Urapidil hydrochloride injection and preparation method thereof

Abstract

The invention provides an urapidil hydrochloride injection and a preparation method thereof, and particularly relates to the field of medicines. The urapidil hydrochloride composition comprises the following components in w / v: 0.4-0.6% of urapidil hydrochloride; 9-11% of a stabilizer; 0.03 to 0.05 percent of anhydrous disodium hydrogen phosphate; 0.1-0.3% of sodium dihydrogen phosphate monohydrate, and the balance of water for injection, which is supplemented to 100%. The defects in the prior art are overcome, the cost is saved, meanwhile, the impurity level of the urapidil hydrochloride injection after sterilization is reduced, the liquid medicine temperature is reduced in the liquid preparation and filling processes, meanwhile, the inert gas is filled, the influence of metal ions in a production assembly is greatly reduced, and the production efficiency is improved. The levels of impurities C and D in the finished product after the urapidil hydrochloride injection is sterilized are reduced; the prepared urapidil hydrochloride injection is low in impurity level and high in stability, the quality of the urapidil hydrochloride injection meets the requirements of current laws and regulations, and the urapidil hydrochloride injection is superior to a reference preparation.

Description

Technical Field

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

[0002] Urapidil hydrochloride injection was first approved for marketing in Germany by Altana Pharma Deutschland GmbH in 1988. The product is now produced by Takeda (Austria) GmbH;

[0003] Urapidil hydrochloride is prone to generate impurities during long-term storage of the injection. High impurity content will reduce the drug efficacy, stability and medication safety of the product. The stabilizer used in the original research formulation is propylene glycol. During the preparation of urapidil hydrochloride injection, both the oxygen control condition and temperature will affect the product quality. For example, urapidil hydrochloride is affected by high temperature during autoclaving at 121°C, and the main component is prone to hydrolysis and oxidative degradation. Existing technologies cannot simultaneously inhibit hydrolysis and oxidative degradation;

[0004] Patent CN200410049988.7 discloses a preparation method of a large-volume injection of urapidil hydrochloride and its application in the preparation of antihypertensive drugs. The preparation contains urapidil hydrochloride, an isotonicity regulator, a pH regulator and water for injection. The isotonicity regulator is selected from sodium chloride, glucose, dextran, mannitol, sorbitol, and the pH regulator is selected from hydrochloric acid and sodium hydroxide. However, the patent still does not fundamentally solve the problems of poor stability and easy decomposition and deterioration of urapidil hydrochloride in the injection solution, which greatly limits the wide application of this drug in the injection dosage form.

[0005] Patent CN 116492297A discloses an urapidil hydrochloride injection and a preparation method thereof. The preparation contains: urapidil hydrochloride, 1,2-propylene glycol, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, and an antioxidant. Among them: the antioxidant is preheated and mixed with 1,2-propylene glycol and then mixed with other components to form an injection. The antioxidant is sodium metabisulfite, sodium thiosulfate, or polyethylene glycol vitamin E succinate. The inventive solution effectively improves the stability of the urapidil injection and inhibits its oxidative degradation to a certain extent during the autoclaving stage, but cannot simultaneously inhibit hydrolysis and oxidative degradation, especially impurity C and impurity D.

[0006] In the prior art, the high temperature condition during autoclaving will cause hydrolysis and oxidative degradation of urapidil hydrochloride, resulting in a decrease in the content of the active ingredient in the urapidil hydrochloride injection and affecting the product quality of the urapidil hydrochloride injection. To improve this defect, the present application provides an urapidil hydrochloride injection and a preparation method thereof. Summary of the Invention

[0007] To overcome the defects of the prior art, save costs and reduce the impurity level after sterilization of urapidil hydrochloride injection, the present invention reduces the temperature of the liquid medicine during the liquid preparation and filling processes, and at the same time fills an inert gas, which greatly reduces the influence of metal ions in the production components and reduces the levels of impurities C and D in the finished product of urapidil hydrochloride injection after sterilization; an urapidil hydrochloride injection with low impurity level, high stability, quality meeting the requirements of current regulations and superior to the reference preparation is prepared.

[0008] The present invention provides the following technical solutions:

[0009] An urapidil hydrochloride injection, calculated by w / v, comprises 0.4 - 0.6% of urapidil hydrochloride; 9 - 11% of a stabilizer; 0.03 - 0.05% of anhydrous disodium hydrogen phosphate; 0.1 - 0.3% of sodium dihydrogen phosphate monohydrate, and the balance is made up to 100% with injection water.

[0010] Preferably, it comprises 0.5% of urapidil hydrochloride; 10% of a stabilizer; 0.04% of anhydrous disodium hydrogen phosphate; 0.20% of sodium dihydrogen phosphate monohydrate; and is made up to 100% with injection water.

[0011] Preferably, the stabilizer is one of xylitol, glycerol, and propylene glycol;

[0012] Preferably, the stabilizer is xylitol.

[0013] A method for preparing an urapidil hydrochloride injection is as follows:

[0014] S1. Liquid medicine preparation: Add 80% of the prescription amount of injection water to the liquid preparation tank, lower the temperature of the injection water to less than 30°C, and continuously introduce an inert gas. Sequentially add the prescription amounts of xylitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate, stir to dissolve, and adjust the pH to 5.5 - 6.5; after stirring and dissolving, add urapidil hydrochloride, and make up to the prescription amount with injection water, and the temperature of the added make-up injection water is less than 30°C.

[0015] S2. Filtration: The liquid medicine passes through a stainless steel pipeline and is filtered for filling.

[0016] S3. Filling and sealing: The liquid medicine prepared in step S1 is filtered through a pipeline and filled into ampoules and then sealed; during the filling process, the temperature of the liquid medicine needs to be maintained below 25°C. During the filling process, the empty ampoules are pre-filled with nitrogen with an inert gas. After injecting the liquid medicine into the ampoules, an inert gas is filled above the liquid medicine, and then it is sealed.

[0017] S4. Sterilization: The filled samples are sterilized at 121°C for 12 minutes.

[0018] Preferably, in step S1, after controlling the dissolved oxygen in the water for injection to not exceed 2 ppm, continue to introduce an inert gas, and sequentially add the prescribed amounts of xylitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate, and stir to dissolve.

[0019] Preferably, in step S1, adjust the pH to 6, and the temperature of the added and volume-fixed water for injection is 25 °C.

[0020] Preferably, in step S2, after filtration through two 0.22 μm microporous membranes, it is ready for filling and sealing.

[0021] Preferably, in step S3, the temperature of the liquid medicine needs to be maintained at 20 °C.

[0022] Advantages of the present invention:

[0023] 1. In the process of preparing the liquid medicine in the method provided by the present invention, by lowering the water for injection to below 30 °C, controlling the temperature during the preparation process and adding a certain dose of stabilizer, the related substance level of the liquid medicine before sterilization can be maintained at a relatively low level, enabling the product to withstand the terminal sterilization conditions and effectively reducing the generation of hydrolysis impurities during the high-temperature sterilization process;

[0024] 2. In the process of preparing the injection of urapidil hydrochloride provided by the present invention, by evacuating the air and filling with an inert gas in the batching system and filling the liquid medicine with an inert gas during the filling process, etc., strictly controlling the dissolved oxygen and the headspace oxygen level in the liquid medicine can effectively reduce the generation of oxidation impurities;

[0025] 3. The injection of urapidil hydrochloride of the present invention contains a phosphate buffer system as a buffer. This buffer system can effectively maintain the pH value of the product within the range of 5.9 - 6.5. During the preparation process, it is not necessary to repeatedly adjust the pH, avoiding the problem that the main drug precipitates during the adjustment process and affects the content, and can effectively ensure the stability of the product quality; compared with other buffer systems, such as the citric acid and sodium citrate buffer system, and the tartaric acid and sodium tartrate buffer system, the phosphate buffer system is superior in maintaining the pH value stability of the liquid medicine and is more beneficial to the quality of the liquid medicine, including quality indicators such as related substances, pH value, and osmotic pressure. Detailed implementation mode

[0026] Example 1

[0027] Prescription composition:

[0028] Name Function Dosage Ratio (g / L) Urapidil Hydrochloride Active ingredient 20 mg 0.4％ Xylitol Stabilizer 450 mg 9.0％ Disodium Hydrogen Phosphate pH regulator 1.5 mg 0.03％ Sodium Dihydrogen Phosphate pH regulator 5 mg 0.10％ Water for Injection Solvent Volume made up to 5 ml /

[0029] (1) Preparation of liquid medicine: Add 80% of the prescribed amount of injection water into the liquid preparation tank, cool the temperature of the injection water to 25°C, and continuously introduce inert gas. After controlling the dissolved oxygen in the injection water not to exceed 2 ppm, continue to introduce inert gas. Then, sequentially add the prescribed amounts of xylitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate, stir to dissolve, and adjust the pH to 6. After stirring and dissolving, add urapidil hydrochloride, and make up the volume to the prescribed amount with injection water. The temperature of the added injection water for volume makeup is cooled to 25°C.

[0030] (2) Filtration: The liquid medicine passes through a stainless - steel pipeline and is filtered through two 0.22 - μm microporous membranes for subsequent filling and sealing.

[0031] (3) Filling and sealing: The liquid medicine prepared in step (1) is filtered through the pipeline and filled into ampoules and then sealed by melting. During the filling and sealing process, the temperature of the liquid medicine needs to be maintained at 20°C. During the filling process, the empty ampoules are pre - filled with nitrogen using inert gas. After injecting the liquid medicine into the ampoules, inert gas is filled above the liquid medicine, and then it is sealed by melting.

[0032] (4) Sterilization: The filled and sealed samples are sterilized at 121°C for 12 minutes.

[0033] Example 2

[0034] Prescription composition (xylitol prescription):

[0035] Name Function Dosage Ratio (g / L) Urapidil Hydrochloride Active ingredient 25 mg 0.5％ Xylitol Stabilizer 500 mg 10.0％ Disodium Hydrogen Phosphate pH regulator 2.0 mg 0.04％ Sodium Dihydrogen Phosphate pH regulator 10.0 mg 0.20％ Water for Injection Solvent Volume made up to 5 ml /

[0036] (1) Preparation of liquid medicine: Add 80% of the prescribed amount of injection water into the liquid preparation tank, cool the temperature of the injection water to 25°C, and continuously introduce inert gas. After controlling the dissolved oxygen in the injection water not to exceed 2 ppm, continue to introduce inert gas. Then, sequentially add the prescribed amounts of xylitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate, stir to dissolve, and adjust the pH to 6. After stirring and dissolving, add urapidil hydrochloride, and make up the volume to the prescribed amount with injection water. The temperature of the added injection water for volume makeup is cooled to 25°C.

[0037] (2) Filtration: The liquid medicine passes through a stainless - steel pipeline and is filtered through two 0.22 - μm microporous membranes for subsequent filling and sealing.

[0038] (3) Filling and sealing: The liquid medicine prepared in step (1) is filtered through the pipeline and filled into ampoules and then sealed by melting. During the filling and sealing process, the temperature of the liquid medicine needs to be maintained at 20°C. During the filling process, the empty ampoules are pre - filled with nitrogen using inert gas. After injecting the liquid medicine into the ampoules, inert gas is filled above the liquid medicine, and then it is sealed by melting.

[0039] (4) Sterilization: The filled and sealed samples are sterilized at 121°C for 12 minutes.

[0040] Example 3

[0041] Prescription composition (xylitol prescription):

[0042]

[0043]

[0044] (1) Preparation of the medicinal solution: Add 80% of the prescribed amount of injection water to the solution preparation tank, cool the temperature of the injection water to 25°C, and continuously introduce inert gas. After controlling the dissolved oxygen in the injection water to not exceed 2 ppm, continue to introduce inert gas. Then, sequentially add the prescribed amounts of xylitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate, stir to dissolve, and adjust the pH to 6. After stirring and dissolving, add urapidil hydrochloride, and make up the volume to the prescribed amount with injection water. The temperature of the added injection water for volume adjustment is reduced to 25°C.

[0045] (2) Filtration: The medicinal solution passes through a stainless-steel pipeline and is filtered through two 0.22-μm microporous membranes for subsequent filling and sealing.

[0046] (3) Filling and sealing: The medicinal solution prepared in step (1) is filtered through a pipeline and then filled into ampoules and sealed by melting. During the filling and sealing process, the temperature of the medicinal solution needs to be maintained at 20°C. During the filling process, the empty ampoules are pre-filled with nitrogen using inert gas. After injecting the medicinal solution into the ampoules, inert gas is filled above the medicinal solution, and then it is sealed by melting.

[0047] (4) Sterilization: The filled and sealed samples are sterilized at 121°C for 12 minutes.

[0048] Control Group 1 (glycerol prescription)

[0049] Prescription composition:

[0050] Name Function Dosage Ratio (g / L) Urapidil Hydrochloride Active ingredient 25 mg 0.5％ Glycerol Stabilizer 500 mg 10.0％ Disodium Hydrogen Phosphate pH regulator 2.0 mg 0.04％ Sodium Dihydrogen Phosphate pH regulator 10.0 mg 0.20％ Water for Injection Solvent Volume made up to 5 ml /

[0051] Preparation process:

[0052] (1) Preparation of the medicinal solution: Add 80% of the prescribed amount of injection water to the solution preparation tank, cool the temperature of the injection water to below 30°C, and continuously introduce inert gas. After controlling the dissolved oxygen in the injection water to not exceed 2 ppm, continue to introduce inert gas. Then, sequentially add the prescribed amounts of glycerol, disodium hydrogen phosphate, and sodium dihydrogen phosphate, stir to dissolve, and adjust the pH to 5.5 - 6.5. Separately, take 10% of the injection water, add urapidil hydrochloride, and make up the volume to the prescribed amount with injection water. The temperature of the added injection water for volume adjustment does not exceed 30°C.

[0053] (2) Filtration: The medicinal solution passes through a stainless-steel pipeline and is filtered through two 0.22-μm microporous membranes for subsequent filling and sealing.

[0054] (3) Sealing: After the liquid medicine prepared in step (1) is filtered through a pipeline, it is sealed in an ampoule bottle and heat-sealed. During the sealing process, the temperature of the liquid medicine needs to be maintained below 25°C. During the sealing process, the empty ampoule bottle is pre-filled with nitrogen using an inert gas. After injecting the liquid medicine into the ampoule bottle, an inert gas is filled above the liquid medicine, and then it is heat-sealed.

[0055] (4) Sterilization: The sealed samples are sterilized at 121°C for 12 minutes.

[0056] Control Group 2 (Process without oxygen control)

[0057] Prescription composition:

[0058] Name Function Dosage Ratio (g / L) Urapidil Hydrochloride Active ingredient 25 mg 0.5％ Xylitol Stabilizer 500 mg 10.0％ Disodium Hydrogen Phosphate pH regulator 2.0 mg 0.04％ Sodium Dihydrogen Phosphate pH regulator 10.0 mg 0.20％ Water for Injection Solvent Volume made up to 5 ml /

[0059] Preparation process:

[0060] (1) Preparation of liquid medicine: Add 80% of the prescription amount of injection water to the liquid preparation tank, lower the temperature of the injection water below 30°C, and sequentially add the prescription amounts of xylitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate, stir to dissolve, and adjust the pH to 5.5 - 6.5; add urapidil hydrochloride, and make up the volume to the prescription amount with injection water. The temperature of the added injection water for volume adjustment does not exceed 30°C.

[0061] (2) Filtration: The liquid medicine passes through a stainless-steel pipeline and is filtered through two 0.22μm microporous membranes for sealing.

[0062] (3) Sealing: After the liquid medicine prepared in step (1) is filtered through a pipeline, it is sealed in an ampoule bottle and heat-sealed. During the sealing process, the temperature of the liquid medicine needs to be maintained below 25°C, and then it is heat-sealed.

[0063] (4) Sterilization: The sealed samples are sterilized at 121°C for 12 minutes.

[0064] (5) Visual inspection and leak detection: The sterilized samples are subjected to visual inspection and leak detection. The qualified samples are packaged, inspected, and stored in the warehouse. Control Group 3

[0065] Prescription composition of Patent CN 114652675 A:

[0066] Name Function Dosage Ratio (g / L) Urapidil Hydrochloride Active ingredient 25 mg 0.5％ 1,2 - Propylene Glycol Stabilizer 500 mg 10.0％ Disodium Hydrogen Phosphate pH regulator 2.1 mg 0.04％ Sodium Dihydrogen Phosphate pH regulator 11.1 mg 0.20％ Water for Injection Solvent Volume made up to 5 ml /

[0067] Preparation process:

[0068] (1) Weigh about 4000g of injection water below 30°C and continuously fill it with nitrogen;

[0069] (2) Under continuous nitrogen filling and stirring, add the prescription amount of 1,2-propanediol and stir to dissolve;

[0070] (3) Under continuous nitrogen filling and stirring, add disodium hydrogen phosphate dihydrate and sodium dihydrogen phosphate dihydrate and stir to dissolve;

[0071] (4) Under continuous nitrogen charging and stirring, add urapidil hydrochloride and stir until dissolved. Measure the pH value (5.5 - 6.5).

[0072] (5) Make up to 5000 mL with injection water (below 30 °C).

[0073] (6) Filter through a 0.22 - um PES membrane filter, fill after filtration, and sterilize at 121 °C for 15 min to obtain an urapidil hydrochloride injection containing 5.47 mg of urapidil hydrochloride per 1 mL (5 mg calculated as urapidil).

[0074] Control group 4

[0075] Prescription composition of Patent CN 116492297 A

[0076] Prescription composition:

[0077]

[0078] Preparation process:

[0079] (1) Measure about 80% of the prescription amount of injection water into a beaker, introduce nitrogen protection at the bottom of the liquid surface, maintain the dissolved oxygen content in the solution at 1000 μg / L, and add the prescription amounts of disodium hydrogen phosphate and sodium dihydrogen phosphate respectively, and stir until dissolved uniformly to prepare solution A.

[0080] (2) Add polyethylene glycol succinate of vitamin E to 1,2 - propanediol of the prescription amount, heat to 40 °C and stir until dissolved uniformly to prepare solution B.

[0081] (3) Add solution B to solution A, stir evenly, weigh the prescription amount of urapidil hydrochloride and add it to the above solution, stir visually until dissolved, and make up to the prescription amount with injection water.

[0082] (4) Filter the liquid medicine through a 0.22 - um microporous membrane filter.

[0083] (5) Seal the filtered liquid medicine into ampoules, control the residual oxygen content in the ampoules below 1%, and put the sealed samples into an autoclave for sterilization at 121 °C for 15 min.

[0084] (6) Filter through a 0.22 - um PES membrane filter, fill after filtration, and sterilize at 121 °C for 15 min to obtain an urapidil hydrochloride injection containing 5.47 mg of urapidil hydrochloride per 1 mL (5 mg calculated as urapidil).

[0085] Place the samples of Examples 1 - 3 and Control groups 1 - 4 under the influencing factor of high temperature at 60 °C for 0 days, 10 days, and 30 days respectively. The test results are shown in the following table:

[0086]

[0087]

[0088] It can be seen from the above control groups that after high-temperature sterilization, urapidil hydrochloride produces hydrolysis impurity C (1,3-dimethylbarbituric acid) and oxidation impurity D (N-(3-aminopropyl)-N'-(2-methoxyphenyl)-piperazine) respectively. In control group 1, by adding glycerol to the prescription, the generation of hydrolysis impurity C (1,3-dimethylbarbituric acid) can be effectively inhibited, and there is no change in oxidation impurity D (N-(3-aminopropyl)-N-(2-methoxyphenyl)-piperazine). It can be concluded from control group 2 that charging inert gas at low temperature in aqueous solution can effectively reduce the generation of oxidation impurities, but there is no obvious change in hydrolysis impurities. Control group 3 is the conventional prescription process. Under the condition of high-temperature sterilization, with the increase of the retention time, the growth rate of impurities is relatively large for both hydrolysis impurities and oxidation impurities.

[0089] In control group 4, vitamin E polyethylene glycol succinate is first dissolved in 1,2-propanediol and then added to the urapidil hydrochloride solution, which can effectively inhibit the oxidative degradation and hydrolysis of the main component. However, vitamin E polyethylene glycol succinate is a water-soluble derivative of vitamin E, which is formed by the reaction of the carboxyl group of vitamin E succinate with the hydroxyl group of polyethylene glycol. Since it contains both the lipophilic group of vitamin E and the hydrophilic long chain of polyethylene glycol, the source of the current excipient level is less, the control risk is higher, it is less used in injections, and the growth rate of impurities is still relatively large. Therefore, it is not recommended to use.

[0090] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, for those skilled in the art, they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent substitution on some of the technical features. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. An injection of urapidil hydrochloride, characterized in that: It contains 0.4 - 0.6% of urapidil hydrochloride (w / v); 9 - 11% of stabilizer; 0.03 - 0.05% of anhydrous disodium hydrogen phosphate; 0.1 - 0.3% of sodium dihydrogen phosphate monohydrate, and the balance is made up to 100% with injection water.

2. The metronidazole tablets according to claim 1, characterized in that: It contains 0.5% of urapidil hydrochloride; 10% of stabilizer; 0.04% of anhydrous disodium hydrogen phosphate; 0.20% of sodium dihydrogen phosphate monohydrate; and is made up to 100% with injection water.

3. The metronidazole tablets according to claim 2, characterized in that: The stabilizer is one of xylitol, glycerol, and propylene glycol.

4. The metronidazole tablets according to claim 3, wherein: The stabilizer is xylitol.

5. The injection of urapidil hydrochloride according to claim 1, characterized in that, The preparation method is as follows: S1. Preparation of the liquid medicine: Add 80% of the prescribed amount of injection water to the liquid preparation tank, lower the temperature of the injection water to less than 30°C, and continuously introduce inert gas. Then add the prescribed amounts of xylitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate in sequence, stir to dissolve, and adjust the pH to 5.5 - 6.

5. After stirring and dissolving, add urapidil hydrochloride, and make up the volume to the prescribed amount with injection water. The temperature of the injection water added for volume adjustment is less than 30°C. S2. Filtration: The liquid medicine passes through a stainless - steel pipeline and is filtered for subsequent filling and sealing. S3. Filling and sealing: The liquid medicine prepared in step S1 is filtered through a pipeline and filled into ampoules, and then sealed by melting. During the filling and sealing process, the temperature of the liquid medicine needs to be kept below 25°C. During the filling and sealing process, the empty ampoules are pre - filled with nitrogen using inert gas. After injecting the liquid medicine into the ampoules, inert gas is filled above the liquid medicine, and then it is sealed by melting. S4. Sterilization: The filled and sealed samples are sterilized at 121°C for 12 minutes.

6. The preparation method of metronidazole tablets according to claim 5, characterized in that: In step S1, after controlling the dissolved oxygen in the injection water not to exceed 2 ppm, continue to introduce inert gas, and then add the prescribed amounts of xylitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate in sequence, and stir to dissolve.

7. The preparation method of metronidazole tablets according to claim 5, characterized in that: In step S1, adjust the pH to 6, and the temperature of the injection water added for volume adjustment is 25°C.

8. The preparation method of the metronidazole tablets according to claim 5, characterized in that: In step S2, after filtration through two 0.22 - μm microporous membranes, it is ready for filling and sealing.

9. The preparation method of the metronidazole tablets according to claim 5, characterized in that: In step S3, the temperature of the liquid medicine needs to be kept at 20°C.

Images