Levocarnitine oral solution and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a levocarnitine oral solution and a preparation method thereof, and every 100 ml of the levocarnitine oral solution comprises 10 g of levocarnitine, 5-15 g of polyvinyl alcohol and 0.5-1.5 g of an edetic acid stabilizer. The levocarnitine oral solution also contains a buffering agent which enables the pH value of the levocarnitine oral solution to be 4.5-5.5, and the balance of water. The polyvinyl alcohol is at least one of 03-88 parts of polyvinyl alcohol, 05-88 parts of polyvinyl alcohol and 24-88 parts of polyvinyl alcohol. The edetic acid stabilizer is edetic acid or edetate salt. The polyvinyl alcohol and the edetic acid stabilizer are synergistically used and are matched with the specific buffer agent to achieve a stable pH value, so that levocarnitine is uniformly dispersed and has good stability, dextrocarnitine is not generated, the limit of dextrocarnitine is strictly controlled, and the product is stable in quality, safe and effective.

Description

Technical Field

[0001] The invention relates to a L-carnitine oral solution and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] L-carnitine is L-carnitine, with the chemical name (R)-3-hydroxy-4-(trimethylamino)butyrate. It is a naturally occurring substance in mammals that participates in energy metabolism. It is the main component of L-carnitine oral solution, and its main function is to promote lipid metabolism. The freeze-drying cycle of powder injection in L-carnitine preparations is long and the energy consumption is large. The powder injection and injection will turn yellow due to the degradation of D-carnitine during use. L-carnitine raw materials have good solubility and strong hygroscopicity. The preparation of solid preparations has high requirements for the humidity of the environment and is not easy to store. Therefore, it is suitable to be prepared into oral solution preparations to overcome the above-mentioned unfavorable factors. Oral solution preparations are accurate in dosage, easy to take, fast in absorption, and quick in action. They can be used by infants and adults.

[0003] The reference preparation of L-carnitine oral solution is manufactured by ALFASIGMA SpA, with specifications of 10ml: 1g. Excipients include sodium benzoate, malic acid, sodium saccharin and purified water. Traditional L-carnitine liquid preparations usually use hydrochloric acid as a pH regulator. When hydrochloric acid is used as a pH regulator, the local pH value will be too low, causing the degradation of L-carnitine (producing dextrocarnitine, etc.), resulting in reduced pharmacology. In addition, the L-carnitine isomer is a harmful component that is harmful to muscle generation and can cause muscle weakness, muscle atrophy, etc. In addition, the oral solution uses hydrochloric acid as a pH regulator, which is irritating and has a poor taste, and is not suitable for children. The existing technology does not solve the problems that L-carnitine oral solution is easily degraded to produce dextrocarnitine and has a poor taste. Through multiple batches of testing, it was found that the dextrocarnitine detection result in the reference preparation was about 0.3%.

[0004] Chinese patent CN112220746B provides a method of achieving a stable pH value by using polyethylene glycol and poloxamer as stabilizers and specific buffers, so that L-carnitine is evenly dispersed and D-carnitine is not easily produced. The D-carnitine limit is strictly controlled to be lower than 0.1%, which can be as low as 0.051%, to ensure product stability, but the degradation problem of D-carnitine is still not solved. Chinese patent CN101564378B provides a L-carnitine oral solution containing L-carnitine, phosphoric acid, aspartame, methylcellulose, rose essence, ethanol and water. However, when phosphoric acid, hydrochloric acid and the like are used to adjust the pH, it is easy to cause local pH changes, produce D-carnitine, and the solution has poor stability. Summary of the invention

[0005] The present invention aims at the deficiencies of the prior art and provides a L-carnitine oral solution and a preparation method thereof. The stable pH value is achieved by using polyvinyl alcohol, edetic acid stabilizer and a specific buffer, so that the L-carnitine is evenly dispersed, no D-carnitine is generated, and the D-carnitine limit is strictly controlled, so that the quality of the product is stable. At the same time, the color change problem of the L-carnitine oral solution caused by the degradation of D-carnitine is solved.

[0006] The technical solution of the present invention to solve the above technical problems is as follows: a L-carnitine oral solution, each 100 ml of the L-carnitine oral solution contains 10 g of L-carnitine, 5-15 g of polyvinyl alcohol, and 0.5-1.5 g of an edetic acid stabilizer; it also contains a buffer so that the pH value of the L-carnitine oral solution is 4.5-5.5, and the balance is water.

[0007] Furthermore, the pH value of the L-carnitine oral solution is 4.8-5.2.

[0008] Furthermore, the polyvinyl alcohol is at least one of polyvinyl alcohol 03-88, polyvinyl alcohol 05-88, and polyvinyl alcohol 24-88.

[0009] Furthermore, the edetic acid stabilizer is edetic acid or edetic acid salt.

[0010] Furthermore, the mass ratio of the polyvinyl alcohol to the edetic acid stabilizer is (9-12):1.

[0011] Furthermore, the buffer is a combination of citric acid and sodium citrate or a combination of acetic acid and sodium acetate.

[0012] Furthermore, every 100 ml of the L-carnitine oral solution also contains 0.04-0.06 g of a sweetener and 0.3-0.5 g of a preservative.

[0013] Furthermore, the sweetener is at least one of saccharin sodium, trehalose and aspartame.

[0014] Furthermore, the preservative is at least one of benzoic acid, sodium benzoate, potassium benzoate, methylparaben and propylparaben.

[0015] The present invention also discloses a method for preparing a L-carnitine oral solution, which comprises:

[0016] The prescribed amount of polyvinyl alcohol and edetic acid stabilizer are dissolved in a certain amount of purified water and mixed evenly; then the prescribed amount of L-carnitine is added and mixed evenly; a buffer is added and mixed evenly to make the pH value 4.5-5.5; then the prescribed amount of preservatives and sweeteners are added and mixed evenly, and then a buffer is added to make the pH value 4.8-5.2; finally, the volume is fixed and filtered to obtain the L-carnitine oral solution.

[0017] The beneficial effects of the present invention are:

[0018] The polyvinyl alcohol used in the present invention can ensure the stability of the solution system, no opalescence, and can also thicken and improve the mouthfeel. Edetic acid has an antioxidant effect and a certain antibacterial activity, and can complex metal ions in the solution to ensure the stability of the solution. When the polyvinyl alcohol and edetic acid are used in combination, the problem of the generation of dextrocarnitine and the discoloration of the solution is unexpectedly solved. The prepared sample solution has good stability, no dextrocarnitine is detected, the degradation of dextrocarnitine is inhibited, and the use safety is ensured. At the same time, when polyvinyl alcohol is used in combination with edetic acid, because of its synergistic antibacterial ability, the antibacterial effect is guaranteed to meet the requirements without sterilization, and the energy consumption is reduced while ensuring the safety of the sample. DETAILED DESCRIPTION

[0019] The specific implementation of the present invention is described in detail below. The present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. The terms used are only for describing specific embodiments and are not intended to limit the present invention.

[0021] The invention discloses a L-carnitine oral solution. Each 100 ml of the L-carnitine oral solution contains 10 g of L-carnitine, 5-15 g of polyvinyl alcohol, 0.5-1.5 g of an edetic acid stabilizer, and a buffer so that the pH value of the L-carnitine oral solution is 4.5-5.5, and the balance is water.

[0022] Specifically, the pH value of the L-carnitine oral solution is 4.8-5.2.

[0023] Specifically, the polyvinyl alcohol is at least one of polyvinyl alcohol 03-88, polyvinyl alcohol 05-88, and polyvinyl alcohol 24-88.

[0024] Preferably, the polyvinyl alcohol is polyvinyl alcohol 05-88.

[0025] Specifically, the edetic acid stabilizer is edetic acid or edetic acid salt.

[0026] Specifically, the mass ratio of the polyvinyl alcohol to the edetic acid stabilizer is (9-12):1.

[0027] Specifically, the buffer is a combination of citric acid and sodium citrate or a combination of acetic acid and sodium acetate.

[0028] Specifically, every 100 ml of the L-carnitine oral solution further contains 0.04-0.06 g of a sweetener and 0.3-0.5 g of a preservative.

[0029] Specifically, the sweetener is at least one of saccharin sodium, trehalose, and aspartame.

[0030] Specifically, the preservative is at least one of benzoic acid, sodium benzoate, potassium benzoate, methylparaben and propylparaben.

[0031] A method for preparing a L-carnitine oral solution, comprising:

[0032] The prescribed amount of polyvinyl alcohol and edetic acid stabilizer are dissolved in a certain amount of purified water and mixed evenly; then the prescribed amount of L-carnitine is added and mixed evenly; a buffer is added and mixed evenly to make the pH value 4.5-5.5; then the prescribed amount of preservatives and sweeteners are added and mixed evenly, and then a buffer is added to make the pH value 4.8-5.2; finally, the volume is fixed and filtered to obtain the L-carnitine oral solution.

[0033] Example 1

[0034] The formulation of the L-carnitine oral solution in this embodiment is shown in Table 1.

[0035] Table 1 Example 1 Formula composition of L-carnitine oral solution

[0036]

[0037]

[0038] The preparation method is:

[0039] Dissolve the prescribed amount of polyvinyl alcohol and sodium edetate in a certain amount of purified water and stir evenly; then add the prescribed amount of L-carnitine to the solution and stir evenly; add an appropriate amount of prepared buffer to the solution and stir evenly to make the pH value 4.5-5.5; then add the prescribed amount of preservatives and sweeteners and stir evenly, add the buffer to make the pH value 4.8-5.2; make up to 100 mL with purified water, filter, and obtain the L-carnitine oral solution.

[0040] Example 2

[0041] The formula composition of L-carnitine oral solution in this embodiment is shown in Table 2 below.

[0042] Table 2 Example 2 Formula composition of L-carnitine oral solution

[0043]

[0044] Preparation method: dissolve the prescribed amount of polyvinyl alcohol and edetic acid in a certain amount of purified water and stir evenly; then add the prescribed amount of L-carnitine to the solution and stir evenly; add an appropriate amount of prepared buffer to the solution and stir evenly to make the pH value 4.5-5.5; then add the prescribed amount of preservatives and sweeteners, stir evenly, and add the buffer to make the pH value 4.8-5.2; dilute to 100 mL with purified water, filter, and obtain the L-carnitine oral solution.

[0045] Example 3

[0046] The formulation of the L-carnitine oral solution in this embodiment is shown in Table 3.

[0047] Table 3 Example 3 Formula composition of L-carnitine oral solution

[0048]

[0049]

[0050] Preparation method: dissolve the prescribed amount of polyvinyl alcohol and sodium edetate in a certain amount of purified water and stir evenly; then add the prescribed amount of L-carnitine to the solution and stir evenly; add an appropriate amount of prepared buffer to the solution and stir evenly to make the pH value 4.5-5.5; then add the prescribed amount of preservatives and sweeteners, stir evenly, and add the buffer to make the pH value 4.8-5.2; dilute to 100 mL with purified water, filter, and obtain the L-carnitine oral solution.

[0051] Example 4

[0052] The formulation of the L-carnitine oral solution in this embodiment is shown in Table 4 below.

[0053] Table 4 Example 4 Formula composition of L-carnitine oral solution

[0054]

[0055] The preparation method is:

[0056] Dissolve the prescribed amount of polyvinyl alcohol and sodium edetate in a certain amount of purified water and stir evenly; then add the prescribed amount of L-carnitine to the solution and stir evenly; add an appropriate amount of prepared buffer to the solution and stir evenly to make the pH value 4.5-5.5; then add the prescribed amount of preservatives and sweeteners and stir evenly, add the buffer to make the pH value 4.8-5.2; make up to 100 mL with purified water, filter, and obtain the L-carnitine oral solution.

[0057] Example 5

[0058] The formulation of the L-carnitine oral solution in this embodiment is shown in Table 5.

[0059] Table 5 Example 5 Formula composition of L-carnitine oral solution

[0060]

[0061] The preparation method is:

[0062] Dissolve the prescribed amount of polyvinyl alcohol and edetic acid in a certain amount of purified water and stir evenly; then add the prescribed amount of L-carnitine to the solution and stir evenly; add an appropriate amount of prepared buffer to the solution and stir evenly to make the pH value 4.5-5.5; then add the prescribed amount of preservatives and sweeteners and stir evenly, add the buffer to make the pH value 4.8-5.2; make up to 100 mL with purified water, filter, and obtain the L-carnitine oral solution.

[0063] Example 6

[0064] The formulation of the L-carnitine oral solution in this embodiment is shown in Table 6 below.

[0065] Table 6 Example 6 Formula composition of L-carnitine oral solution

[0066]

[0067] The preparation method is:

[0068] Dissolve the prescribed amount of polyvinyl alcohol and sodium edetate in a certain amount of purified water and stir evenly; then add the prescribed amount of L-carnitine to the solution and stir evenly; add an appropriate amount of prepared buffer to the solution and stir evenly to make the pH value 4.5-5.5; then add the prescribed amount of preservatives and sweeteners and stir evenly, add the buffer to make the pH value 4.8-5.2; make up to 100 mL with purified water, filter, and obtain the L-carnitine oral solution.

[0069] Example 7

[0070] The formulation of the L-carnitine oral solution in this embodiment is shown in Table 7.

[0071] Table 7 Example 7 Formula composition of L-carnitine oral solution

[0072]

[0073] The preparation method is:

[0074] Dissolve the prescribed amount of polyvinyl alcohol and sodium edetate in a certain amount of purified water and stir evenly; then add the prescribed amount of L-carnitine to the solution and stir evenly; add an appropriate amount of prepared buffer to the solution and stir evenly to make the pH value 4.5-5.5; then add the prescribed amount of preservatives and sweeteners and stir evenly, add the buffer to make the pH value 4.8-5.2; make up to 100 mL with purified water, filter, and obtain the L-carnitine oral solution.

[0075] Comparative Example 1

[0076] The same method as in Example 1 was used to prepare the L-carnitine oral solution, except that no edetic acid stabilizer was added in this comparative example 1. The specific formulation composition is shown in Table 8 below.

[0077] Table 8 Example 8 Formula composition of L-carnitine oral solution

[0078]

[0079] The preparation method is:

[0080] Dissolve the prescribed amount of polyvinyl alcohol in a certain amount of purified water and stir evenly; then add the prescribed amount of L-carnitine to the solution and stir evenly; add an appropriate amount of prepared buffer to the solution and stir evenly to make the pH value 4.5-5.5; then add the prescribed amount of preservatives and sweeteners and stir evenly, add the buffer to make the pH value 4.8-5.2; make up to 100 mL with purified water, filter, and obtain the L-carnitine oral solution.

[0081] Comparative Example 2

[0082] The same method as in Example 1 was used to prepare the L-carnitine oral solution, except that polyvinyl alcohol was not added in this comparative example 1. The specific formulation composition is shown in Table 9 below.

[0083] Table 9 Example 9 Formula composition of L-carnitine oral solution

[0084]

[0085] The preparation method is:

[0086] Dissolve the prescribed amount of sodium edetate in a certain amount of purified water and stir evenly; then add the prescribed amount of L-carnitine to the solution and stir evenly; add an appropriate amount of prepared buffer to the solution and stir evenly to make the pH value 4.5-5.5; then add the prescribed amount of preservatives and sweeteners and stir evenly, add the buffer to make the pH value 4.8-5.2; make up to 100 mL with purified water, filter, and obtain the L-carnitine oral solution.

[0087] 1. The L-carnitine oral solutions prepared in the above examples and comparative examples were tested for influencing factors at a high temperature of 60° C. The specific test results are shown in Table 10.

[0088] Table 10 Test results of influencing factors at high temperature 60℃

[0089]

[0090]

[0091] Note: "ND" in Table 10 stands for: Not Detected; "Content %" in Table 10 means: the ratio of the tested content of L-carnitine in L-carnitine oral solution to its standard value; "D-carnitine %" means: the percentage of D-carnitine in L-carnitine oral solution.

[0092] 2. Antibacterial efficacy test: The test was conducted according to the antibacterial efficacy test method in 1121 of the General Rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The antibacterial efficacy judgment criteria are shown in Table 11.

[0093] Table 11 Antibacterial efficacy judgment criteria

[0094]

[0095]

[0096] Note: NI means that the increase of the experimental bacteria does not exceed 0.5lg in the previous measurement time.

[0097] The antibacterial results of the L-carnitine oral solutions prepared in the above examples and comparative examples are shown in Table 12 below.

[0098] Table 12 Antibacterial efficacy test results

[0099]

[0100]

[0101] From the data in Table 10 and Table 12 above, it can be seen that Examples 1 to 7 are L-carnitine oral solutions prepared by the preparation method of the present invention. By using polyvinyl alcohol and edetic acid as stabilizers and coordinating with a specific buffer to achieve a stable pH value, not only can L-carnitine be evenly dispersed, but it is not easy to produce D-carnitine, and the limit of D-carnitine is strictly controlled. When Examples 1 to 7 are placed at a high temperature of 60°C for 30 days, no D-carnitine is produced. Moreover, the antibacterial ability of the L-carnitine oral solution is enhanced by the use of polyvinyl alcohol and edetic acid in Examples 1 to 7, and the antibacterial effect can be guaranteed to meet the requirements without sterilization. The quality of the L-carnitine oral solution is stable, safe and effective. In addition, by comparing the data of Examples 1 to 5 and Examples 6 to 7, it can be seen that when the mass ratio of polyvinyl alcohol and edetic acid stabilizer in the formula of the L-carnitine oral solution meets (9-12):1, the synergistic effect of polyvinyl alcohol and edetic acid stabilizer is better, and the antibacterial effect of the product is more excellent.

[0102] From the comparison of the data of Example 1 and Comparative Example 1, it can be seen that if the edetic acid stabilizer is not added to the formula composition, the L-carnitine oral solution will produce D-carnitine when placed at a high temperature of 60° C. for 30 days; and the antibacterial efficacy of the L-carnitine oral solution will be reduced.

[0103] From the data comparison of Example 1 and Comparative Example 2, it can be seen that if polyvinyl alcohol is not added to the formula composition, the L-carnitine oral solution will produce D-carnitine when placed at a high temperature of 60°C for 30 days; and the antibacterial effect of the L-carnitine oral solution is reduced. It can be seen that the use of polyvinyl alcohol and edetic acid stabilizers in the L-carnitine oral solution is more conducive to improving the stability and antibacterial properties of the L-carnitine oral solution.

[0104] The present invention uses polyvinyl alcohol and edetic acid stabilizers in combination with a specific buffer to achieve a stable pH value. Polyvinyl alcohol has a thickening effect and improves the mouthfeel. Edetic acid can complex metal ions to ensure the stability of the system. When the two are combined, it is unexpectedly found that the stability of the solution quality can be ensured, and the degradation of dextrocarnitine can be inhibited. At the same time, the antibacterial ability of polyvinyl alcohol and edetic acid stabilizers is enhanced after being used together. The antibacterial effect of the sample solution can also be guaranteed to meet the requirements without sterilization, so that energy consumption is reduced, and the product quality is stable, safe and effective. Moreover, the dosage of polyvinyl alcohol and edetic acid stabilizers specified in the present invention is more conducive to the control of uniform and stable dispersion of the oral solution and the pH regulation operation, thereby facilitating the preparation process and filling operation.

[0105] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are exhaustively listed. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0106] For those skilled in the art, several modifications and improvements may be made without departing from the concept of the present invention, all of which belong to the protection scope of the present invention. The protection scope of the present invention shall be based on the attached claims.

Claims

1. A L-carnitine oral solution, characterized in that: Each 100 ml of the L-carnitine oral solution contains 10 g of L-carnitine, 5-15 g of polyvinyl alcohol, 0.5-1.5 g of an edetic acid stabilizer, and a buffer to make the pH value of the L-carnitine oral solution 4.5-5.5, and the balance is water.

2. A L-carnitine oral solution according to claim 1, characterized in that: The pH value of the L-carnitine oral solution is 4.8-5.

2.

3. A L-carnitine oral solution according to claim 1, characterized in that: The polyvinyl alcohol is at least one of polyvinyl alcohol 03-88, polyvinyl alcohol 05-88, and polyvinyl alcohol 24-88.

4. A L-carnitine oral solution according to claim 1, characterized in that: The edetic acid stabilizer is edetic acid or edetic acid salt.

5. A L-carnitine oral solution according to claim 1, characterized in that: The mass ratio of the polyvinyl alcohol to the edetic acid stabilizer is (9-12):

1.

6. A L-carnitine oral solution according to claim 1, characterized in that: The buffer is a combination of citric acid and sodium citrate or a combination of acetic acid and sodium acetate.

7. A L-carnitine oral solution according to claim 1, characterized in that: Every 100 ml of the L-carnitine oral solution also contains 0.04-0.06 g of a sweetener and 0.3-0.5 g of a preservative.

8. A L-carnitine oral solution according to claim 7, characterized in that: The sweetener is at least one of saccharin sodium, trehalose and aspartame.

9. A L-carnitine oral solution according to claim 7, characterized in that: The preservative is at least one of benzoic acid, sodium benzoate, potassium benzoate, methylparaben and propylparaben.

10. A method for preparing a L-carnitine oral solution according to any one of claims 1 to 9, characterized in that: The preparation method is: The prescribed amount of polyvinyl alcohol and edetic acid stabilizer are dissolved in a certain amount of purified water and mixed evenly; then the prescribed amount of L-carnitine is added and mixed evenly; a buffer is added and mixed evenly to make the pH value 4.5-5.5; then the prescribed amount of preservatives and sweeteners are added and mixed evenly, and then a buffer is added to make the pH value 4.8-5.2; finally, the volume is fixed and filtered to obtain the L-carnitine oral solution.

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