Preparation method of atomoxetine hydrochloride oral solution

Abstract

The invention relates to the technical field of medical preparations, in particular to a preparation method of an atomoxetine hydrochloride oral solution. The atomoxetine hydrochloride oral solution disclosed by the invention is prepared from the following raw materials in parts by weight: 5 to 15 parts of atomoxetine hydrochloride inclusion compound, 0.3 to 0.5 part of sodium benzoate, 16 to 17 parts of sorbitol, 165 to 170 parts of xylitol, 5 to 10 parts of sucralose, 1 to 2 parts of raspberry essence and 300 to 350 parts of deionized water. The atomoxetine hydrochloride oral solution disclosed by the invention has the advantages that in a taste experiment, the atomoxetine hydrochloride oral solution has obvious sweet taste and is well received by testers, the bitter taste of atomoxetine hydrochloride does not exist after the atomoxetine hydrochloride oral solution is eaten, and most importantly, after an acceleration experiment, the atomoxetine hydrochloride oral solution still has good taste and stability.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a method for preparing an atomoxetine hydrochloride oral solution. Background Art

[0002] Atomoxetine Hydrochloride is a selective norepinephrine reuptake inhibitor used primarily to treat attention deficit hyperactivity disorder. It works by increasing the levels of norepinephrine in the brain to help improve attention and reduce hyperactive and impulsive behavior.

[0003] Patent technology document CN112451476A discloses an oral solution of atomoxetine hydrochloride and a preparation method thereof. The oral solution of the invention comprises atomoxetine hydrochloride, hydroxypropyl-β-cyclodextrin, a pH regulator, a preservative, a flavor, 50% ethanol and water. The oral aqueous solution of the invention greatly improves the stability of atomoxetine hydrochloride and brings greater social value.

[0004] Patent technology document CN106727291B discloses an atomoxetine hydrochloride oral solution and a preparation method thereof. The invention uses β-cyclodextrin combined with tartaric acid for taste masking to prepare an atomoxetine hydrochloride oral solution preparation with good taste. The preparation method provided is simple, has good taste, does not add a large amount of sweeteners and flavors, reduces toxic side effects, solves the shortcomings of existing atomoxetine hydrochloride preparations such as poor compliance of children's medication, improves the medication compliance of pediatric patients, and meets the clinical medication needs of children.

[0005] However, the above method still results in the coexistence of bitterness and sweetness in the oral solution, and the bitter taste is strong after taking it, which still affects medication compliance. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a method for preparing an atomoxetine hydrochloride oral solution, so as to provide an atomoxetine hydrochloride oral solution that is easy for patients to accept and has good stability.

[0007] Based on the above purpose, the present invention provides a method for preparing atomoxetine hydrochloride oral solution, comprising the following steps: At 40°C, add atomoxetine hydrochloride inclusion complex, sodium benzoate, sorbitol, xylitol, and sucralose to deionized water in sequence, stir to dissolve and disperse evenly, then add raspberry essence, stir evenly, adjust the pH to neutral, and dilute to volume with deionized water to obtain the product; The preparation steps of the atomoxetine hydrochloride inclusion compound are as follows: S1: Dissolve chloroacetic acid in deionized water, then add NaOH solution, then add β-cyclodextrin, stir at 55-60°C for 12-14 h, after the reaction is completed, adjust the pH to 4.0 with HCl solution, then dialyze with water, precipitate, and dry to obtain carboxymethylated β-cyclodextrin; S2: Dissolve ethylene glycol chitosan and carboxymethylated β-cyclodextrin in deionized water, respectively, mix, then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stir at room temperature at 300 rpm for 1 h, continue stirring for 24 h, then dialyze in distilled water, and freeze-dry to obtain chitosan-β-cyclodextrin inclusion material; S3: Dissolve atomoxetine hydrochloride and chitosan-β-cyclodextrin inclusion material in deionized water at room temperature, stir evenly, and freeze-dry at 223 K and 0.03 mbar for 48 h to obtain an atomoxetine hydrochloride inclusion complex.

[0008] Preferably, the atomoxetine hydrochloride oral solution comprises the following raw materials in parts by weight: 5-15 parts of atomoxetine hydrochloride inclusion complex, 0.3-0.5 parts of sodium benzoate, 16-17 parts of sorbitol, 165-170 parts of xylitol, 5-10 parts of sucralose, 1-2 parts of raspberry essence, and 300-350 parts of deionized water.

[0009] Preferably, in step S1, the dosage ratio of chloroacetic acid, deionized water, NaOH solution and β-cyclodextrin is 4.5-5 g: 5-10 ml: 8-10 ml: 7-8 g.

[0010] Preferably, the concentration of the NaOH solution in step S1 is 7.5M.

[0011] Preferably, in step S2, the usage ratio of ethylene glycol chitosan, carboxymethylated β-cyclodextrin, deionized water, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloric acid is 10-11 g:20-25 g:100 ml:15-20 g.

[0012] Preferably, the weight ratio of atomoxetine hydrochloride to chitosan-β-cyclodextrin in step S3 is 0.9-2:4-9.

[0013] Preferably, the atomoxetine hydrochloride oral solution contains 1-3 g of atomoxetine hydrochloride per 500 ml of atomoxetine hydrochloride oral solution.

[0014] Beneficial effects of the present invention: The atomoxetine hydrochloride oral solution of the present invention adopts chitosan and β-cyclodextrin as inclusion materials. On the one hand, β-cyclodextrin can play an inclusion role due to its unique structure, and chitosan itself has good compatibility and film-forming properties. On the one hand, it can further enhance the inclusion effect of atomoxetine hydrochloride, and on the other hand, it can make the inclusion material more compatible with the dispersion medium.

[0015] The atomoxetine hydrochloride oral solution of the present invention adopts an inclusion compound to add atomoxetine hydrochloride, so that the taste and stability of the oral solution are improved. DETAILED DESCRIPTION

[0016] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments.

[0017] Example 1: A method for preparing atomoxetine hydrochloride oral solution, the specific steps are as follows: (1) Dissolve 4.5 g of chloroacetic acid in 5 ml of deionized water, then add 8 ml of 7.5 M NaOH solution, and then add 7 g of β-cyclodextrin. Stir at 55 °C for 12 h. After the reaction is completed, adjust the pH to 4.0 with HCl solution, then dialyze with water, and finally precipitate the final solution with acetone. Dry under vacuum at room temperature for 12 h to obtain carboxymethylated β-cyclodextrin. (2) Dissolve 10 g of ethylene glycol chitosan and 20 g of carboxymethylated β-cyclodextrin in 100 ml of deionized water, mix, then add 15 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stir at room temperature at 300 rpm for 1 h, continue stirring for 24 h, then dialyze in distilled water, and freeze-dry to obtain chitosan-β-cyclodextrin inclusion material; (3) dissolving atomoxetine hydrochloride and chitosan-β-cyclodextrin inclusion material in deionized water at room temperature in a weight ratio of 0.9:4, stirring evenly, and freeze-drying at 223 K and 0.03 mbar for 48 h to obtain an atomoxetine hydrochloride inclusion complex; (4) At 40°C, add 5 g of atomoxetine hydrochloride inclusion complex, 0.3 g of sodium benzoate, 16 g of sorbitol, 165 g of xylitol, and 5 g of sucralose to 100 ml of deionized water in sequence, stir to dissolve and disperse evenly, then add 1 g of raspberry essence, stir evenly, adjust the pH to neutral, and dilute to volume with deionized water.

[0018] Example 2: A method for preparing atomoxetine hydrochloride oral solution, the specific steps are as follows: (1) Dissolve 4.8 g of chloroacetic acid in 8 ml of deionized water, then add 9 ml of 7.5 M NaOH solution, and then add 7.5 g of β-cyclodextrin. Stir at 58 °C for 13 h. After the reaction is completed, adjust the pH to 4.0 with HCl solution, then dialyze with water, and finally precipitate the final solution with acetone. Dry under vacuum at room temperature for 12 h to obtain carboxymethylated β-cyclodextrin. (2) Dissolve 10.5 g of ethylene glycol chitosan and 23 g of carboxymethylated β-cyclodextrin in 100 ml of deionized water, mix, then add 18 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stir at room temperature at 300 rpm for 1 h, continue stirring for 24 h, then dialyze in distilled water, and freeze-dry to obtain a chitosan-β-cyclodextrin inclusion material; (3) dissolving atomoxetine hydrochloride and chitosan-β-cyclodextrin inclusion material in deionized water at room temperature in a weight ratio of 1.5:6, stirring evenly, and freeze-drying at 223 K and 0.03 mbar for 48 h to obtain an atomoxetine hydrochloride inclusion complex; (4) At 40°C, add 10 g of atomoxetine hydrochloride inclusion complex, 0.4 g of sodium benzoate, 16 g of sorbitol, 170 g of xylitol, and 8 g of sucralose to 150 ml of deionized water in sequence, stir to dissolve and disperse evenly, then add 1.5 g of raspberry essence, stir evenly, adjust the pH to neutral, and dilute to volume with deionized water.

[0019] Example 3: A method for preparing atomoxetine hydrochloride oral solution, the specific steps are as follows: (1) Dissolve 5 g of chloroacetic acid in 10 ml of deionized water, then add 10 ml of 7.5 M NaOH solution, and then add 8 g of β-cyclodextrin. Stir at 60 °C for 14 h. After the reaction is completed, adjust the pH to 4.0 with HCl solution, then dialyze with water, and finally precipitate the final solution with acetone. Dry under vacuum at room temperature for 12 h to obtain carboxymethylated β-cyclodextrin. (2) Dissolve 11 g of ethylene glycol chitosan and 25 g of carboxymethylated β-cyclodextrin in 100 ml of deionized water, respectively, and mix. Then add 20 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stir at room temperature at 300 rpm for 1 h, continue stirring for 24 h, then dialyze in distilled water, and freeze-dry to obtain a chitosan-β-cyclodextrin inclusion material. (3) dissolving atomoxetine hydrochloride and chitosan-β-cyclodextrin inclusion material in deionized water at room temperature in a weight ratio of 2:9, stirring evenly, and freeze-drying at 223 K and 0.03 mbar for 48 h to obtain an atomoxetine hydrochloride inclusion complex; (4) At 40°C, add 15 g of atomoxetine hydrochloride inclusion complex, 0.5 g of sodium benzoate, 17 g of sorbitol, 170 g of xylitol, and 10 g of sucralose to 200 ml of deionized water in sequence, stir to dissolve and disperse evenly, then add 2 g of raspberry essence, stir evenly, adjust the pH to neutral, and dilute to volume with deionized water.

[0020] Comparative Example 1: A method for preparing atomoxetine hydrochloride oral solution, the specific steps are as follows: (1) At 40°C, add 10 g of atomoxetine hydrochloride, 35 g of chitosan, 5 g of β-cyclodextrin, 0.4 g of sodium benzoate, 16 g of sorbitol, 170 g of xylitol, and 8 g of sucralose to 150 ml of deionized water in sequence, stir to dissolve and disperse evenly, then add 1.5 g of raspberry essence, stir evenly, adjust the pH to neutral, and dilute to volume with deionized water.

[0021] Comparative Example 2: A method for preparing atomoxetine hydrochloride oral solution, the specific steps are as follows: (1) dissolving atomoxetine hydrochloride and β-cyclodextrin inclusion material in deionized water at room temperature in a weight ratio of 1.5:6, stirring evenly, and freeze-drying at 223 K and 0.03 mbar for 48 h to obtain an atomoxetine hydrochloride inclusion complex; (2) At 40°C, add 10 g of atomoxetine hydrochloride inclusion complex, 0.4 g of sodium benzoate, 16 g of sorbitol, 170 g of xylitol, and 8 g of sucralose to 150 ml of deionized water in sequence, stir to dissolve and disperse evenly, then add 1.5 g of raspberry essence, stir evenly, adjust the pH to neutral, and dilute to volume with deionized water.

[0022] Comparative Example 3: A method for preparing atomoxetine hydrochloride oral solution, the specific steps are as follows: (1) At 40°C, add 10 g of atomoxetine hydrochloride, 35 g of chitosan, 0.4 g of sodium benzoate, 16 g of sorbitol, 170 g of xylitol, and 8 g of sucralose to 150 ml of deionized water in sequence, stir to dissolve and disperse evenly, then add 1.5 g of raspberry essence, stir evenly, adjust the pH to neutral, and dilute to volume with deionized water.

[0023] Performance Testing Taste test: 10 subjects were randomly selected to conduct taste tests on the embodiments and comparative examples, and 5 points, 4 points, 3 points, 2 points, and 1 point were given according to the taste. 5 points was the best taste, and 1 point was the worst taste. Whether the aftertaste was bitter was also recorded. The test results are shown in Table 1; Accelerated test: Store at 40℃±2℃ and RH75%±5% for 6 months, then taste test and observe the oral liquid form. The test results are shown in Table 1. Table 1 Performance test results

[0024] Data Analysis: It can be seen from Example 2 and Comparative Example 1 in Table 1 that the oral solution of atomoxetine hydrochloride of the present invention, by adding atomoxetine hydrochloride in the form of an inclusion compound, makes the taste of the oral solution better. This is mainly because the chitosan-cyclodextrin composite material can effectively wrap the atomoxetine hydrochloride and seal the drug in its internal cavity, which not only reduces the chance of the drug directly contacting the oral mucosa, but also reduces the bitterness or other unpleasant taste of the drug itself. The impact on the patient; at the same time, chitosan has good film-forming properties and biocompatibility, and can make the coating material form a protective film on the surface of the drug, slowing down the release rate of the drug, thereby helping to reduce the immediate taste exposure of the drug in the oral cavity, thereby significantly improving the taste; on the other hand, the chitosan-cyclodextrin composite material can effectively wrap the atomoxetine hydrochloride and enhance its solubility in the oral liquid, so that the atomoxetine hydrochloride will not escape after the accelerated test, thereby affecting the taste and morphology of the oral liquid.

[0025] It can be seen from Example 2 and Comparative Examples 2 and 3 in Table 1 that the atomoxetine hydrochloride oral solution of the present invention uses chitosan and β-cyclodextrin as inclusion materials. On the one hand, β-cyclodextrin can play an inclusion role due to its unique structure. At the same time, chitosan itself has good compatibility and film-forming properties. On the one hand, it can further enhance the inclusion effect of atomoxetine hydrochloride. On the other hand, it can make the inclusion material more compatible with the dispersion medium.

[0026] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present invention is limited to these examples. Under the concept of the present invention, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of simplicity.

Claims

1. A method for preparing atomoxetine hydrochloride oral solution, characterized in that: The following steps are involved: At 40°C, add atomoxetine hydrochloride inclusion complex, sodium benzoate, sorbitol, xylitol, and sucralose to deionized water in sequence, stir to dissolve and disperse evenly, then add raspberry essence, stir evenly, adjust the pH to neutral, and dilute to volume with deionized water to obtain the product; The preparation steps of the atomoxetine hydrochloride inclusion compound are as follows: S1: Dissolve chloroacetic acid in deionized water, then add NaOH solution, then add β-cyclodextrin, stir at 55-60°C for 12-14 h, after the reaction is completed, adjust the pH to 4.0 with HCl solution, then dialyze with water, precipitate, and dry to obtain carboxymethylated β-cyclodextrin; S2: Dissolve ethylene glycol chitosan and carboxymethylated β-cyclodextrin in deionized water, respectively, mix, then add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stir at room temperature at 300 rpm for 1 h, continue stirring for 24 h, then dialyze in distilled water, and freeze-dry to obtain chitosan-β-cyclodextrin inclusion material; S3: Dissolve atomoxetine hydrochloride and chitosan-β-cyclodextrin inclusion material in deionized water at room temperature, stir evenly, and freeze-dry at 223 K and 0.03 mbar for 48 h to obtain an atomoxetine hydrochloride inclusion complex.

2. The method for preparing atomoxetine hydrochloride oral solution according to claim 1, characterized in that: The atomoxetine hydrochloride oral solution comprises the following raw materials in parts by weight: 5-15 parts of atomoxetine hydrochloride inclusion compound, 0.3-0.5 parts of sodium benzoate, 16-17 parts of sorbitol, 165-170 parts of xylitol, 5-10 parts of sucralose, 1-2 parts of raspberry essence, and 300-350 parts of deionized water.

3. The method for preparing atomoxetine hydrochloride oral solution according to claim 1, characterized in that: The usage ratio of chloroacetic acid, deionized water, NaOH solution and β-cyclodextrin in step S1 is 4.5-5g:5-10ml:8-10ml:7-8g.

4. The method for preparing atomoxetine hydrochloride oral solution according to claim 1, characterized in that: The concentration of the NaOH solution in step S1 is 7.5M.

5. The method for preparing atomoxetine hydrochloride oral solution according to claim 1, characterized in that: In step S2, the usage ratio of ethylene glycol chitosan, carboxymethylated β-cyclodextrin, deionized water, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloric acid is 10-11 g:20-25 g:100 ml:15-20 g.

6. The method for preparing atomoxetine hydrochloride oral solution according to claim 1, characterized in that: The weight ratio of atomoxetine hydrochloride to chitosan-β-cyclodextrin in step S3 is 0.9-2:4-9.

7. The method for preparing atomoxetine hydrochloride oral solution according to claim 1, characterized in that: The atomoxetine hydrochloride oral solution contains 1-3 g of atomoxetine hydrochloride per 500 ml of the atomoxetine hydrochloride oral solution.

Images