection, and then uses a polyethersulfone filter element with a pore size of 0.22 μm to terminate the injection. Filtration to remove pyrogenic bacterial endotoxins in the injection, combined with the specific addition and mixing sequence of the main drug urapidil hydrochloride and other excipients, further reduces the chance of urapidil hydrochloride deterioration and improves the efficiency of sterilization.

The present application does not use activated carbon in the preparation process, simplifies the process steps, avoids the introduction of impurities when adding activated carbon, and reduces the adsorption of activated carbon to the main drug urapidil hydrochloride, thereby causing a large amount of loss.

In one of the embodiments, in step 2, the amount of water for the part of the injection is 40% to 80% of the total volume of the injection; the remaining water for injection is used to add to the total volume of the injection .

Under the condition that the temperature of water for injection is 20°C~60°C, the applicant sequentially added acid-base buffer pair, osmotic pressure regulator and urapidil hydrochloride to the water for injection. Based on the short dissolution time and the uniformity of content, the applicant The volume of water for injection initially added is selected to be 40% to 80% of the total volume of injection solution preparation.

In one embodiment, in Step 3, the sterilization temperature is 121° C., and the sterilization time is 7 minutes to 15 minutes.

Specifically, in Step 3, the sterilization temperature is 121° C., and the sterilization time is 8 minutes.

The optimal sterilization conditions can significantly reduce the impurity content in the injection.

It can be understood that the numerical range disclosed in the present application can be any value in the range interval; the disclosed numerical value is only a better choice. Certainly, in other embodiments, other numerical values may also be used, and are not limited thereto.

Beneficial effect

Compared with the prior art, the urapidil hydrochloride injection provided by the application has the following advantages:

This application uses citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate as the acid-base buffer pair, and adjusts the pH value of the injection to 5.9~6.5, which significantly improves the The stability of the injection promotes the large-scale industrial production of urapidil hydrochloride injection.

Based on the fact that the main drug urapidil hydrochloride is sensitive to high temperature and light, it is prone to deterioration under conditions such as high temperature and light, so the selection of auxiliary materials in the injection becomes a key condition for the stability of the injection. Adding other excipients, such as adding a metal ion complexing agent to the injection or adjusting the pH of the system with sodium hydroxide-hydrochloric acid, etc., but the above method cannot avoid the darkening of the solution in some products after the accelerated test and the content of related substances is higher than 2.5% of cases occur.

Compared with the prior art, the preparation method of urapidil hydrochloride injection provided by the application has the following advantages:

In this application, by adjusting the addition and mixing sequence of the main drug urapidil hydrochloride and other excipients, and controlling the temperature during the preparation process to be lower than 60°C, the probability of deterioration of urapidil hydrochloride is effectively reduced, and the stability of the injection is significantly improved. .

Embodiment of this application

In order to make the purpose, technical solution and advantages of the present application clearer, the present application will be further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described here are only used to explain the present application, and are not intended to limit the present application.

A kind of urapidil hydrochloride injection is provided in the embodiment of this application, and every 1000mL urapidil hydrochloride injection contains the following raw materials: urapidil hydrochloride 5g, osmotic pressure regulator 100g and acid-base buffer pair, the acid-base The buffer pair is citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate, and the pH value of the urapidil hydrochloride injection is 5.9-6.5.

The preparation method of above-mentioned urapidil hydrochloride injection comprises the following steps at least:

Step 1: weighing each component according to the ratio of the above-mentioned raw materials;

Step 2: Under the protection of inert gas, add the acid-base buffer pair, osmotic pressure regulator and urapidil hydrochloride to part of the water for injection at 20°C~60°C. Adjust the pH value of the solution to 5.9 to 6.5 with the remaining water for injection at 60°C, and filter to obtain the filtrate;

Step 3: filling, sterilizing, and cooling the filtrate to 40° C. to 60° C. to obtain the urapidil hydrochloride injection.

The acid-base buffer pair is citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate.

Example 1

The embodiment of the present application provides a kind of urapidil hydrochloride injection, and every 1000mL of urapidil hydrochloride injection contains the following raw materials: 5 g of urapidil hydrochloride, 100 g of polyethylene glycol, 0.3 g of citric acid and 2.6 g of sodium citrate g, the pH value of the urapidil hydrochloride injection is 6.2.

The preparation method of above-mentioned urapidil hydrochloride injection comprises the following steps:

Step 1: weighing each component according to the above-mentioned raw material ratio;

Step 2: Cool the water for injection with 60% of the total volume of the injection solution to 50°C, under nitrogen protection, add citric acid, sodium citrate, polyethylene glycol and urapidil hydrochloride, after the raw materials are dissolved evenly, Add the remaining water for injection at a temperature of 50°C, adjust the pH of the solution to 6.2, filter through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.2 μm in sequence, and collect the filtrate;

Step 3: Fill the filtrate, sterilize at 121°C/12min, and cool to 40°C to obtain the urapidil hydrochloride injection.

Example 2

The embodiment of the present application provides a kind of urapidil hydrochloride injection, and every 1000mL of urapidil hydrochloride injection contains the following raw materials: 5 g of urapidil hydrochloride, 100 g of polyethylene glycol, 0.3 g of citric acid and 3.3 g of sodium citrate g, the pH value of the urapidil hydrochloride injection is 6.3.

The preparation method of above-mentioned urapidil hydrochloride injection comprises the following steps:

Step 1: weighing each component according to the above-mentioned raw material ratio;

Step 2: Cool down 80% of the total volume of water for injection preparation to 30°C. Under nitrogen protection, add citric acid, sodium citrate, polyethylene glycol and urapidil hydrochloride. After the raw materials are dissolved evenly, Add the remaining water for injection at a temperature of 45°C, adjust the pH of the solution to 6.3, filter through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.2 μm in sequence, and collect the filtrate;

Step 3: Fill the filtrate, sterilize at 121°C/10min, and cool to 45°C to obtain the urapidil hydrochloride injection.

Example 3

The embodiment of the present application provides a kind of urapidil hydrochloride injection, each 1000mL of urapidil hydrochloride injection contains the following raw materials: 5 g of urapidil hydrochloride, 100 g of polyethylene glycol, 0.3 g of citric acid and 2.3 g of sodium citrate g, the pH value of the urapidil hydrochloride injection is 6.1.

The preparation method of above-mentioned urapidil hydrochloride injection comprises the following steps:

Step 1: weighing each component according to the above-mentioned raw material ratio;

Step 2: Cool the water for injection with 70% of the total volume of the injection solution to 35°C, add citric acid, sodium citrate, polyethylene glycol and urapidil hydrochloride under nitrogen protection, dissolve the raw materials evenly and add Adjust the pH value of the solution to 6.1 for the remaining water for injection at a temperature of 40°C, filter through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.2 μm in sequence, and collect the filtrate;

Step 3: Fill the filtrate, sterilize at 121°C/15min, and cool to 40°C to obtain the urapidil hydrochloride injection.

Example 4

The embodiment of the present application provides a kind of urapidil hydrochloride injection, and every 1000mL of urapidil hydrochloride injection contains the following raw materials: 5 g of urapidil hydrochloride, 100 g of glycerin, 0.3 g of citric acid and 2.8 g of sodium citrate. The pH value of said urapidil hydrochloride injection is 6.2.

The preparation process of the above-mentioned urapidil hydrochloride injection is as described in Example 1, and will not be repeated.

Example 5

The embodiment of the present application provides a kind of urapidil hydrochloride injection, and every 1000mL of urapidil hydrochloride injection contains the following raw materials: urapidil hydrochloride 5g, polyethylene glycol 100g, acetic acid 0.2g and sodium acetate 8.0g, the The pH value of urapidil hydrochloride injection is 6.2.

The preparation process of the above-mentioned urapidil hydrochloride injection is as described in Example 2, and will not be repeated.

Example 6

The embodiment of the present application provides a kind of urapidil hydrochloride injection, and every 1000mL of urapidil hydrochloride injection contains the following raw materials: 5 g of urapidil hydrochloride, 100 g of polyethylene glycol, 0.3 g of citric acid and 0.8 g of disodium hydrogen phosphate g, the pH value of the urapidil hydrochloride injection is 6.2.

The preparation process of the above-mentioned urapidil hydrochloride injection is as described in Example 3, and will not be repeated.

Example 7

The embodiment of the present application provides a kind of urapidil hydrochloride injection, and every 1000mL of urapidil hydrochloride injection contains the following raw materials: urapidil hydrochloride 5g, polyethylene glycol 100g, phosphoric acid 1.8g and sodium phosphate 9.8g, the The pH value of urapidil hydrochloride injection is 6.2.

The preparation process of the above-mentioned urapidil hydrochloride injection is as described in Example 1, and will not be repeated.

In order to better illustrate the characteristics of the preparation method of urapidil hydrochloride injection provided by the present application, referring to the guiding principles of drug stability, the urapidil hydrochloride injection prepared in Example 1 was subjected to experimental investigation of influencing factors and accelerated test research.

Test example 1

Influencing factor test: high temperature test, the temperature is 60°C, urapidil hydrochloride injection was subjected to high temperature test for 0 day, 5 days, 10 days, 15 days and 30 days respectively, the results are shown in Table 1 below. It can be seen from Table 1 that after being placed at 60°C for 30 days, there was no significant change in the pH value and insoluble particles in the various inspection indicators in the injection, the content of the main drug decreased slightly, and the related substances increased, and the range of change was not large. Large, all meet quality standards. Show that the urapidil hydrochloride injection prepared in Example 1 has good stability.

Table 1 High temperature test results

the 0 days 5 days 10 days 15 days 30 days character colorless clear liquid colorless clear liquid colorless clear liquid colorless clear liquid colorless clear liquid Main drug content% 99.9% 99.2% 98.7% 98.3% 97.2% pH value 6.2 6.21 6.20 6.22 6.21 Insoluble particles% 4.9/0.7 4.8/0.3 5.5/0.3 6.6/0.0 11.1/0.7 relative substance% 0.22 0.67 1.17 1.72 3.12

Test example 2

Influencing factor test: light test, the light conditions are total illuminance ≥ 1.2×10 ⁶ Lux·hr, near ultraviolet energy ≥ 200w·hr/m ² The results of the 15-day and 30-day light tests are shown in Table 2 below. As can be seen from Table 2, there was no significant change in the inspection indexes in the injection after being placed under light conditions for 30 days, indicating that the urapidil hydrochloride injection prepared in Example 1 had good stability.

Table 2 Lighting test results

the 0 days 5 days 10 days 15 days 30 days character colorless clear liquid colorless clear liquid colorless clear liquid colorless clear liquid colorless clear liquid Main drug content% 99.9% 100.0% 99.0% 98.7% 99.7% pH value 6.2 6.21 6.21 6.21 6.22 Insoluble particles% 4.9/0.7 2.4/0.3 4.5/0.0 4.2/0.0 9.7/0.0 relative substance% 0.22 0.25 0.34 0.43 0.68

Test example 3

Influencing factor test: freeze-thaw test, the specific conditions are: three freeze-thaw cycles, each cycle is placed at a temperature of -10°C to -20°C for 2 days, and then placed at 40°C for 2 days, the results are shown in the table below 3. As can be seen from Table 3, after the freeze-thaw test of 3 cycles, there is no obvious change in the inspection indicators in the injection, indicating that the urapidil hydrochloride injection prepared in Example 1 has good stability.

Table 3 Freeze-thaw test results

the 0 days freeze-thaw once Freeze and thaw 2 times freeze-thaw 3 times character colorless clear liquid colorless clear liquid colorless clear liquid colorless clear liquid Main drug content% 99.9% 99.4% 99.4% 99.8% pH value 6.2 6.20 6.20 6.22 Insoluble particles% 4.9/0.7 3.5/0.7 4.2/0.7 1.0/0.3 relative substance% 0.22 0.27 0.33 0.33

Test example 4

The prescription quantity and the preparation method of the urapidil hydrochloride injection provided in Example 1 are used to prepare three batches of pilot test samples, and the pilot test samples are carried out accelerated test research; the accelerated test is put into 40 ℃ stable under the market packaging conditions Investigated in the test box, the results are shown in Table 4, as can be seen from Table 4, there is no significant change in the inspection indicators in the injection, showing that the injection has good stability.

Table 4 Accelerated test results

The experimental results of the urapidil hydrochloride injection prepared in Examples 2 to 7 are consistent with those of Example 1, and have excellent stability.

As long as the pH value of urapidil hydrochloride injection, the amount of acid-base buffer pair, and the temperature of water for injection in the preparation method, the amount of water for part of the injection, and the sterilization conditions are within the preferred range of the application, the present invention can be achieved. The same or corresponding technical effects in application embodiment 1.

The above description is only a preferred embodiment of the application, and is not intended to limit the application. Any modification, equivalent replacement or improvement made within the spirit and principles of the application shall be included in the protection of the application. within range.

Claims (10)

A kind of urapidil hydrochloride injection, it is characterized in that: every 1000mL urapidil hydrochloride injection contains following raw materials: urapidil hydrochloride 5g, osmotic pressure regulator 100g and acid-base buffer pair, described acid-base buffer pair is Citric acid-sodium citrate, acetic acid-sodium acetate, citric acid-disodium hydrogen phosphate or phosphoric acid-sodium phosphate, and the pH value of the urapidil hydrochloride injection is 5.9-6.5. The urapidil hydrochloride injection according to claim 1, wherein the pH value of the urapidil hydrochloride injection is 6.2. The urapidil hydrochloride injection according to claim 1, wherein the osmotic pressure regulator is polyethylene glycol or glycerin. The urapidil hydrochloride injection according to claim 1, wherein the osmotic pressure regulator is polyethylene glycol, and the acid-base buffer pair is citric acid-sodium citrate. The urapidil hydrochloride injection according to claim 4, characterized in that: every 1000 mL of urapidil hydrochloride injection contains the following raw materials: 5 g of uradil hydrochloride, 100 g of polyethylene glycol, 0.2 g to 0.6 g of citric acid g and sodium citrate 1.8g ~ 6g. A preparation method of urapidil hydrochloride injection, characterized in that: at least comprising the following steps: Step 1: taking each component according to the proportioning of raw materials as described in any one of claims 1 to 5; Step 2: under the protection of an inert gas, add the acid-base buffer pair, the osmotic pressure regulator, and the urapidil hydrochloride into part of the water for injection at 20°C~60°C, and after the raw materials are evenly dissolved, Adding the remaining water for injection at a temperature of 20°C to 60°C, adjusting the pH of the solution to 5.9 to 6.5, and filtering to obtain a filtrate; Step 3: filling, sterilizing, and cooling the filtrate to 40° C. to 60° C. to obtain the urapidil hydrochloride injection. The preparation method of urapidil hydrochloride injection as claimed in claim 6, is characterized in that: in step 2, described filtration is the two-stage filtration that the aperture of filter core decreases successively, wherein, the filter core aperture of first-stage filtration is 0.45 μm, the pore size of the second stage filter is 0.2μm. The preparation method of urapidil hydrochloride injection as claimed in claim 7, is characterized in that: the filter element of described first level filter and described second level filter is polyethersulfone filter element. The preparation method of urapidil hydrochloride injection as claimed in claim 6, is characterized in that: in step 2, the amount of water for said part of the injection is 40% ~ 80% of the total volume of the injection preparation. The preparation method of urapidil hydrochloride injection according to claim 6, characterized in that: in step 3, the sterilization temperature is 121° C., and the sterilization time is 7 minutes to 15 minutes.