Clemastine fumarate injection and preparation method thereof

Abstract

The invention provides a clemastine fumarate injection and a preparation method thereof. According to the clemastine fumarate injection, the pH value is adjusted to 6.9-7.2, it is found that the impurity A, the impurity C and the total impurity increase range are all obviously reduced, and the product stability is obviously improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to clemastine fumarate injection and a preparation method thereof. Background Art

[0002] Clemastine Fumarate is an antihistamine successfully developed by Sandoz in Switzerland in the 1960s. It was subsequently launched in the United States, Japan, Germany, etc. This product is a typical and representative second-generation H1 receptor antagonist, clinically used to treat various allergic diseases caused by histamine, and is currently recognized as one of the best antihistamines in the world.

[0003] After more than 40 years of clinical practice summary abroad and domestic clinical verification, clemastine fumarate is a fast-acting, long-acting, highly effective, safe and reliable antihistamine. At present, clemastine fumarate is mainly administered orally and by injection, and the dosage forms include tablets, capsules and injections. Among them, clemastine fumarate injection is used to treat acute allergic diseases (such as urticaria, allergic rhinitis, etc.), and the impurities involved in its quality control are shown in the following table.

[0004] serial number Chemical name source Impurity A (2R)-2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine-1-oxide Degradation products Impurity C 1-(4-Chlorophenyl)-1-phenylethanol Degradation products .

[0005] Tavegil, the original formulation marketed in the EU ® Stability studies revealed that the growth rates of impurities A, C and total impurities were very large during the test, and the stability needs to be improved. Summary of the invention

[0006] The technical problem solved by the present invention is to provide a clemastine fumarate injection and a preparation process thereof, thereby improving the stability of the clemastine fumarate injection.

[0007] In order to achieve the above-mentioned object, in a first aspect, the present invention provides a clemastine fumarate injection, wherein the pH value of the clemastine fumarate injection is 6.9-7.2.

[0008] Specifically, the raw materials and auxiliary materials of the clemastine fumarate injection include clemastine fumarate, sorbitol, a cosolvent, a pH regulator, and water for injection.

[0009] Specifically, in the clemastine fumarate injection, the cosolvent is ethanol or propylene glycol, or a mixture of the two.

[0010] Specifically, in the clemastine fumarate injection, the pH regulator is sodium citrate.

[0011] In a second aspect, the present invention provides a clemastine fumarate injection, characterized in that it includes the steps of weighing, preparing, filtering, encapsulating and sterilizing.

[0012] Specifically, the preparation process includes: preparing the cosolvent into a 40% solution, cooling the temperature to 25°C to 35°C, adding clemastine fumarate and sorbitol to dissolve, and adding the pH adjuster to adjust the pH value of the solution to 6.9 to 7.2.

[0013] Specifically, in the encapsulation process, nitrogen is charged before and after encapsulation until the residual oxygen content in the headspace is less than 5.0%.

[0014] Specifically, in the sterilization process, the sterilization temperature is 121° C. and the sterilization time is 15 minutes.

[0015] Compared with the prior art, the advantages of the present invention are as follows.

[0016] 1. The present invention helps to reduce the growth rate of impurity C during the stability period by controlling the pH value of the drug solution between 6.9 and 7.2.

[0017] 2. The preparation method of clemastine fumarate injection provided by the present invention performs nitrogen filling before and after encapsulation to control the headspace residual oxygen to less than 5.0%, which is beneficial to reducing the growth rate of impurity A during the stability period.

[0018] In the clemastine fumarate injection prepared by the above technology, the growth trend of impurity A, impurity C and total impurities is significantly reduced during the stability process. DETAILED DESCRIPTION

[0019] In the following examples, unless otherwise specified, the test machines and instruments used are reagents and instruments commonly used in the art, and the methods used are conventional methods in the art. Those skilled in the art can know how to specifically implement the methods and achieve corresponding results based on the contents of the examples. Example

[0020] A clemastine fumarate injection, the prescription is as follows: Clemastine Fumarate 2.68g Sorbitol 90g 95% ethanol 140g Propylene glycol 600g Sodium Citrate Adjust pH to 6.9 Water for injection Make up to 2000ml Packed into 1000 pieces .

[0021] The preparation method of the clemastine fumarate injection comprises the following steps.

[0022] ① Weighing: Weigh the batch prescription amount of clemastine fumarate and excipients and set aside.

[0023] ② Liquid preparation: Add about 1.0 kg of water for injection (temperature 25℃~35℃) to the liquid preparation tank, add the prescribed amount of ethanol and propylene glycol in sequence, set the stirring frequency to 200rpm, and start stirring for 10 minutes; add the prescribed amount of clemastine fumarate to the liquid preparation tank and stir until completely dissolved; add the prescribed amount of sorbitol and stir until completely dissolved; add 10% sodium citrate solution to adjust the pH value of the solution; add water for injection to the full amount.

[0024] ③Filtration: The drug liquid is pressurized with compressed air and filtered through a 0.45μm primary filter; two 0.22μm sterilization filters are then passed to the filling buffer tank.

[0025] ④Filling: Use an ampoule filling machine for filling, the filling volume range is controlled at 2.15ml~2.35ml, and the filling speed is adjusted to 400 bottles / min.

[0026] ⑤Sterilization: Use a moist heat sterilizer for sterilization, the sterilization temperature is 121℃, and the sterilization time is 15 minutes.

[0027] ⑥Leak detection and packaging. Example

[0028] A clemastine fumarate injection, the prescription is as follows: Clemastine Fumarate 2.68g Sorbitol 90g 95% ethanol 140g Propylene glycol 600g Sodium Citrate Adjust pH to 7.1 Water for injection Make up to 2000ml Packed into 1000 pieces .

[0029] The preparation method of the clemastine fumarate injection comprises the following steps.

[0030] ① Weighing: Weigh the batch prescription amount of clemastine fumarate and excipients and set aside.

[0031] ② Liquid preparation: Add about 1.0 kg of water for injection (temperature 15℃~25℃) to the liquid preparation tank, add the prescribed amount of ethanol and propylene glycol in sequence, set the stirring frequency to 200rpm, and start stirring for 10 minutes; add the prescribed amount of clemastine fumarate to the liquid preparation tank and stir until completely dissolved; add the prescribed amount of sorbitol and stir until completely dissolved; add 20% sodium citrate solution to adjust the pH value of the solution; add water for injection to the full amount.

[0032] ③Filtration: The drug liquid is pressurized with compressed air and filtered through a 0.45μm primary filter; two 0.22μm sterilization filters are then passed to the filling buffer tank.

[0033] ④Filling: Use an ampoule filling machine for filling, the filling volume range is controlled at 2.15ml~2.35ml, and the filling speed is adjusted to 400 bottles / min.

[0034] ⑤Sterilization: Use a moist heat sterilizer for sterilization, the sterilization temperature is 121℃, and the sterilization time is 15 minutes.

[0035] ⑥Leak detection and packaging. Example

[0036] A clemastine fumarate injection, the prescription is as follows: Clemastine Fumarate 2.68g Sorbitol 90g 95% ethanol 140g Propylene glycol 600g Sodium Citrate Adjust pH to 7.2 Water for injection Make up to 2000ml Packed into 1000 pieces .

[0037] The preparation method of the clemastine fumarate injection comprises the following steps.

[0038] ① Weighing: Weigh the batch prescription amount of clemastine fumarate and excipients and set aside.

[0039] ② Liquid preparation: Add about 1.0 kg of water for injection (temperature 15℃~25℃) to the liquid preparation tank, add the prescribed amount of ethanol and propylene glycol in sequence, set the stirring frequency to 200rpm, and start stirring for 10 minutes; add the prescribed amount of clemastine fumarate to the liquid preparation tank and stir until completely dissolved; add the prescribed amount of sorbitol and stir until completely dissolved; add 30% sodium citrate solution to adjust the pH value of the solution; add water for injection to the full amount.

[0040] ③Filtration: The drug liquid is pressurized with compressed air and filtered through a 0.45μm primary filter; two 0.22μm sterilization filters are then passed to the filling buffer tank.

[0041] ④Filling: Use an ampoule filling machine for filling, the filling volume range is controlled at 2.15ml~2.35ml, and the filling speed is adjusted to 400 bottles / min.

[0042] ⑤Sterilization: Use a moist heat sterilizer for sterilization, the sterilization temperature is 121℃, and the sterilization time is 15 minutes.

[0043] ⑥Leak detection and packaging. Example

[0044] A clemastine fumarate injection, which differs from Example 3 in that no front and back nitrogen filling operation is performed during the filling process, and the pH value is adjusted to 6.2-6.3 similar to that of the reference preparation.

Claims

1. A clemastine fumarate injection, characterized in that: The pH value of the clemastine fumarate injection is 6.9-7.

2.

2. Clemastine fumarate injection according to claim 1, characterized in that, The raw and auxiliary materials include clemastine fumarate, sorbitol, a solvent, a pH adjuster and water for injection.

3. Clemastine fumarate injection according to claim 1, characterized in that, The cosolvent is ethanol or propylene glycol, or a mixture of the two.

4. The clemastine fumarate injection according to claim 1, characterized in that: The pH regulator is sodium citrate.

5. The clemastine fumarate injection according to claim 1, characterized in that: It includes the steps of weighing, preparing, filtering, filling and sterilizing.

6. The clemastine fumarate injection according to claim 5, characterized in that: The preparation process includes: preparing the cosolvent into a 40% solution, cooling the solution to 25°C to 35°C, adding clemastine fumarate and sorbitol to dissolve the solution, and adding the pH adjuster to adjust the pH value of the solution to 6.9 to 7.

2.

7. The clemastine fumarate injection according to claim 5, characterized in that: In the encapsulation process, nitrogen is filled before and after encapsulation until the residual oxygen content in the headspace is less than 5.0%.

8. The clemastine fumarate injection according to claim 5, characterized in that: In the sterilization process, the sterilization temperature is 121° C. and the sterilization time is 15 minutes.