Hydroxychloroquine sulfate syrup without antibacterial agent and preparation method thereof

Abstract

The invention discloses a hydroxychloroquine sulfate syrup without antibacterial agent and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. The preparation method of the hydroxychloroquine sulfate syrup of the present invention comprises the following steps: (1) adding the sucrose of the formula amount into water, heating to completely dissolve, and obtaining syrup; (2) adding the hydroxychloroquine sulfate of the formula amount into the syrup obtained by step (1), and completely dissolving; (3) adjusting the pH to 4-6, and obtaining the hydroxychloroquine sulfate syrup without antibacterial agent. The hydroxychloroquine sulfate syrup obtained by the preparation method can achieve good stability and antibacterial efficacy without adding antibacterial agent, and has good taste, higher safety, and is more suitable for children.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a hydroxychloroquine sulfate syrup containing no antibacterial agent and a preparation method thereof. Background Art

[0002] Hydroxychloroquine belongs to the 4-aminoquinoline antimalarial drug, which is composed of two aromatic rings. Compared with chloroquine, the difference is that one of the ethyl groups in chloroquine is replaced by hydroxyethyl in hydroxychloroquine, which increases the water solubility, promotes the absorption of the drug in the human body, and has a lower incidence of adverse reactions. While retaining the original efficacy of chloroquine, hydroxychloroquine has significantly lower toxic and side effects than chloroquine. Hydroxychloroquine sulfate can be used to treat rheumatic diseases and is currently a drug for the treatment of rheumatoid arthritis and lupus erythematosus.

[0003] The current dosage form of hydroxychloroquine sulfate is mainly hydroxychloroquine sulfate tablets, and the dosage for children over 6 years old is no more than 6.5 mg / kg / day or 400 mg / day, or even less. The content of the tablets is difficult to meet the demand, and hydroxychloroquine has a cumulative effect and takes several weeks to play its role. Therefore, for children, taking hydroxychloroquine sulfate tablets has the problem of difficult dosage control.

[0004] Chinese patent CN116211798A discloses a hydroxychloroquine sulfate oral solution and a preparation method thereof, wherein each 1000 mL of the hydroxychloroquine sulfate oral solution contains the following ingredients: 5-50 g of hydroxychloroquine sulfate, 1-10 g of flavoring agent, 0.8-3 g of preservative, and a pH adjuster to adjust the pH to 2.0-6.0. The hydroxychloroquine sulfate oral solution of the invention uses sodium benzoate as a preservative, which is less toxic, safe, highly stable, has a good taste, a simple prescription, and is easy to industrialize. It is also an improved innovative preparation, more suitable for use by teenagers and children, with easy-to-divided doses and more accurate dosages. The dosage can be flexibly adjusted according to the treatment effect and adverse reactions of the disease. The amount of antibacterial agent (preservative) added in the invention is relatively large.

[0005] For many antimicrobial agents, data on safe exposure levels for children of different age groups are still limited, so there is a great demand for children's formulations without added antimicrobial agents. Summary of the invention

[0006] The object of the invention is to provide a hydroxychloroquine sulfate syrup without antibacterial agent and a preparation method thereof, which can achieve good stability and antibacterial efficacy without adding antibacterial agent, and has good mouthfeel, higher safety, reduces the potential safety hazard caused by long-term medication, and is more suitable for children. In addition, the hydroxychloroquine sulfate syrup obtained by the prescription has good taste, is easy to divided dose, has stable quality, is convenient to long-term storage, and is taken repeatedly.

[0007] The inventors unexpectedly discovered that when hydroxychloroquine sulfate is prepared as a syrup, by adjusting the specific syrup concentration and pH value, excellent antibacterial effect and stability can be achieved without adding antibacterial agents or preservatives, while meeting the requirements of the new dosage form.

[0008] To achieve the above-mentioned object of the invention, the technical solution of the present invention is as follows:

[0009] On the one hand, the present invention provides a method for preparing a hydroxychloroquine sulfate syrup without an antibacterial agent, comprising the following steps:

[0010] (1) adding a formula amount of sucrose into water and heating until completely dissolved to obtain a syrup, wherein the concentration of sucrose in the syrup is 60%-85%;

[0011] (2) adding a formulated amount of hydroxychloroquine sulfate to the syrup obtained in step (1) and completely dissolving it;

[0012] (3) Adjust the pH to 4-6 to obtain hydroxychloroquine sulfate syrup without antibacterial agent.

[0013] Preferably, in step (1), the heating temperature is 80-100°C.

[0014] Preferably, in step (1), the concentration of sucrose in the syrup is 60%-80%, more preferably 75%.

[0015] Preferably, in step (3), the pH is adjusted by adding a pH adjuster. Further preferably, the pH adjuster is selected from at least one of citric acid, sodium citrate, hydrochloric acid, malic acid, and sodium hydroxide; further preferably, at least one of hydrochloric acid and malic acid; and most preferably, malic acid.

[0016] Preferably, in step (3), the pH is adjusted to 5.

[0017] Preferably, the mass ratio of sucrose to hydroxychloroquine sulfate is 75:1-4, more preferably 75:1.

[0018] On the other hand, the present invention provides hydroxychloroquine sulfate syrup prepared according to the above preparation method.

[0019] Preferably, the hydroxychloroquine sulfate syrup consists of the following ingredients: hydroxychloroquine sulfate, sucrose, a pH regulator and water.

[0020] The beneficial effects of the present invention are:

[0021] (1) The present invention provides a syrup of hydroxychloroquine sulfate, which can achieve good stability and antibacterial efficacy without adding an antibacterial agent, is beneficial to reducing the safety risks caused by long-term medication, has a better taste, and is more suitable for children.

[0022] (2) For the syrup system of the present invention, by controlling the sucrose concentration and the pH range, it is possible to achieve a long-term antibacterial effect even without adding an antibacterial agent, and has good stability.

[0023] (3) For the preparation process of the present invention, the stability can be further improved by selecting a specific type of pH adjuster.

[0024] (4) The preparation process of the present invention is simple and easy to scale up for production. Compared with tablets, it is more convenient for children to take the drug in divided doses. DETAILED DESCRIPTION

[0025] In order to make the technical means, creative features, purpose and efficacy of the present invention easy to understand, the present invention is further explained in conjunction with specific embodiments below, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without creative work all belong to the protection scope of the present invention. In the following embodiments, unless otherwise specified, the operating methods used are conventional operating methods, the equipment used are conventional equipment, and the equipment materials used in each embodiment are the same.

[0026] In the following examples, the "parts" are all parts by weight. The concentration of sucrose in the syrup is the mass concentration, that is, the percentage of the mass of sucrose to the total mass of the syrup.

[0027] Example 1

[0028] Follow these steps to prepare hydroxychloroquine sulfate syrup:

[0029] (1) Add 750 parts of sucrose into water, heat and stir at 80-100°C until completely dissolved to obtain syrup. The concentration of sucrose in the syrup is 75%;

[0030] (2) adding 20 parts of hydroxychloroquine sulfate to the syrup obtained in step (1) and stirring until completely dissolved;

[0031] (3) Adjust the pH to 4.0 using L-malic acid.

[0032] Example 2

[0033] The difference from Example 1 is that in step (2), the amount of hydroxychloroquine sulfate added is 40 parts. The rest is the same.

[0034] Example 3

[0035] The difference from Example 1 is that in step (2), the amount of hydroxychloroquine sulfate added is 10 parts, and in step (3), the pH is adjusted to 5.0. The rest are the same.

[0036] Example 4

[0037] The difference from Example 3 is that in step (3), sodium citrate is used to adjust the pH to 6.0. The rest is the same.

[0038] Example 5

[0039] The difference from Example 3 is that in step (3), the pH is adjusted to 4.0. The rest is the same.

[0040] Example 6

[0041] The difference from Example 3 is that in step (3), hydrochloric acid is used as a pH adjuster. The rest is the same.

[0042] Example 7

[0043] The difference from Example 3 is that in step (3), citric acid is used as a pH regulator. The rest is the same.

[0044] Example 8

[0045] The difference from Example 3 is that in step (1), the concentration of sucrose in the syrup is 60%. The rest is the same.

[0046] Example 9

[0047] The difference from Example 3 is that in step (1), the concentration of sucrose in the syrup is 80%. The rest is the same.

[0048] Comparative Example 1

[0049] The difference from Example 1 is that the amount of sucrose is 300 parts. The rest is the same.

[0050] Comparative Example 2

[0051] The difference from Example 1 is that the pH is adjusted to 3.6. The rest is the same.

[0052] Comparative Example 3

[0053] The difference from Example 1 is that the pH is adjusted to 7.0. The rest is the same.

[0054] Comparative Example 4

[0055] The difference from Example 3 is that in step (1), the concentration of sucrose in the syrup is 50%. The rest is the same.

[0056] Comparative Example 5

[0057] The difference from Example 3 is that in step (1), the concentration of sucrose in the syrup is 87%. The rest is the same.

[0058] Results

[0059] 1. Investigation of antibacterial efficacy

[0060] Detection method: Determine according to the antibacterial efficacy test method in 1121 of the 2020 edition of the Chinese Pharmacopoeia.

[0061] The test results are as follows:

[0062] Table 1

[0063]

[0064] The results of comparative example 1 show that when the amount of sucrose is reduced, the antibacterial effect will be affected; the results of comparative example 4 show that when the sucrose concentration is 50%, the antibacterial effect does not meet the requirements; the results of comparative example 5 show that when the sucrose concentration is too high, precipitation will occur.

[0065] 2. Stability test

[0066] 2.1 Detection method: High performance liquid chromatography, to detect stability at high temperature of 60°C.

[0067] Limit requirements:

[0068] Table 2

[0069]

[0070] Impurity A is a specific impurity with the structural formula:

[0071] ;

[0072] Impurity C is a specific impurity with the structural formula:

[0073] ;

[0074] Impurity D is a non-specific impurity with the structural formula:

[0075] ;

[0076] Impurity E is a non-specific impurity with the structural formula:

[0077] .

[0078] The test results of Example 1-Example 5 are as follows:

[0079] Table 3

[0080]

[0081] The test results of Example 6-Example 9 are as follows:

[0082] Table 4

[0083]

[0084] The test results of Comparative Examples 1-3 are as follows:

[0085] Table 5

[0086]

[0087] The results show that when the pH is less than 4.0, the related substances in the product increase rapidly under high temperature conditions of 60°C; when the pH increases to 7.0, impurity A, impurity C, impurity D and other individual impurities show obvious growth under light conditions, indicating that there is a risk of exceeding the limit for related substances during the stability period.

[0088] 2.2 Stability test results

[0089] The products of Examples 1 to 9 and Comparative Examples 1 to 4 were stored at a high temperature of 60°C for 10 days, and their properties were no different from those at 0 days. After the configuration of Comparative Example 5 was completed, precipitation occurred upon storage at room temperature, and the properties did not meet the requirements.

[0090] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a hydroxychloroquine sulfate syrup without an antibacterial agent, characterized in that: The following steps are involved: (1) adding a formula amount of sucrose into water and heating until completely dissolved to obtain a syrup, wherein the concentration of sucrose in the syrup is 60%-85%; (2) adding a formulated amount of hydroxychloroquine sulfate to the syrup obtained in step (1) and completely dissolving it; (3) adjusting the pH to 4-6 to obtain a hydroxychloroquine sulfate syrup without antibacterial agent; The mass ratio of sucrose to hydroxychloroquine sulfate is 75:1-4.

2. The preparation method according to claim 1, characterized in that: In step (1), the concentration of sucrose in the syrup is 60%-80%.

3. The preparation method according to claim 2, characterized in that: In step (1), the concentration of sucrose in the syrup is 75%.

4. The preparation method according to claim 1, characterized in that: In step (3), the pH is adjusted by adding a pH adjuster, and the pH adjuster is selected from at least one of citric acid, sodium citrate, hydrochloric acid, malic acid, and sodium hydroxide.

5. The preparation method according to claim 4, characterized in that: The pH adjuster is selected from at least one of hydrochloric acid and malic acid.

6. The preparation method according to claim 5, characterized in that: The pH adjuster is malic acid.

7. The preparation method according to claim 1, characterized in that: In step (3), the pH is adjusted to 5.

8. The preparation method according to claim 1, characterized in that: The mass ratio of sucrose to hydroxychloroquine sulfate is 75:

1.

9. the hydroxychloroquine sulfate syrup prepared according to any one of the preparation methods described in claim 1-8.

10. Hydroxychloroquine sulfate syrup according to claim 9, characterized in that, It is composed of the following ingredients: hydroxychloroquine sulfate, sucrose, pH adjuster and water.

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