Sertraline hydrochloride oral solution and preparation method thereof

Abstract

The application discloses a sertraline hydrochloride oral liquid and a preparation method thereof, and belongs to the technical field of medicines. The oral liquid comprises the following components in mass percentage: 22.4g of sertraline hydrochloride, 10-30g of polyoxyethylene 40 hydrogenated castor oil, 0.2-2g of a flavoring agent, and polyethylene glycol 400 added to 1000ml. The sertraline hydrochloride oral liquid provided by the application does not contain ethanol and does not need an antioxidant, is suitable for children, and has excellent stability in stability tests for 6 months, low-temperature cycle tests and freeze-thaw cycle tests, and has good application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a sertraline hydrochloride oral solution and its preparation method. Background Technology

[0002] The information disclosed in the background section of this invention is intended only to enhance the understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Sertraline hydrochloride, a selective serotonin reuptake inhibitor (SSRI), improves mood and anxiety symptoms by increasing serotonin levels in the synaptic cleft. Its oral formulations include tablets and concentrates, and it is indicated for various mental health conditions such as depression, generalized anxiety disorder, and panic disorder. ZOLOFT, a classic drug from Pfizer, has become one of the most commonly prescribed psychiatric medications globally due to its good tolerability and proven efficacy, and is recommended in numerous clinical guidelines. The widespread use of this drug provides many patients with a safe and effective treatment option, continuously contributing to the advancement of mental health treatment.

[0004] Compared to conventional tablets, oral solutions can improve patient compliance, are easier for patients with swallowing difficulties to use, and ensure accurate dosage. However, because sertraline hydrochloride is poorly soluble and unstable in water, the development of oral solution formulations usually requires the addition of special excipients such as glycerin, ethanol, and antioxidants. Currently, commercially available oral concentrates use a glycerin-ethanol system as a mixed solvent. This system is unstable and prone to generating oxidizing substances, leading to degradation of the active pharmaceutical ingredient. Therefore, a certain amount of antioxidant is usually added to the formulation. The addition of these excipients, whether ethanol or antioxidants, poses certain risks to pediatric patients. Therefore, it is necessary to provide a stable, safe, and suitable oral solution of sertraline hydrochloride for children. Summary of the Invention

[0005] In view of this, the present invention provides a sertraline hydrochloride oral solution and its preparation method. The sertraline hydrochloride oral solution provided by the present invention does not contain ethanol and does not require antioxidants, making it suitable for children. Furthermore, it exhibits excellent stability in stability tests of 6 months, low temperature cycling, and freeze-thaw cycles, and has good application value.

[0006] In a first aspect, the present invention provides a sertraline hydrochloride oral solution, wherein each 1000 ml of the oral solution comprises the following components: Sertraline hydrochloride 22.4g; 10-30g of polyoxyethylene castor oil derivative; Flavoring agent 0.2~2g; Add polyethylene glycol 400 to 1000ml.

[0007] In some embodiments, the polyoxyethylene castor oil derivative is selected from one or more of polyoxyethylene 5 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, and polyoxyethylene 40 hydrogenated castor oil.

[0008] In some embodiments, the polyoxyethylene castor oil derivative is preferably polyoxyethylene 40 hydrogenated castor oil.

[0009] In some embodiments, the mass ratio of sertraline hydrochloride to polyoxyethylene castor oil derivative is 1:0.446~1.339.

[0010] In some embodiments, the flavoring agent is selected from one or more of sweeteners and flavorings.

[0011] In some embodiments, the sweetener is selected from one or more of sorbitol, mannitol, xylitol, and menthol.

[0012] In some embodiments, the fragrance is selected from one or more of the following: orange flavoring, strawberry flavoring, lemon flavoring, blueberry flavoring, raspberry flavoring, blackberry flavoring, and cherry flavoring.

[0013] Secondly, the present invention provides a method for preparing the above-mentioned sertraline hydrochloride oral solution, comprising the following steps: Polyoxyethylene castor oil derivatives were added to a portion of polyethylene glycol 400 and stirred until homogeneous. The temperature of the solution was controlled at 30℃~40℃. Nitrogen gas was introduced to control the dissolved oxygen content to be below 4mg / L. Sertraline hydrochloride and flavoring agent were then added and stirred until dissolved. The remaining polyethylene glycol 400 was used to make up the volume. The solution was then filtered and bottled.

[0014] In some embodiments, the dissolved oxygen content is controlled at 1~4 mg / L.

[0015] Compared with the prior art, the present invention has achieved the following beneficial effects: (1) The oral liquid of the present invention does not contain ethanol and does not require the addition of any antioxidants, thus avoiding the potential stimulation of children's nervous system by ethanol and the additional safety risks brought by antioxidants. It solves the safety hazards of excipients for pediatric patients in the prior art of sertraline hydrochloride oral preparations, and has better tolerability, meeting the safety needs of children's medication.

[0016] (2) By adjusting the ratio of sertraline hydrochloride to polyoxyethylene castor oil derivatives and combining the process of introducing nitrogen to control dissolved oxygen during preparation, this invention effectively inhibits the oxidative degradation of sertraline hydrochloride without relying on antioxidants. This results in the oral liquid exhibiting excellent stability in the 6-month stability test, low-temperature cycling and freeze-thaw cycle test, ensuring stable content of active ingredients and extending the shelf life of the oral liquid.

[0017] (3) In this invention, sertraline hydrochloride and polyoxyethylene castor oil derivatives are combined in a specific ratio, and polyethylene glycol 400 is used as a solvent to produce a unique stabilizing effect on sertraline hydrochloride. The polyoxyethylene castor oil derivatives and polyethylene glycol 400 form mixed micelles, which not only increase the solubility of sertraline hydrochloride, but also encapsulate sertraline hydrochloride molecules in the micelles, thereby improving the stability of sertraline hydrochloride. Furthermore, due to the presence of nitrogen, the formulation still exhibits the characteristics of slow growth of related substances and stable content of the active pharmaceutical ingredient in accelerated and long-term stability tests without the addition of any traditional antioxidants.

[0018] (4) The preparation process of sertraline hydrochloride oral solution provided by the present invention is simple, the raw materials are inexpensive and readily available, the preparation properties are stable, and it is suitable for large-scale industrial production, thus having broad application prospects. Detailed Implementation

[0019] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0020] The technical solution of the present invention will be further described below with reference to specific embodiments. The present invention does not impose any special restrictions on the source of reagents used in the following embodiments; commercially available products well known to those skilled in the art can be used.

[0021] Example 1 Weigh each raw material according to the following mass: Sertraline hydrochloride: 22.4 g; Polyoxyethylene 40 hydrogenated castor oil: 20 g; Menthol: 0.5 g; Polyethylene glycol 400: Add to 1000 mL.

[0022] Preparation: Stir 800ml of polyethylene glycol 400 and polyoxyethylene 40 hydrogenated castor oil evenly, control the temperature of the solution at 35℃, introduce nitrogen gas to control the dissolved oxygen content at 1.6mg / L, then add sertraline hydrochloride and menthol, stir to dissolve, and use the remaining polyethylene glycol 400 to make up the volume. After filtering the solution, fill and seal it.

[0023] Example 2 Weigh each raw material according to the following mass: Sertraline hydrochloride: 22.4 g; Polyoxyethylene 40 hydrogenated castor oil: 30g; Menthol: 0.2g; Polyethylene glycol 400: Add to 1000 mL.

[0024] Preparation: Stir 800ml of polyethylene glycol 400 and polyoxyethylene 40 hydrogenated castor oil evenly, control the temperature of the solution at 40℃, introduce nitrogen gas to control the dissolved oxygen content at 1.8mg / L, then add sertraline hydrochloride and menthol, stir to dissolve, and use the remaining polyethylene glycol 400 to make up the volume. After filtering the solution, fill and seal it.

[0025] Example 3 Weigh each raw material according to the following mass: Sertraline hydrochloride: 22.4g; Polyoxyethylene 40 hydrogenated castor oil: 10g; Menthol: 2g; Polyethylene glycol 400: Add to 1000 mL.

[0026] Preparation: Stir 800ml of polyethylene glycol 400 and polyoxyethylene 40 hydrogenated castor oil evenly, control the temperature of the solution at 30℃, introduce nitrogen gas to control the dissolved oxygen content at 1.6mg / L, then add sertraline hydrochloride and menthol, stir to dissolve, and use the remaining polyethylene glycol 400 to make up the volume. After filtering the solution, fill and seal it.

[0027] Example 4 Weigh each raw material according to the following mass: Sertraline hydrochloride: 22.4 g; Polyoxyethylene 40 hydrogenated castor oil: 20 g; Menthol: 0.2 g; Strawberry flavoring: 1 g; Polyethylene glycol 400: Add to 1000 mL.

[0028] Preparation: Stir 800ml of polyethylene glycol 400 and polyoxyethylene 40 hydrogenated castor oil evenly, control the temperature of the solution at 35℃, introduce nitrogen gas to control the dissolved oxygen content at 2.4mg / L, then add sertraline hydrochloride, menthol and strawberry flavor, stir to dissolve, and use the remaining polyethylene glycol 400 to make up the volume. After filtering the solution, fill and seal it.

[0029] Example 5 Weigh each raw material according to the following mass: Sertraline hydrochloride: 22.4 g; Polyoxyethylene 35 castor oil: 20 g; Cherry flavoring: 0.5 g; Polyethylene glycol 400: Add to 1000 mL.

[0030] Preparation: Stir 800ml of polyethylene glycol 400 and polyoxyethylene 35 castor oil evenly, control the temperature of the solution at 35℃, introduce nitrogen gas to control the dissolved oxygen content at 1.6mg / L, then add sertraline hydrochloride and cherry flavor, stir to dissolve, and use the remaining polyethylene glycol 400 to make up the volume. After filtering the solution, fill and seal it.

[0031] Comparative Example 1 This embodiment provides a sertraline hydrochloride oral solution, the only difference between its formulation and that of Example 1 is that it does not contain polyoxyethylene 40 hydrogenated castor oil. The preparation method is the same as in Example 1.

[0032] Comparative Example 2 Weigh each raw material according to the following mass: Sertraline hydrochloride: 22.4g; Polyoxyethylene 40 hydrogenated castor oil: 40g; Menthol: 0.5g; Polyethylene glycol 400: Add to 1000 mL.

[0033] The preparation method is the same as in Example 1. Comparative Example 3 This embodiment provides a sertraline hydrochloride oral solution, the formulation of which is completely consistent with that of Example 1.

[0034] Preparation: Stir 800ml of polyethylene glycol 400 and polyoxyethylene 40 hydrogenated castor oil evenly, control the temperature of the solution at 35℃, introduce nitrogen gas to control the dissolved oxygen content at 4~8mg / L, then add sertraline hydrochloride and menthol, stir to dissolve, and use the remaining polyethylene glycol 400 to make up the volume. After filtering the solution, fill and seal it.

[0035] Comparative Example 4 This embodiment provides a sertraline hydrochloride oral solution, the formulation of which is the same as that in Example 1.

[0036] Preparation: Stir 800ml of polyethylene glycol 400 and polyoxyethylene 40 hydrogenated castor oil evenly, control the temperature of the solution at 45℃, introduce nitrogen gas to control the dissolved oxygen content at 1~4mg / L, then add sertraline hydrochloride and menthol, stir to dissolve, use the remaining polyethylene glycol 400 to make up the volume, filter the solution and fill and seal.

[0037] Comparative Example 5 This embodiment provides a sertraline hydrochloride oral solution, the formulation of which is the same as that in Example 1.

[0038] Preparation: Stir 800ml of polyethylene glycol 400 and polyoxyethylene 40 hydrogenated castor oil evenly, control the temperature of the solution at 25℃, introduce nitrogen gas to control the dissolved oxygen content at 1~4mg / L, then add sertraline hydrochloride and menthol, stir to dissolve, and use the remaining polyethylene glycol 400 to make up the volume. After filtering the solution, fill and seal it.

[0039] Comparative Example 6 This embodiment provides a sertraline hydrochloride oral solution, the only difference between its formulation and that of Example 1 is the replacement of polyethylene glycol 400 with glycerin. The preparation method is the same as in Example 1.

[0040] In Comparative Examples 1 and 5, the materials remained undissolved and unclear after being stirred for 24 hours during sample preparation.

[0041] Experimental Example 1 The stability of the above embodiments and comparative examples was investigated.

[0042] Test method: Accelerated testing: Accelerated testing was conducted on Examples 1-5, Comparative Examples 2-4, and Comparative Example 6. Samples were placed at 40℃±2℃ and 75%RH±5%RH for 6 months, with samples taken at months 1, 3, and 6 to analyze their properties, related substances, and content. Data were also compared with data from day 0.

[0043] Low-temperature cycling test: Examples 1-5, Comparative Examples 2-4, and Comparative Example 6 were subjected to low-temperature cycling tests. Samples were placed at low temperatures (2–8°C) for 2 days, then transferred to 40°C for 2 days, and this process was repeated for 3 cycles. Samples were taken after the third cycle to analyze their properties, related substances, and content. Data were also compared with data from day 0.

[0044] Freeze-thaw cycle test: Freeze-thaw cycle tests were conducted on Examples 1-5, Comparative Examples 2-4, and Comparative Example 6. Samples were placed under freeze-thaw conditions (-20℃ to -10℃) for 2 days, then transferred to 40℃ for 2 days. This process was repeated for 3 cycles. Samples were taken after the 3rd cycle to analyze their properties, related substances, and content. Data were also compared with data from day 0.

[0045] Physical properties testing: Visual inspection is used for testing.

[0046] Related substances and concentrations: The methods for testing were performed according to the Sertraline Hydrochloride Oral Solution section of the United States Pharmacopeia (USP-NF2025).

[0047] The experimental results are detailed in Table 1 below.

[0048] Table 1. Experimental results of Examples 1-5, Comparative Examples 2-4, and Comparative Example 6

[0049] As shown in Table 1, the sertraline hydrochloride oral solution provided by the present invention exhibits excellent stability in accelerated 6-month, low-temperature cycling, and freeze-thaw cycling tests.

[0050] By comparing Example 1 with Comparative Example 1, it can be seen that polyoxyethylene 40 hydrogenated castor oil plays a very good solubilizing role; without it, the formulation cannot form a homogeneous solution.

[0051] By comparing Examples 1-3 with Comparative Example 2, it can be seen that the amount of polyoxyethylene 40 hydrogenated castor oil used needs to be controlled within the range of 10-30g. Exceeding this range will accelerate the degradation of the main drug and cause related substances to exceed the standard.

[0052] By comparing Example 1 with Comparative Example 3, it can be seen that the dissolved oxygen content needs to be controlled at 1~4 mg / L during preparation. Too high a dissolved oxygen content will lead to excessive levels of related substances and a decrease in the content of the main drug, thus failing to guarantee the stability of the formulation.

[0053] By comparing Example 1 with Comparative Examples 4-5, it can be seen that a low solution preparation temperature prolongs the dissolution time of the active pharmaceutical ingredient, preventing the rapid formation of a homogeneous solution. Conversely, a high solution preparation temperature leads to excessive levels of key related substances, compromising the stability of the formulation.

[0054] By comparing Example 1 with Comparative Example 6, it can be seen that polyethylene glycol 400 as a matrix has a much better effect on inhibiting the oxidative degradation of the active pharmaceutical ingredient than glycerol, and can significantly improve the stability of the formulation.

[0055] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A sertraline hydrochloride oral solution, characterized in that, The oral liquid comprises the following components per 1000ml: Sertraline hydrochloride 22.4g; 10-30g of polyoxyethylene castor oil derivative; Flavoring agent 0.2~2g; Add polyethylene glycol 400 to 1000ml.

2. The sertraline hydrochloride oral solution as described in claim 1, characterized in that, The polyoxyethylene castor oil derivative is selected from one or more of polyoxyethylene 5 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, and polyoxyethylene 40 hydrogenated castor oil. The polyoxyethylene castor oil derivative is preferably polyoxyethylene 40 hydrogenated castor oil.

3. The sertraline hydrochloride oral solution as described in claim 1, characterized in that, The mass ratio of sertraline hydrochloride to polyoxyethylene castor oil derivative is 1:0.446~1.

339.

4. The sertraline hydrochloride oral solution as described in claim 1, characterized in that, The flavoring agent is selected from one or more of sweeteners and flavorings.

5. The sertraline hydrochloride oral solution as described in claim 4, characterized in that, The sweetener is selected from one or more of sorbitol, mannitol, xylitol, and menthol.

6. The sertraline hydrochloride oral solution as described in claim 4, characterized in that, The fragrance is selected from one or more of the following: orange essence, strawberry essence, lemon essence, blueberry essence, raspberry essence, blackberry essence, and cherry essence.

7. The method for preparing sertraline hydrochloride oral solution according to any one of claims 1 to 6, characterized in that, Includes the following steps: Polyoxyethylene castor oil derivatives were added to a portion of polyethylene glycol 400 and stirred until homogeneous. The temperature of the solution was controlled at 30℃~40℃. Nitrogen gas was introduced to control the dissolved oxygen content to be below 4mg / L. Sertraline hydrochloride and flavoring agent were then added and stirred until dissolved. The remaining polyethylene glycol 400 was used to make up the volume. The solution was then filtered and bottled.

8. The preparation method according to claim 7, characterized in that, Dissolved oxygen levels should be controlled between 1 and 4 mg / L.

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