CN112402375A - Levocarnitine injection and preparation method thereof - Google Patents

Abstract

The invention discloses a levocarnitine injection and a preparation method thereof, wherein the levocarnitine injection comprises the following components: cooling 50-80% of injection water to 25-35 ℃, adding the levocarnitine bulk drug in the prescription, stirring until the levocarnitine bulk drug is completely dissolved, keeping the temperature for 10-30 min, adding the injection water to 90-98% of the prescription, adjusting the pH of the solution to 6.0-7.0 by using a pH regulator, and adding the injection water to the full amount; secondly, introducing nitrogen into the solution obtained in the step one, and controlling the oxygen content of the solution to be less than or equal to 30 percent; thirdly, sequentially using polyether sulfone filter cores with the diameters of 0.45 mu m and 0.22 mu m to perform terminal filtration sterilization; and fourthly, encapsulating the mixture into an ampoule, and sterilizing the mixture to obtain the levocarnitine injection. According to the method, activated carbon is not adopted for adsorbing pyrogens, so that impurities introduced by the activated carbon can be effectively avoided, and the content of bacterial endotoxin can be effectively controlled by adopting a polyether sulfone filter core for terminal filtration sterilization.

Description

Levocarnitine injection and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a levocarnitine injection and a preparation method thereof.

Background

Levocarnitine, also known as L (L) -carnitine, is a kind of amino acid capable of promoting fat to be converted into energy, has no toxic side effect on human body, is essential for fat metabolism, can be used for treating chronic renal failure, cardiomyopathy, coronary heart disease, organic acidemia and the like, can be used as an auxiliary treatment medicine for chronic liver diseases, and is widely applied to the fields of nutrition and health products, medical treatment, food additives, feed additives and the like at present.

Common dosage forms of levocarnitine include levocarnitine tablets, oral solutions of levocarnitine, levocarnitine for injection (e.g. lyophilized powder), and injections of levocarnitine.

The activated carbon is the most common pyrogen adsorbent for injection, has been used for many years, and plays an important role in improving the quality of the injection. But due to the source of the activated carbon and the diversity of production, the activated carbon can easily introduce impurities while adsorbing pyrogens. The use of activated carbon to control pyrogen levels in injectables has not been suggested.

However, activated carbon is used to adsorb pyrogens in the existing levocarnitine injection during the preparation process (see chinese patent documents CN101278928A, CN102379843A, CN105853347A, CN109431991A, etc.).

Disclosure of Invention

The invention aims to solve the problems and provides a levocarnitine injection which can effectively control pyrogen level (bacterial endotoxin content) and related impurity content and a preparation method thereof.

The technical scheme for realizing the purpose of the invention is as follows: a preparation method of levocarnitine injection comprises the following steps:

cooling 50-80% of injection water to 25-35 ℃, adding the levocarnitine bulk drug in the prescription, stirring until the levocarnitine bulk drug is completely dissolved, keeping the temperature for 10-30 min, adding the injection water to 90-98% of the prescription, adjusting the pH of the solution to 6.0-7.0 by using a pH regulator, and adding the injection water to the full amount.

Secondly, introducing nitrogen into the solution obtained in the step one, and controlling the oxygen content of the solution to be less than or equal to 30 percent.

③ using polyethersulfone filter elements with 0.45 μm and 0.22 μm to carry out terminal filtration sterilization.

And fourthly, encapsulating the mixture into an ampoule, and sterilizing the mixture to obtain the levocarnitine injection.

The prescription amount of the levocarnitine raw material medicine in the step (i) is 200mg/mL or 400 mg/mL.

In the step (i), the pH regulator is sodium hydroxide or hydrochloric acid.

In the second step, the oxygen content of the solution is preferably controlled to be 5-30%, and more preferably controlled to be 10-20%.

In the third step, the ampoule is a glass ampoule, preferably a brown medium borosilicate glass ampoule.

In the third step, the sterilization temperature is 115-123 ℃, and the sterilization time is 12-40 min.

The invention has the following positive effects:

(1) the method does not adopt activated carbon to adsorb pyrogen, so that impurities introduced by the activated carbon can be effectively avoided, and the content of related impurities in the levocarnitine injection can be effectively controlled.

(2) According to the method, the polyether sulfone filter core is adopted for terminal filtration sterilization, so that the content of bacterial endotoxin can be effectively controlled, the prepared levocarnitine injection is ensured to have low impurity content, the content of bacterial endotoxin meets the requirement, and the effectiveness, safety and stability of the product are ensured.

Detailed Description

(example 1)

The prescribed amount of levocarnitine injection of this example is as follows: 2000g of levocarnitine and 10000mL of water for injection.

The preparation method of the levocarnitine injection of the embodiment comprises the following steps:

cooling 6000mL of water for injection to 25 ℃, adding 2000g of levocarnitine bulk drug, stirring until the levocarnitine bulk drug is completely dissolved, keeping the solution for 20 +/-2 min, then adding the water for injection to 9500mL, adjusting the pH value of the solution to 6.5, and adding the water for injection to the full amount.

Secondly, fully introducing nitrogen into the solution obtained in the step one, and controlling the oxygen content of the solution to be 10 percent.

③ using polyethersulfone filter elements with 0.45 μm and 0.22 μm to carry out terminal filtration sterilization.

And fourthly, encapsulating the mixture into a brown medium borosilicate glass ampoule bottle, and sterilizing the mixture for 30min at 121 ℃ to obtain the levocarnitine injection.

(examples 2 to 3)

The preparation method of the levocarnitine injection of each example is basically the same as that of example 1, except that: and controlling the oxygen content in the step II, which is shown in the table 1.

TABLE 1

	Example 1	Example 2	Example 3	Comparative example 1
					Step II oxygen content	10%	15%	20%	50%

Comparative example 1

The preparation method of the levocarnitine injection of the comparative example 1 is basically the same as that of the example 1, except that: and controlling the oxygen content in the step II, which is shown in the table 1.

Comparative example 2

The preparation method of the levocarnitine injection of the comparative example 2 is substantially the same as that of the levocarnitine injection of the example 1, except that: step two is omitted.

(comparative example 3)

The preparation method of the levocarnitine injection of the comparative example 3 is substantially the same as that of the levocarnitine injection of the example 1, except that: step three is omitted.

Comparative example 4

The preparation method of the levocarnitine injection of the comparative example 4 is substantially the same as that of example 1, except that the steps of (i): cooling 6000mL of water for injection to 25 ℃, adding 2000g of levocarnitine bulk drug, stirring until the levocarnitine bulk drug is completely dissolved, adding 0.2% (w/v) of activated carbon for injection, stirring and adsorbing for 10min, filtering, then adding water for injection to 9500mL, adjusting the pH value of the solution to 6.5, and finally adding water for injection to the full amount.

(test example)

The levocarnitine injection prepared in each example and each proportion is tested for related substances and bacterial endotoxin content, and the conditions under high temperature, illumination and acceleration conditions are further tested, and the results are shown in table 2.

Wherein the content of the bacterial endotoxin is 20EU/mL, and is lower than the content which meets the specification, otherwise, the content does not meet the specification.

TABLE 2

In table 2: the impurity A is E-4- (trimethyl ammonium) butyl-2-gadoleic acid inner salt; the specific high temperature condition is 60 +/-2 ℃; the specific condition of the strong light is 5000LX, 90UV/cm²(ii) a The specific conditions of the accelerated test are 40 +/-2 ℃ and RH75 +/-5%.

Claims (10)

1. A preparation method of levocarnitine injection comprises the following steps: cooling 50-80% of injection water to 25-35 ℃, adding the levocarnitine bulk drug in the prescription, stirring until the levocarnitine bulk drug is completely dissolved, keeping the temperature for 10-30 min, adding the injection water to 90-98% of the prescription, adjusting the pH of the solution to 6.0-7.0 by using a pH regulator, and adding the injection water to the full amount; secondly, introducing nitrogen into the solution obtained in the step one, and controlling the oxygen content of the solution to be less than or equal to 30 percent; thirdly, sequentially using polyether sulfone filter cores with the diameters of 0.45 mu m and 0.22 mu m to perform terminal filtration sterilization; and fourthly, encapsulating the mixture into an ampoule, and sterilizing the mixture to obtain the levocarnitine injection.

2. The method for preparing levocarnitine injection according to claim 1, which comprises the following steps: the prescription amount of the levocarnitine raw material medicine in the step (i) is 200mg/mL or 400 mg/mL.

3. The method for preparing levocarnitine injection according to claim 1, which comprises the following steps: in the step (i), the pH regulator is sodium hydroxide or hydrochloric acid.

4. The method for preparing levocarnitine injection according to claim 1, which comprises the following steps: in the third step, the ampoule is a medium borosilicate glass ampoule.

5. The method for preparing levocarnitine injection according to claim 1, which comprises the following steps: in the third step, the sterilization temperature is 115-123 ℃, and the sterilization time is 12-40 min.

6. The method for preparing levocarnitine injection according to any one of claims 1 to 5, wherein: and controlling the oxygen content of the solution in the second step to be 5-30%.

7. The method for preparing levocarnitine injection according to claim 6, which comprises the following steps: and controlling the oxygen content of the solution in the second step to be 10-20%.

8. A levocarnitine injection prepared by the method according to any one of claims 1 to 5.

9. A levocarnitine injection prepared by the method of claim 6.

10. A levocarnitine injection prepared by the method of claim 7.