A kind of L-carnitine liquid preparation and preparation method

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a L-carnitine liquid preparation and a preparation method thereof. The L-carnitine liquid preparation of the present invention contains L-carnitine, ectoine and / or hydroxyectoine, a pH regulator and water, wherein the weight ratio of L-carnitine to ectoine and / or hydroxyectoine is 100:(7-40). Through preparation optimization, the stabilizing effect of ectoine and / or hydroxyectoine is utilized to improve the stability of the L-carnitine liquid preparation, and the impurity I and the total impurity content, especially the impurity content during the heat treatment process, can be reduced. The L-carnitine liquid preparation of the present invention has a simple configuration process, a wide process tolerance temperature range, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a L-carnitine liquid preparation and a preparation method thereof. Background Art

[0002] L-Carnitine is a natural substance essential for the energy metabolism of mammals. The L-Carnitine synthesized by the human body is mainly distributed in the myocardium and skeletal muscles. Currently available L-Carnitine drugs include L-Carnitine tablets, oral solutions and injections, which are approved for a series of complications caused by secondary L-Carnitine deficiency in patients with chronic renal failure and long-term hemodialysis.

[0003] L-carnitine has poor stability, and liquid preparations are easily affected by external environments such as light and heat. The prepared liquid needs to undergo heating treatment and other processes, such as heating to accelerate dissolution and high-temperature sterilization, which leads to more impurities (for example: CN116359401A), and is significantly affected by the process, especially the heat treatment process (for example: Li Mo et al. The effect of packaging material selection of L-carnitine injection on sterilization stability. Central South Pharmacy. 2017; Zhao Xiaohui. Study on the formulation process and stability of L-carnitine oral solution. Shandong University. 2019; CN114831929A).

[0004] Patent document CN112220746A provides a L-carnitine oral solution, which uses polyethylene glycol and poloxamer as main excipients to improve the stability of the L-carnitine oral solution. However, the amount of polyethylene glycol used is large, reaching 50% of the amount of L-carnitine, while the content of L-carnitine in the L-carnitine oral solution is as high as 0.1g / mL. The recommended daily dose of L-carnitine for adults is 1~3g, which is equivalent to the need to consume 0.5~1.5g of polyethylene glycol per day. According to the "Guidelines for the Application of Pharmaceutical Excipients", WHO stipulates that the safe dose of polyethylene glycol acceptable to the human body is 10mg / kg body weight / d (about 0.6g / d). As a result, although the L-carnitine oral solution improves the stability of the preparation, there is a risk of excessive intake of polyethylene glycol. In addition, polyethylene glycol is incompatible with preservatives such as sorbitol and hydroxyphenyl esters, and the preservatives of some L-carnitine oral solutions that have been marketed are hydroxyphenyl ester preservatives. As a result, the selection of polyethylene glycol limits the selection of other excipients for L-carnitine oral solution.

[0005] Cyclodextrin inclusion has a multi-faceted stabilizing effect on drug molecules, including improving the light, heat, oxygen, and moisture stability of the drug. However, the high concentration of L-carnitine in the liquid preparation of L-carnitine will result in a large amount of cyclodextrin inclusion. Intravenous β-cyclodextrin has a certain risk of nephrotoxicity and is not suitable for patients with renal failure corresponding to L-carnitine (for example: Hu Yudi et al. Solubilization mechanism of sulfobutyl ether-β-cyclodextrin and its application in poorly soluble drug preparations. Chinese Journal of Pharmaceutical Industry. 2018; Wang Shuyan et al. Toxicity study of commonly used excipient hydroxypropyl-β-cyclodextrin. Proceedings of the 6th National Annual Conference on Drug Toxicology in 2016. 2016).

[0006] Therefore, it is necessary to optimize the formulation of L-carnitine liquid preparations to improve the stability of L-carnitine liquid preparations and the level of impurity control while avoiding the health risks of the excipients themselves to L-carnitine corresponding renal failure patients and avoiding the excipient incompatibility limiting the selection range of other excipients. Summary of the invention

[0007] In view of the above problems, in order to improve the stability of L-carnitine liquid preparations and improve the level of impurity control, the object of the present invention is to provide a L-carnitine liquid preparation and a preparation method thereof.

[0008] The technical solution of the present invention is as follows:

[0009] A levocarnitine liquid preparation contains levocarnitine, a stabilizer, a pH regulator and water, wherein the stabilizer at least comprises ectoine and / or hydroxyectoine. The weight ratio of levocarnitine to ectoine and / or hydroxyectoine in the levocarnitine liquid preparation is 100:(7-40). The levocarnitine liquid preparation can be a levocarnitine oral solution or a levocarnitine injection.

[0010] Ectoine is also called 1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid, ectoine, and hydroxyectoine is also called 1,4,5,6-tetrahydro-2-methyl-5-hydroxy-4-pyrimidinecarboxylic acid, 5-hydroxy-ectoine. Both are small molecule water-soluble compatible solutes that have protective and stabilizing effects against adverse effects such as high temperature.

[0011] Preferably, the weight ratio of levocarnitine to ectoine and / or hydroxyectoine in the levocarnitine liquid preparation is 100:(10-35). Further preferably, the weight ratio of levocarnitine to ectoine and / or hydroxyectoine in the levocarnitine liquid preparation is 100:(10-30).

[0012] Preferably, the stabilizer is ectoine.

[0013] Preferably, the stabilizer is hydroxyectoine.

[0014] Preferably, the stabilizer is ectoine and hydroxyectoine.

[0015] Preferably, the pH adjuster is at least one of DL-malic acid, citric acid and hydrochloric acid.

[0016] Preferably, the L-carnitine liquid preparation is a L-carnitine oral solution. Further preferably, the L-carnitine oral solution contains a preservative. Further preferably, the preservative is sodium benzoate.

[0017] Preferably, the L-carnitine oral solution further contains a sweetener, and more preferably, the sweetener is saccharin sodium.

[0018] Preferably, the L-carnitine oral solution is composed of water and the following ingredients: 100 g / L of L-carnitine, 4.8 g / L of sodium benzoate, 1-3.5 g / L of DL-malic acid, 10-35 g / L of ectoine, and 0.5 g / L of sodium saccharin.

[0019] Preferably, the L-carnitine oral solution is composed of water and the following ingredients: 100 g / L of L-carnitine, 4.8 g / L of sodium benzoate, 1-3.5 g / L of DL-malic acid, 10-30 g / L of hydroxyectoine, and 0.5 g / L of sodium saccharin.

[0020] It is known in the art that Ecdoin and hydroxy Ecdoin are similar in nature. After the preparation is completed, during the storage process, a small amount of Ecdoin may be partially converted into hydroxy Ecdoin. Therefore, when the aforementioned stabilizer is limited to Ecdoin, a small amount of hydroxy Ecdoin is allowed to exist in the solution during storage.

[0021] A method for preparing a levocarnitine oral solution, wherein the levocarnitine oral solution is made of water, levocarnitine, sodium benzoate, DL-malic acid, ectoine and / or hydroxyectoine, and saccharin sodium, and the method for preparing the levocarnitine oral solution comprises the following steps:

[0022] S1 Add water to the preparation container, add ectoine and / or hydroxyectoine, and stir until clear to obtain the first preparation solution;

[0023] S2: adding sodium benzoate, L-carnitine and sodium saccharin to the first prepared solution of step S1, stirring until clear, to obtain a second prepared solution;

[0024] S3: adding DL-malic acid to the second prepared solution of step S2, stirring until clarified, adding water to the required concentration (according to common specifications, the concentration of L-carnitine is usually 100 g / L), filtering, packaging, and steam sterilizing.

[0025] Preferably, the steam sterilization temperature is 100°C to 135°C, and the time is 15min to 30min.

[0026] Preferably, the filtration is carried out using a microporous filter material with a pore size of 0.45 μm to 0.5 μm; further preferably, the microporous filter material is selected from a microporous filter membrane or a titanium rod filter.

[0027] The present invention has the following beneficial effects:

[0028] (1) The present invention optimizes the formulation of the L-carnitine liquid preparation, wherein ectoine and / or hydroxyectoine have multiple stabilizing effects on the drug, including thermal stability, etc., and ectoine and / or hydroxyectoine have extremely high safety. The acute toxic dose LD50 of ectoine is greater than 2000 mg / kg, and the dose level at which no toxic effect is observed after repeated administration is 300 mg / kg body weight / d, and there is no "three-cause" effect.

[0029] (2) After the formulation is optimized, the L-carnitine liquid preparation of the present invention can withstand high temperature sterilization process and is conducive to reducing the content of impurity I and the total impurity content, thereby facilitating the terminal heat sterilization of the preparation and reducing the quality problems of the preparation caused by membrane damage during membrane filtration, thereby improving the quality control level of the pharmaceutical preparation.

[0030] (3) Compared with the formula of polyethylene glycol and the like, the formula of the present invention has fewer types and amounts of auxiliary materials, and the auxiliary materials are more safe. Among them, ectoine and / or hydroxyectoine have been proven to be liver and kidney friendly, and are more suitable for the indication population of L-carnitine liquid preparation.

[0031] (4) Compared with the formulation of polyethylene glycol and the like, the formulation excipients of the present invention are selected from ectoine and / or hydroxyectoine, and no incompatibility with other excipients has been found so far, which will not limit the selection range of other excipients in the L-carnitine liquid preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is the HPLC chromatogram of the sample stability experiment of Example 1 of the present invention;

[0033] Figure 2 This is the HPLC chromatogram of the sample stability experiment of Example 2 of the present invention;

[0034] Figure 3 This is the HPLC chromatogram of the sample stability experiment of Example 3 of the present invention;

[0035] Figure 4 It is the HPLC chromatogram of the stability experiment of the comparative example sample of the present invention. DETAILED DESCRIPTION

[0036] The scheme of the present invention is illustrated by specific examples below. The examples are only used to illustrate and display the present invention, but not to limit the scope of protection of the present invention.

[0037] In the following examples, the HPLC detection conditions for the content of L-carnitine and impurity I are as follows: column filler: amidosilane bonded silica gel; column: Welch Ulitimate HILIC Amide column (4.6mmx250mm, 5μm); mobile phase: 0.05mol / L phosphate buffer (NaOH adjusted to pH 4.7)-acetonitrile with a volume ratio of 35:65; mobile phase flow rate 0.7mL / min; column temperature 30°C; detection wavelength 205nm; injection volume 20μl. The L-carnitine reference substance is added with a solvent to prepare a main drug reference solution (about 1mg / mL); the impurity I specified in the 2020 edition of the Chinese Pharmacopoeia L-carnitine quality standard is added with a solvent to prepare an impurity I reference solution (about 20μg / mL). The solvent is 0.05mol / L phosphate buffer (NaOH adjusted to pH 4.7)-acetonitrile with a volume ratio of 35:65. The content of impurity I and L-carnitine is conventionally calculated by peak area using the external standard method.

[0038] In the following embodiments:

[0039] The method for accelerated stability testing of drug preparations is as follows: the samples are sealed and placed in a drug stability test box at 60°C for 30 days, and samples are taken for testing at different time points after placement.

[0040] Example 1 Preparation of small-size oral solution of L-carnitine (2.5 mL or 10 mL, 0.1 g / mL)

[0041] Weighing of raw and auxiliary materials: Weigh the following raw and auxiliary materials, label them, and set aside: 2500mL of purified water, 250g of L-carnitine, 12g of sodium benzoate, 7.5g of DL-malic acid, 25g of ectoine, and 1.25g of saccharin sodium.

[0042] Preparation: Take 2000mL of purified water, add ectoine at room temperature (10℃~30℃), and stir until the solution is clear; continue to add sodium benzoate, L-carnitine, and sodium saccharin to the solution, and stir until it is clear; then add DL-apple to the solution, stir until the solution is clear, and add the remaining amount of purified water to obtain L-carnitine oral solution.

[0043] Preparation packaging sterilization: L-carnitine oral solution is filtered through a 0.5 μm microporous filter membrane, packaged at 2.5 mL / bottle or 10 mL / bottle, and steam sterilized at 120°C for 30 min.

[0044] Example 2 Preparation of small-size oral solution of L-carnitine (2.5 mL or 10 mL, 0.1 g / mL)

[0045] Weighing of raw and auxiliary materials: Weigh the following raw and auxiliary materials, label them, and set aside: 2500mL of purified water, 250g of L-carnitine, 12g of sodium benzoate, 6.25g of DL-malic acid, 50g of ectoine, and 1.25g of saccharin sodium.

[0046] Preparation: Take 2000mL of purified water, add ectoine at room temperature (10℃~30℃), and stir until the solution is clear; continue to add sodium benzoate, L-carnitine, and sodium saccharin to the solution, and stir until it is clear; then add DL-apple to the solution, stir until the solution is clear, and add the remaining amount of purified water to obtain L-carnitine oral solution.

[0047] Preparation packaging sterilization: L-carnitine oral solution is filtered through a 0.5 μm microporous filter membrane, packaged at 2.5 mL / bottle or 10 mL / bottle, and steam sterilized at 120°C for 30 min.

[0048] Example 3 Preparation of small-size oral solution of L-carnitine (2.5 mL or 10 mL, 0.1 g / mL)

[0049] Weighing of raw and auxiliary materials: Weigh the following raw and auxiliary materials, label them, and set aside: 2500mL of purified water, 250g of L-carnitine, 12g of sodium benzoate, 3.75g of DL-malic acid, 87.5g of ectoine, and 1.25g of sodium saccharin.

[0050] Preparation: Take 2000mL of purified water, add ectoine at room temperature (10℃~30℃), and stir until the solution is clear; continue to add sodium benzoate, L-carnitine, and sodium saccharin to the solution, and stir until it is clear; then add DL-apple to the solution, stir until the solution is clear, and add the remaining amount of purified water to obtain L-carnitine oral solution.

[0051] Preparation packaging sterilization: L-carnitine oral solution is filtered through a 0.5 μm microporous filter membrane, packaged at 2.5 mL / bottle or 10 mL / bottle, and steam sterilized at 120°C for 30 min.

[0052] Comparative Example 1 Preparation of small-size oral solution of L-carnitine (2.5 mL or 10 mL, 0.1 g / mL)

[0053] Weighing of raw and auxiliary materials: Weigh the following raw and auxiliary materials, label them, and set aside: 2500 mL of purified water, 250 g of L-carnitine, 12 g of sodium benzoate, 10 g of DL-malic acid, and 1.25 g of saccharin sodium.

[0054] Preparation: Take 2000mL of purified water, add sodium benzoate, L-carnitine and sodium saccharin at room temperature (10℃~30℃), and stir until clear; then add DL-apple to the solution, stir until the solution is clear, add the remaining amount of purified water to obtain L-carnitine oral solution.

[0055] Sterilization of preparations: Filter the L-carnitine oral solution through a 0.5 μm microporous filter membrane and package at 2.5 mL / bottle or 10 mL / bottle.

[0056] Example 4 Stability Study of Different Small-Scale L-Carnitine Oral Solutions

[0057] The samples were prepared according to the methods of Examples 1-3 and Comparative 1, and the accelerated stability was tested. The results are shown in Table 1 and Figure 1-4 shown.

[0058] From Table 1 and Figure 1-Figure 4 It can be seen that in the accelerated stability experiment, the sample impurity I content (%) and total impurity content (%) of Examples 1-3 are all lower than those of Comparative Example 1. Among them, the sample impurity I content (%) and total impurity content (%) of Example 2 are relatively low, both lower than 0.1%. The sample impurity I content (%) and total impurity content (%) of Examples 1 and 3 are relatively high, but both lower than 0.18%. It can be seen that for L-carnitine oral solution, especially for the conventional L-carnitine oral solution formula containing L-carnitine, sodium benzoate, DL-malic acid, and saccharin sodium, Ecdoin is conducive to improving the thermal stability of L-carnitine oral solution, reducing impurity I and total impurity content, and making total impurity content lower than 0.2%. Especially the formula of Example 2 can make impurity I and total impurity content lower than 0.1%.

[0059] Table 1 Accelerated stability test results of different small-scale oral solutions of L-carnitine

[0060]

[0061] In addition, a light stability test (5000LX) was conducted on the samples of Examples 1-3 and Comparative Examples. Under the same sampling time, the impurity I and total impurity contents of the samples of Examples 1-3 and Comparative Examples were lower than the results of the 60°C accelerated stability test.

[0062] The implementation and effect of the present invention are described above through some embodiments. It should be noted that, without departing from the basic idea of ​​the present invention, the ordinary technicians in this field do not need creative work, based on the common sense of the field or the prior art, based on reasonable reasoning, etc., the scheme obtained by simple replacement should also belong to the protection scope of the present invention. For example, simple replacement of pH regulators, simple replacement of preservatives, flavoring agents / sweeteners. Although the embodiments of the present invention use oral solutions as examples, the oral solutions use the general process of filtration and high-temperature steam sterilization, and there is no conflict between the raw materials and injections, so the above embodiments also support the protection of L-carnitine injection preparations, which is self-evident to ordinary technicians in this field.

Claims

1. A L-carnitine liquid preparation, which is a L-carnitine oral solution or a L-carnitine injection; the L-carnitine liquid preparation contains L-carnitine, a pH regulator and water, and is characterized in that: The L-carnitine liquid preparation also contains a stabilizer, which includes at least ectoine and / or hydroxyectoine. In the L-carnitine liquid preparation, the weight ratio of L-carnitine to ectoine and / or hydroxyectoine is 100:(7-40).

2. A L-carnitine liquid preparation according to claim 1, characterized in that: In the L-carnitine liquid preparation, the weight ratio of L-carnitine to ectoine and / or hydroxyectoine is 100:(10-35).

3. A L-carnitine liquid preparation according to claim 2, characterized in that: In the L-carnitine liquid preparation, the weight ratio of L-carnitine to ectoine and / or hydroxyectoine is 100:(10-30).

4. A L-carnitine liquid preparation according to claim 1, characterized in that: The stabilizer is ectoine.

5. A L-carnitine liquid preparation according to claim 1, characterized in that: The stabilizer is hydroxyectoine.

6. A L-carnitine liquid preparation according to claim 1, characterized in that: The stabilizers are ectoine and hydroxyectoine.

7. A L-carnitine liquid preparation according to claim 1, characterized in that: The pH regulator is at least one of DL-malic acid, citric acid and hydrochloric acid.

8. A L-carnitine liquid preparation according to claim 1, characterized in that: The L-carnitine liquid preparation is a L-carnitine oral solution, and the L-carnitine oral solution contains a preservative.

9. A L-carnitine liquid preparation according to claim 8, characterized in that: The preservative is sodium benzoate.

10. A L-carnitine liquid preparation according to claim 8, characterized in that: The L-carnitine oral solution also contains a sweetener.

11. A L-carnitine liquid preparation according to claim 10, characterized in that: The sweetener is sodium saccharin.

12. A L-carnitine liquid preparation according to claim 8, characterized in that: The L-carnitine oral solution is composed of water and the following ingredients: 100 g / L of L-carnitine, 4.8 g / L of sodium benzoate, 1-3.5 g / L of DL-malic acid, 10-35 g / L of ectoine and 0.5 g / L of saccharin sodium.

13. A L-carnitine liquid preparation according to claim 8, characterized in that: The L-carnitine oral solution is composed of water and the following ingredients: 100 g / L of L-carnitine, 4.8 g / L of sodium benzoate, 1-3.5 g / L of DL-malic acid, 10-30 g / L of hydroxyectoine and 0.5 g / L of sodium saccharin.

14. A method for preparing a L-carnitine oral solution, characterized in that: The levocarnitine oral solution is made of water, levocarnitine, sodium benzoate, DL-malic acid, ectoine and / or hydroxyectoine and saccharin sodium, and the preparation method of the levocarnitine oral solution comprises the steps: S1 Add water to the preparation container, add ectoine and / or hydroxyectoine, and stir until clear to obtain the first preparation solution; S2: adding sodium benzoate, L-carnitine and sodium saccharin to the first prepared solution of step S1, stirring until clear, to obtain a second prepared solution; S3: adding DL-malic acid to the second prepared solution of step S2, stirring until clarified, adding water to a desired concentration, filtering, packaging, and steam sterilizing.

15. The method for preparing a L-carnitine oral solution according to claim 14, characterized in that: The steam sterilization temperature is 100°C to 135°C, and the time is 15min to 30min.

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