Preparation process of nicardipine hydrochloride injection

Abstract

The invention relates to the field of injection preparation, and discloses a nicardipine hydrochloride injection preparation process, which comprises: 1, adding injection water accounting for 90% of the total preparation amount into a preparation tank, starting nitrogen filling for 10 min, starting stirring, filling nitrogen below the liquid level, and maintaining the nitrogen filling; 2, adding a 1mol / L hydrochloric acid solution into the mixing tank, and stirring for 5 minutes; the preparation method comprises the following steps: adding a nicardipine hydrochloride raw material according to a prescription dosage into a mixing tank, stirring for 15-40 minutes until the nicardipine hydrochloride raw material is completely dissolved, and continuously stirring for 5 minutes after no visible particles are seen; and step 3, adding the sorbitol according to the prescription dosage into the mixing tank, and stirring for not less than 10 minutes until the sorbitol is completely dissolved. Measuring the pH value of the liquid medicine; 4, supplementing the water for injection to full dose, and circularly stirring for 15 minutes; a vacuum attenuation method is adopted as a method for leak detection of leakproofness in the process of verifying the stability of batch samples in three batch processes, no leakage is detected in the samples which are subjected to stable sample reserving for 0 day, acceleration for 3 months, acceleration for 6 months and long-term 6 months, and the leakproofness of the samples which are subjected to stable sample reserving is good.

Description

Technical Field

[0001] The present invention relates to the field of injection preparation, and particularly to a preparation process of nicardipine hydrochloride injection. Background Art

[0002] Nicardipine hydrochloride exerts a vasodilatory effect by inhibiting the influx of Ca2+ into vascular smooth muscle cells, and can inhibit phosphodiesterase, increasing cerebral, coronary and renal blood flow and playing a hypotensive role. Clinically, it is applicable to essential hypertension, sequelae of cerebral infarction, sequelae of cerebral hemorrhage, and cerebral arteriosclerosis, and is a calcium antagonist and vasodilator. It inhibits the transmembrane calcium ion influx of myocardium and vascular smooth muscle without changing the blood calcium concentration, and has a strong selectivity for blood vessels. In animal experiments, it can dilate coronary vascular smooth muscle, and the blood drug concentration at this time does not produce a negative inotropic effect on the myocardium. In humans, it can reduce peripheral vascular resistance, and this effect is greater in hypertensive patients than in normal blood pressure patients. During hypotensive treatment, there is a reflexive increase in heart rate, increasing cardiac ejection fraction and cardiac output with little change in left ventricular end-diastolic pressure, and increasing coronary blood flow. Now, a preparation process of nicardipine hydrochloride injection is proposed. Summary of the Invention

[0003] Aiming at the deficiencies of the prior art, the technical solution adopted by the present invention to solve its technical problems is: A preparation process of nicardipine hydrochloride injection according to the present invention includes the following steps:

[0004] Step 1: Add 90% of the total amount of injection water into a preparation tank, start nitrogen filling for 10 min, then start stirring, and keep nitrogen filling under the liquid surface.

[0005] Step 2: Add 1 mol / L hydrochloric acid solution into a mixing tank and stir for 5 min.

[0006] Add the prescribed amount of nicardipine hydrochloride raw material into the mixing tank, stir for 15 - 40 min until completely dissolved, continue stirring for 5 min after visually observing no visible particles.

[0007] Step 3: Add the prescribed amount of sorbitol into the mixing tank and stir for not less than 10 min until completely dissolved.

[0008] Measure the pH value of the liquid medicine.

[0009] Step 4: Make up the injection water to the full volume and circulate and stir for 15 min.

[0010] Step 5: Filter the injection through a microporous filter.

[0011] Step 6: Use an automatic filling and sealing system for filling, nitrogen filling and heat sealing operations.

[0012] Step 7: Place the potted product into a stainless steel tray, and then evenly arrange it in the sterilizer for sterilization.

[0013] Preferably, the water temperature of the water for injection in Step 1 is controlled at 25°C to 45°C.

[0014] Preferably, the pH value in Step 3 is between 3.0 - 4.5. If not, adjust the pH value of the liquid medicine to the target range with 1mol / L hydrochloric acid solution.

[0015] Preferably, the target pH value in Step 3 is 3.4.

[0016] Preferably, after adding water for injection to the full volume in Step 4, the density is 1.012mg / ml.

[0017] Preferably, the microporous filter in Step 5 includes a 0.45μm primary filter and a 0.22μm secondary filter.

[0018] Preferably, the filter element material of the filter is polytetrafluoroethylene, the filtration temperature ≤ 45°C, and the filtration pressure of the 0.22μm filter element ≤ 0.3MPa.

[0019] Preferably, the filling volume in Step 6 is controlled at 10.6ml - 10.8ml, adjust the nitrogen filling amount to control the residual oxygen in the potted sample < 3%, and the pressure difference range of the 0.22μm sterilizing filter is 0 - 0.2MPa.

[0020] Preferably, the sterilization condition in Step 7 is 15 minutes at 121°C. Specific Embodiments

[0021] The present invention will be further described in detail below in conjunction with specific embodiments. The embodiments of the present invention are given for purposes of illustration and description, and are not intended to be exhaustive or to limit the invention to the disclosed form. Many modifications and variations are obvious to those of ordinary skill in the art. The embodiments are selected and described in order to better illustrate the principles and practical applications of the present invention, and to enable those of ordinary skill in the art to understand the present invention and thus design various embodiments with various modifications suitable for specific purposes.

[0022] Example 1, A preparation process of nicardipine hydrochloride injection according to the present invention includes the following steps:

[0023] Step 1: Add 90% of the total preparation amount of water for injection into the preparation tank, start nitrogen filling for 10 minutes, then start stirring, and fill nitrogen under the liquid surface and maintain it;

[0024] The intermediate liquid medicine was placed at 25°C under nitrogen filling / non-nitrogen filling, light protection / non-light protection conditions for 24 hours. The properties, pH value, and related substances of the liquid medicine showed no obvious changes and were relatively stable within 24 hours. To reduce the risk to the quality of the liquid medicine during the preparation process, in combination with the actual production situation in the production workshop and the determination results of the residual oxygen in the reference preparation (headspace residual oxygen < 2%), the nitrogen filling method was adopted during the production and preparation process;

[0025] Step 2: Add 1 mol / L hydrochloric acid solution to the mixing tank and stir for 5 minutes;

[0026] Add the prescribed amount of nicardipine hydrochloride raw material to the mixing tank and stir for 15 - 40 minutes until completely dissolved. After visually observing no visible particles, continue to stir for 5 minutes;

[0027] Step 3: Add the prescribed amount of sorbitol to the mixing tank and stir for no less than 10 minutes until completely dissolved.

[0028] Measure the pH value of the liquid medicine;

[0029] Step 4: Make up the volume to the full amount with injection water and circulate and stir for 15 minutes;

[0030] Step 5: Filter the injection solution using a microporous filter;

[0031] Step 6: Use an automatic filling and sealing system for filling, nitrogen filling, and heat sealing operations;

[0032] Step 7: Place the filled and sealed products into a stainless - steel tray and then evenly arrange them in the sterilization cabinet for sterilization.

[0033] In Step 1, the water temperature of the injection water is controlled at 25°C to 45°C;

[0034] The liquid - preparation temperature may affect the quality of the intermediate liquid medicine, so it is necessary to investigate the liquid - preparation temperature. The quality and stability of the intermediate liquid medicine prepared at different temperatures such as 25°C - 75°C were compared and studied. The results showed that when the liquid was prepared and kept warm at 25°C - 75°C for 6 hours, the properties and pH value of the prepared liquid showed no obvious changes. There was a tendency for impurity A to increase when the intermediate liquid medicine was placed at a liquid - preparation temperature of 75°C for 3 hours. To reduce the risk of the influence of the preparation process on the related substances of the preparation, combined with the actual production situation in the workshop and the dissolution rate of the raw materials, the liquid - preparation temperature control range during production is 25°C - 45°C.

[0035] In Step 3, the pH value is between 3.0 - 4.5. If not, adjust the pH value of the liquid medicine to the target range with 1 mol / L hydrochloric acid solution.

[0036] The target pH value in Step 3 is 3.4.

[0037] After making up the volume to the full amount with injection water in Step 4, the density is 1.012 mg / ml;

[0038] The measured value of the liquid medicine density at the laboratory stage was 1.012 g / ml, and the density of the self-made sample was basically the same as that of the reference preparation. When the self-developed preparation was produced, the raw materials were fed according to this liquid medicine density. From the small-scale test to the process validation stage, the density of the self-developed preparation was basically the same as the proposed density. Finally, the density of this product was determined to be 1.012 mg / ml.

[0039] In step five, the microporous filter includes a 0.45 μm primary filter and a 0.22 μm secondary filter.

[0040] The filter element material of the filter is polytetrafluoroethylene, the filtration temperature ≤ 45°C, and the filtration pressure of the 0.22 μm filter element ≤ 0.3 MPa;

[0041] The results of the chemical compatibility study between the filter membrane and the liquid medicine showed that when three different filter membranes of PES, PTFE, and PVDF were immersed in the liquid medicine for 24 hours, there were no obvious changes in the properties, pH value, and related substances of the liquid medicine, and no erosion of the filter membrane by the liquid medicine was observed. The results of the adsorption investigation showed that after continuously filtering the liquid medicine multiple times with filter membranes of different materials and detecting the content, there was obvious adsorption of the liquid medicine content by the PES filter membrane, and there was no obvious adsorption of the liquid medicine by the other two filter membrane materials. During the production process, a hydrophilic PTFE filter element was intended to be selected for filtering the liquid medicine, and a complete filter verification of the filter element was carried out during the process validation stage.

[0042] In step six, the filling volume is controlled at 10.6 ml to 10.8 ml, the nitrogen filling amount is adjusted to control the residual oxygen in the sample after filling and sealing < 3%, and the pressure difference range of the 0.22 μm sterilizing filter is 0 - 0.2 MPa.

[0043] In step seven, the sterilization condition is 15 minutes at 121°C;

[0044] The terminal sterilization overkill production process was adopted, and sterilization was carried out at 121°C for 12 min, 121°C for 15 min, and 121°C for 30 min respectively. There were no significant differences in the properties, pH value, and related substances of each sample. According to the decision tree for the selection of the injection sterilization process, the sterilization process of "121°C for 15 min" was preferentially selected, and F0 > 12 was controlled to ensure the aseptic level of the product.

[0045] Summary of the test results of representative batches of the preparation

[0046]

[0047]

[0048] The color water method is adopted as the method for full inspection of leak detection after sterilization of self-developed preparations, and the vacuum decay method is adopted as the method for leak detection of the sealing performance during the stability process of 3 batches of process validation batch samples. No leakage was detected in the samples with 0-day stability retention, 3-month acceleration, 6-month acceleration, and 6-month long-term stability retention. The sealing performance of the samples with stability retention is good. The study on the sample stability is still in progress, and the container sealing performance of the preparation during the stability process is continuously studied. The results are shown in the following table.

[0049] Results of Sealing Performance Sampling Inspection of Process Validation Product Stability

[0050]

[0051] Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all embodiments. All other embodiments obtained by those of ordinary skill in the art and related fields based on the embodiments of the present invention without creative efforts shall fall within the scope of protection of the present invention. Structures, devices, and operation methods not specifically described and explained in the present invention shall be implemented by conventional means in the art without special instructions and limitations.

Claims

1. A process for preparing nicardipine hydrochloride injection, characterized in that: The following steps are involved: Step 1: Add 90% of the total amount of injection water into the preparation tank, start nitrogen filling for 10 minutes, start stirring, and fill nitrogen below the liquid surface and maintain; Step 2: Add 1 mol / L hydrochloric acid solution to the mixing tank and stir for 5 minutes; Add the prescribed amount of nicardipine hydrochloride raw material into the mixing tank, stir for 15 to 40 minutes until it is completely dissolved, and continue stirring for 5 minutes after no visible particles are found; Step 3: Add the prescribed amount of sorbitol into the mixing tank and stir for at least 10 minutes until it is completely dissolved. Determine the pH value of the solution; Step 4: Add water for injection to the full amount and circulate and stir for 15 minutes; Step 5: Filter the injection solution using a microporous filter; Step 6: Use the automatic filling and sealing system to perform filling, nitrogen filling and sealing operations; Step 7: Place the filled products into stainless steel trays and place them evenly in the sterilization cabinet for sterilization.

2. A process for preparing nicardipine hydrochloride injection according to claim 1, characterized in that: The temperature of the water for injection in the step 1 is controlled at 25°C to 45°C.

3. A process for preparing nicardipine hydrochloride injection according to claim 1, characterized in that: In step 3, the pH value is between 3.0-4.

5. If not, the pH value of the solution is adjusted to the target range with 1 mol / L hydrochloric acid solution.

4. A process for preparing nicardipine hydrochloride injection according to claim 3, characterized in that: The pH target value in step 3 is 3.

4.

5. A process for preparing nicardipine hydrochloride injection according to claim 1, characterized in that: After adding water for injection to the full amount in step 4, the density is 1.012 mg / ml.

6. A process for preparing nicardipine hydrochloride injection according to claim 1, characterized in that: The microporous filter in step 5 includes a 0.45 μm primary filter and a 0.22 μm secondary filter.

7. The process for preparing nicardipine hydrochloride injection according to claim 1, characterized in that: The filter element of the filter is made of polytetrafluoroethylene, the filtration temperature is ≤45°C, and the filtration pressure of the 0.22μm filter element is ≤0.3MPa.

8. The process for preparing nicardipine hydrochloride injection according to claim 1, characterized in that: In step six, the filling volume is controlled at 10.6 ml to 10.8 ml, the nitrogen filling volume is adjusted to control the residual oxygen of the sample after filling to be less than 3%, and the pressure difference range of the 0.22 μm sterilizing filter is 0-0.2 MPa.

9. The process for preparing nicardipine hydrochloride injection according to claim 1, characterized in that: The sterilization condition in step 7 is 121° C. for 15 minutes.

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