Capsule containing atomoxetine hydrochloride and application thereof

Abstract

The invention relates to the field of medicine, in particular to a capsule containing atomoxetine hydrochloride and application of the capsule. The capsule is composed of atomoxetine hydrochloride, saproturone, sorbitol and pharmaceutically acceptable auxiliary materials, the saproturone is added in the capsule, the stability of atomoxetine hydrochloride is improved, sorbitol in a molten state is utilized, atomoxetine hydrochloride and saproturone are combined to prepare a solid dispersion, and the solid dispersion can be used as a capsule for treating atomoxetine hydrochloride and saproturone. The crystal form of the atomoxil hydrochloride is ensured, and the solubility and the curative effect of the medicine are improved.

Description

Technical Field

[0001] The invention relates to the field of medicine, and in particular to a capsule containing atomoxetine hydrochloride and application thereof. Background Art

[0002] Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that occurs frequently in children. Its main clinical symptoms are inattention, impulsive behavior, and hyperactivity, which persist for a long time and seriously affect children's learning, social interaction, and daily life.

[0003] Atomoxetine hydrochloride is a psychostimulant and a selective norepinephrine reuptake inhibitor used to treat attention deficit / hyperactivity disorder (ADHD) in children and adolescents. It has the advantages of good tolerance, strong selective action, long-term use, no addiction, and few side effects. Atomoxetine hydrochloride has low solubility in water and is a slightly soluble substance. It also tastes bitter and has poor palatability, which affects the compliance of children and adolescents.

[0004] Chinese patent CN112076154A discloses a kind of atomoxetine hydrochloride oral solution and its preparation method, and the atomoxetine hydrochloride oral solution is mainly composed of atomoxetine hydrochloride, preservative, pH adjusting agent, sweetener and mouthfeel improver, wherein the mouthfeel improver is composed of thickener, mint flavor and sweet orange flavor. The mouthfeel improver formed by thickener, mint flavor and sweet orange flavor can significantly improve the mouthfeel of atomoxetine hydrochloride oral solution during taking. The bitter taste when taking and the bitter feeling of the mouth after taking are significantly reduced.

[0005] Chinese patent CN106727291A provides an oral solution of atomoxetine hydrochloride and a preparation method thereof. The invention uses β-cyclodextrin combined with tartaric acid for taste masking to prepare an oral solution of atomoxetine hydrochloride 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, improves the compliance of pediatric patients, and meets the clinical medication needs of children. Chinese Patent

[0006] CN112451476A discloses an oral solution of atomoxetine hydrochloride and a preparation method thereof. The invention also adopts inclusion technology and uses hydroxypropyl-β-cyclodextrin to include the drug, thereby covering up the bad taste of the drug, while also improving the stability of the drug and better improving the compliance of patients with the drug.

[0007] In traditional medicine, trimethoprim is used to prevent and treat a variety of diseases, and modern research has gradually focused on its potential applications in anti-tumor, cardiovascular disease and metabolic syndrome. The structural formula of trimethoprim is as follows:

[0008] Summary of the invention

[0009] Based on the prior art, the present invention provides a capsule containing atomoxetine hydrochloride and application thereof, which solves the problem of ADHD and the problem that atomoxetine hydrochloride and trichlorfon cannot be made into medicine.

[0010] Specifically, the inventors solved the problem through the following technical solutions:

[0011] A capsule containing atomoxetine hydrochloride, which consists of atomoxetine hydrochloride, trichlorfon, sorbitol and pharmaceutically acceptable excipients, wherein the weight ratio of atomoxetine hydrochloride: trichlorfon: sorbitol is 1:0.05-0.15:2-10; the capsule preparation process comprises: adding sorbitol into a melt granulator, heating to 90-100°C in a molten state, adding trichlorfon and atomoxetine hydrochloride, extruding strips, cooling, drying and crushing, controlling the particle size, then adding pharmaceutically acceptable excipients, mixing evenly, filling in a capsule shell, and preparing atomoxetine hydrochloride capsules.

[0012] Further preferably, the weight ratio of atomoxetine hydrochloride: trichlorfon: sorbitol is 1:0.1:6. The particle size control after drying and crushing is: D90 is 40 μm to 49 μm; D50 is 20 μm to 29 μm; D10 is 12 μm to 19 μm;

[0013] More preferably, the particle size is controlled as follows: D90 is 45 μm; D50 is 25 μm; and D10 is 15 μm.

[0014] Further preferably, the pharmaceutically acceptable excipient is selected from one or a combination of fillers, disintegrants, and lubricants. The filler is one or more of mannitol, microcrystalline cellulose, sorbitol, lactose, calcium hydrogen phosphate, sorbitol, compressible starch, starch, and pregelatinized starch; the disintegrant is one or more of sodium carboxymethyl starch, alginic acid, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose; the lubricant is one or more of magnesium stearate, micropowdered silica gel, talc, magnesium aluminum silicate, polyethylene glycol, and sodium stearate fumarate.

[0015] Furthermore, according to the specifications currently on the market, the capsule of the present invention contains 10 mg, 18 mg, 25 mg or 40 mg of atomoxetine hydrochloride.

[0016] Furthermore, the capsule contains 0.5 mg, 1 mg, 1.8 mg, 2.5 mg, 4 mg or 6 mg of trichlorfon.

[0017] In a preferred embodiment of the present invention, the atomoxetine hydrochloride, trichlorfon and sorbitol are composed, wherein the weight ratio of the atomoxetine hydrochloride: trichlorfon: sorbitol is 1:0.1:6; the capsule preparation process is: adding sorbitol to a melt granulator, heating to 90-100°C in a molten state, adding trichlorfon and atomoxetine hydrochloride, extruding strips, cooling, drying and crushing, controlling the particle size D90 to 45μm; D50 to 25μm; D10 to 15μm, then adding pharmaceutically acceptable excipients, mixing evenly, adding microcrystalline cellulose PH101 and magnesium stearate to fill the capsule shell to obtain atomoxetine hydrochloride capsules.

[0018] In a preferred embodiment of the present invention, the amount of atomoxetine hydrochloride, microcrystalline cellulose PH101 and magnesium stearate is 1:1-5:0.01-0.05 calculated by weight ratio.

[0019] In a preferred embodiment of the present invention, the amount of atomoxetine hydrochloride, microcrystalline cellulose PH101 and magnesium stearate is 1:3:0.03 calculated by weight ratio.

[0020] Compared with the prior art, the advantages of the present invention are mainly reflected in the following aspects:

[0021] The capsule of the present invention is used in the preparation of drugs for treating ADHD. The inventors created a method of using trichlorfon together with atomoxetine hydrochloride. Compared with the control group, the total effective rate was higher than that of the control group, indicating that the capsule mixture of the present invention has a significant therapeutic effect compared with atomoxetine hydrochloride alone, and there is a significant difference between the two groups (P<0.05).

[0022] Tomoxetine hydrochloride is sensitive to light and humidity and is easily degraded under adverse environmental conditions. The capsule of the present invention adds trichlorfon to improve the stability of Tomoxetine hydrochloride, and at the same time utilizes sorbitol in a molten state. Tomoxetine hydrochloride is combined with trichlorfon to form a solid dispersion, which ensures the crystal form of Tomoxetine hydrochloride and improves the solubility of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 :Comparison of SNAP-Ⅳ scores between the control group and the observation group.

[0024] Figure 2 : Comparison of ASQ scores between the control group and the observation group.

[0025] Figure 3 :Comparison of YGTSS scores between the control group and the observation group.

[0026] Figure 4 : Comparison of theta wave strength between the control group and the observation group.

[0027] Figure 5 : Comparison of alpha wave strength between the control group and the observation group.

[0028] Figure 6 : Comparison of β wave strength between the control group and the observation group.

[0029] Figure 7 : Comparison of SMR wave strength between the control group and the observation group. DETAILED DESCRIPTION

[0030] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0031] Example 1: A capsule containing atomoxetine hydrochloride

[0032]

[0033] The capsule preparation process is as follows: adding sorbitol into a melt granulator, heating to 90° C. to a molten state, adding trichlorfon and atomoxetine hydrochloride, extruding strips, cooling, drying and crushing, controlling the particle size (D90 is 40 μm; D50 is 20 μm; D10 is 12 μm), then adding pharmaceutically acceptable excipients, mixing evenly, filling in a capsule shell, and preparing atomoxetine hydrochloride capsules.

[0034] Example 2: A capsule containing atomoxetine hydrochloride

[0035]

[0036] The capsule preparation process is as follows: adding sorbitol into a melt granulator, heating to 100° C. to a molten state, adding trichlorfon and atomoxetine hydrochloride, extruding strips, cooling, drying and crushing, controlling the particle size (D90 is 49 μm; D50 is 29 μm; D10 is 19 μm), then adding pharmaceutically acceptable excipients, mixing evenly, filling in a capsule shell, and preparing atomoxetine hydrochloride capsules.

[0037] Example 3: A capsule containing atomoxetine hydrochloride

[0038]

[0039] The capsule preparation process is as follows: adding sorbitol into a melt granulator, heating to 95° C. to a molten state, adding trichlorfon and atomoxetine hydrochloride, extruding strips, cooling, drying and crushing, controlling the particle size (D90 is 45 μm; D50 is 25 μm; D10 is 15 μm), then adding pharmaceutically acceptable excipients, mixing evenly, filling in a capsule shell, and preparing atomoxetine hydrochloride capsules.

[0040] Example 4: A capsule containing atomoxetine hydrochloride

[0041]

[0042] The method for preparing capsules is the same as that in Example 3.

[0043] Example 5: A capsule containing atomoxetine hydrochloride

[0044]

[0045] The method for preparing capsules is the same as that in Example 3.

[0046] Example 6: A capsule containing atomoxetine hydrochloride

[0047]

[0048]

[0049] The method for preparing capsules is the same as that in Example 3.

[0050] Example 7: A capsule containing atomoxetine hydrochloride

[0051] The method for preparing capsules is the same as that in Example 3.

[0052] Example 8: A capsule containing atomoxetine hydrochloride

[0053] The method for preparing capsules is the same as that in Example 3.

[0054] Example 9: A capsule containing atomoxetine hydrochloride

[0055] The method for preparing capsules is the same as that in Example 3.

[0056] Example 10: A capsule containing atomoxetine hydrochloride

[0057] The method for preparing capsules is the same as that in Example 3.

[0058] Example 11: A capsule containing atomoxetine hydrochloride

[0059] The method for preparing capsules is the same as that in Example 3.

[0060] Example 12: A capsule containing atomoxetine hydrochloride

[0061] The method for preparing capsules is the same as that in Example 3.

[0062] Example 13: A capsule containing atomoxetine hydrochloride

[0063] The method for preparing capsules is the same as that in Example 3.

[0064] Example 14: A capsule containing atomoxetine hydrochloride

[0065] The method for preparing capsules is the same as that in Example 3.

[0066] Example 15: A capsule containing atomoxetine hydrochloride

[0067]

[0068] Povidone K30

[0069] The method for preparing capsules is the same as that in Example 3.

[0070] Comparative Example 1:

[0071]

[0072] 1. Physical verification: limitations of related substances and dissolution

[0073] 1.1 Dissolution test: Determine according to the dissolution and release test method (General Rule 0931 Method 1).

[0074] Preparation of test solution: The dissolution conditions are phosphate buffer (take 68.05 g of potassium dihydrogen phosphate, add 56 mL of 1 mol / L sodium hydroxide solution, dilute to 1 L with water, shake well, the pH value should be 6.0±0.05) 900 mL as the dissolution medium, the rotation speed is 75 revolutions per minute, and 10 mL of the dissolution solution is taken at the 10th minute as the test solution.

[0075] Preparation of reference solution: Take about 15 mg of atomoxetine hydrochloride reference substance, accurately weigh it, place it in a 50 mL volumetric flask, add 2 mL of methanol to dissolve it, dilute it to the scale with dissolution medium, and shake well.

[0076] Chromatographic conditions: octadecylsilane bonded silica gel as filler; methanol-acetonitrile-water-phosphoric acid (65:10:25:0.03) as mobile phase; detection wavelength at 225 nm; injection volume 10 μl.

[0077] 1.2 Detection of related substances: Determine according to high performance liquid chromatography (General Rule 0512).

[0078] Preparation of test solution: Take an appropriate amount of 25 mg of the product, place it in a 25 mL volumetric flask, add 20 mL of methanol, ultrasonicate for 15 minutes to dissolve, dilute to the scale with mobile phase, shake well, filter, and take the filtrate.

[0079] Preparation of control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with the mobile phase to make a solution containing approximately 6 μg of atomoxetine hydrochloride per 1 mL.

[0080] Chromatographic conditions: octadecylsilane bonded silica gel as filler; methanol water (54:46) (pH adjusted to 3.0 with phosphoric acid) as mobile phase; detection wavelength 230 nm; injection volume 15 μl.

[0081] 1.3 Under accelerated conditions, the data of 1) and 2) were repeated at the 6th month and the content and solubility of the atomoxetine hydrochloride of each example were measured, as shown in the following Table 1:

[0082] Table 1 Dissolution and related substance test data of each example

[0083]

[0084] As shown in Table 1, the atomoxetine hydrochloride obtained in the present invention has a low content of drug-related substances and a good in vitro dissolution effect.

[0085] 2. Determination of clinical efficacy

[0086] 2.1 General Information

[0087] A total of 108 ADHD patients admitted and screened by Changzhou Children's Hospital from October 2022 to October 2023 were randomly divided into two groups, namely the control group and the observation group. The specific screened cases are as follows:

[0088] The control group included 54 cases, aged 9 to 15 years old, with an average age of (11.12±2.13) years old; the course of disease ranged from 10 to 33 months, with an average course of (24.22±1.96) months.

[0089] There were 54 cases in the observation group, with an age range of 9 to 16 years old, with an average age of (12.59±1.44) years old; the course of disease ranged from 11 to 35 months, with an average course of (25.28±2.28) months.

[0090] There was no significant difference in the above general data between the two groups of patients (P>0.05). The two groups were comparable, and relevant experiments were conducted on this basis.

[0091] 2.2 Inclusion criteria

[0092] On the basis of normal intelligence, physical and nervous systems, the requirements of “2.2.1, 2.2.2 and 2.2.3” are met.

[0093] 2.2.1 Western medicine standards

[0094] It meets the relevant diagnostic criteria for ADHD in the "Recommendations for the Diagnosis and Treatment of Tic Disorders in Children".

[0095] 2.2.2 Traditional Chinese Medicine Standards

[0096] Meet the criteria for kidney deficiency and liver hyperactivity syndrome in the "Guidelines for Clinical Diagnosis and Treatment of Pediatrics in Traditional Chinese Medicine: Tic Disorders (Revised)"

[0097] Main symptoms: distracted mind, inattention, restlessness, impulsiveness and willfulness.

[0098] Secondary symptoms: poor memory, dizziness / headache, dry mouth and throat, irritability, hot flashes in the five parts of the body, restless sleep, enuresis, night sweats, dry stool, red tongue with little fluid, little coating, and thin and rapid or stringy pulse.

[0099] Syndrome differentiation criteria: The diagnosis is established if three main symptoms and four secondary symptoms are present, combined with tongue and pulse.

[0100] 2.2.3 Exclusion criteria

[0101] (1) Developmental disorders and mental illness; (2) Poor compliance; (3) Allergy to the drugs in the study. If any of (1)-(3) is met, the study will be excluded.

[0102] The study was approved by the Medical Ethics Committee of Changzhou Children's Hospital, and the patients' legal guardians signed informed consent.

[0103] 2.3 Treatment methods

[0104] Control group: At the beginning of oral administration of atomoxetine hydrochloride capsules (Zhejiang Huahai Pharmaceutical Co., Ltd., national medicine standard number H20234533, specification: 100mL: 0.4g / piece), the total daily dose of atomoxetine hydrochloride should be about 0.5mg / kg, and the dosage should be increased after 3 days of minimum dosage to the total daily target dose of about 1.2mg / kg, which can be taken once in the morning or divided into 2 doses in the morning and evening.

[0105] Observation group: oral administration of atomoxetine hydrochloride capsules (capsules prepared in Example 1). The dosage of atomoxetine hydrochloride should be about 0.5 mg / kg, and the dosage should be increased after the minimum dosage for 3 days to a total daily target dose of about 1.2 mg / kg, which can be taken once a day in the morning or twice in the morning and evening. All patients continued to take the medication for 3 months.

[0106] 2.4 Observation indicators

[0107] 2.4.1 Symptom score.

[0108] 2.4.1.1 Screening scale for attention deficit hyperactivity disorder (SNAP-IV)

[0109] The questionnaire is filled in by the clinician based on the information provided by the parents, guardians or teachers. For each question, the doctor needs to score between 0 and 3 points based on the answers of the parents, guardians or teachers. 0 points are used for never appearing or rarely appearing; 1 point is used for occasional appearance and no adverse effects on others; 2 points are used for several appearances per week and adverse effects on oneself or others; 3 points are used for at least one appearance per day and a very large impact on oneself or others. If the rater has a hard time choosing between 1 and 2 points, he or she can choose 1 point as the lowest, and finally add up the scores of all questions and divide by all questions to get the total score, which is the score for this time.

[0110] The scoring range is as follows:

[0111] 0 points ≤ indicates normal ≤ 1 point; 1 point < indicates marginal state ≤ 1.5 points; 1.5 points < indicates moderate problems ≤ 2 points, and severe symptoms > 2 points.

[0112] 2.4.1.2 Conner's Brief Symptom Questionnaire (ASQ)

[0113] The 10 items are scored using a four-level scoring method of 0, 1, 2, and 3 points. If the total score exceeds 15 points, it is considered that there is a possibility of ADHD.

[0114] 2.4.1.3 Yale Comprehensive Tic Severity Scale (YGTSS) Scoring Criteria

[0115] It includes motor tics and vocal tics, with a total score of 100 points. The higher the score, the more severe the tic symptoms.

[0116] 2.4.2 Brain waves.

[0117] The abnormal activities of theta waves, alpha waves, beta waves, and SMR waves in the EEG of ADHD patients are due to the dysfunction of their brain neural network. Specifically, theta wave activity is enhanced, reflecting excessive resting state or distraction; the weakening of alpha waves indicates a disordered arousal level, affecting information processing efficiency; the weakening or instability of beta waves is related to difficulty in maintaining attention and impulsive behavior; and the weakening of SMR waves indicates motor control defects.

[0118] The equipment and system used were an EEG signal acquisition system compatible with PPB dry and wet electrodes (Shanghai Xingzhou Digital Technology Co., Ltd.), and the EEG waves (θ wave, α wave, β wave, SMR wave) of the two groups of patients were tested before and after treatment.

[0119] 2.5 Statistical methods

[0120] GraphPad Prism 6 statistical software was used to analyze the data. The measurement data were confirmed to be normally distributed by SW test and expressed as (X±s). The independent sample t test was used for comparison between groups, and the paired t test was used for comparison before and after treatment. The count data were expressed as X. 2 P<0.05 was considered statistically significant.

[0121] 2.6 Results

[0122] 2.6.1 Comparison of symptom scores between the two groups

[0123] Compared with before treatment, the symptom scores (SNAP-Ⅳ, ASQ, and YGTSS scores) of the two groups of patients decreased after treatment, and the observation group was lower than the control group, with significant differences (all P<0.05). Figure 1-3 .

[0124] Figure 1 : Comparison of SNAP-Ⅳ scores between the control group and the observation group, ** represents that the control group has a significant difference compared with before treatment (P<0.01); @@ represents that the observation group has a significant difference compared with before treatment (P<0.01); ## represents that the observation group has a significant difference compared with the control group (P<0.01).

[0125] Figure 2 : Comparison of ASQ scores between the control group and the observation group, ** represents that the control group has a significant difference compared with before treatment (P<0.01); @@ represents that the observation group has a significant difference compared with before treatment (P<0.01); ## represents that the observation group has a significant difference compared with the control group (P<0.01).

[0126] Figure 3: Comparison of YGTSS scores between the control group and the observation group, ** represents that the control group has a significant difference compared with before treatment (P<0.01); @@ represents that the observation group has a significant difference compared with before treatment (P<0.01); ## represents that the observation group has a significant difference compared with the control group (P<0.01).

[0127] 2.6.2 Comparison of EEG between the two groups of patients

[0128] Compared with before treatment, the θ wave of both groups was weakened after treatment, and it was weaker in the observation group than in the control group; α wave, β wave and SMR wave were all enhanced, and they were stronger in the observation group than in the control group, with significant differences (all P<0.05). Figure 4-7 .

[0129] Figure 4 : Comparison of theta wave strength between the control group and the observation group, ** represents that the control group has a significant difference compared with before treatment (P<0.01); @@ represents that the observation group has a significant difference compared with before treatment (P<0.01); ## represents that the observation group has a significant difference compared with the control group (P<0.01).

[0130] Figure 5 : Comparison of alpha wave strength between the control group and the observation group, ** represents that the control group has a significant difference compared with before treatment (P<0.01); @@ represents that the observation group has a significant difference compared with before treatment (P<0.01); ## represents that the observation group has a significant difference compared with the control group (P<0.01).

[0131] Figure 6 : Comparison of β wave strength between the control group and the observation group, ** represents that the control group has a significant difference compared with before treatment (P<0.01); @@ represents that the observation group has a significant difference compared with before treatment (P<0.01); ## represents that the observation group has a significant difference compared with the control group (P<0.01).

[0132] Figure 7 : Comparison of SMR wave strength between the control group and the observation group, ** represents that the control group has a significant difference compared with before treatment (P<0.01); @@ represents that the observation group has a significant difference compared with before treatment (P<0.01); ## represents that the observation group has a significant difference compared with the control group (P<0.01).

[0133] 2.6.3 Comparison of treatment conditions

[0134] Table 1 Comparison of treatment between the control group and the observation group

[0135]

[0136] It can be seen that the total effective rate is higher than that of the control group, which indicates that the combined medication of the present invention has a significant therapeutic effect compared with the use of atomoxetine hydrochloride alone.

Claims

1. A capsule containing atomoxetine hydrochloride, characterized in that: The capsule is composed of atomoxetine hydrochloride, trichlorfon, sorbitol and pharmaceutically acceptable excipients, wherein the weight ratio of atomoxetine hydrochloride: trichlorfon: sorbitol is 1:0.05-0.15:2-10; the capsule preparation process is: adding sorbitol into a melt granulator, heating to a molten state of 90-100°C, adding trichlorfon and atomoxetine hydrochloride, extruding strips, cooling and drying and crushing, controlling the particle size, then adding pharmaceutically acceptable excipients, mixing evenly, filling in a capsule shell, and preparing atomoxetine hydrochloride capsules.

2. The capsule according to claim 1, characterized in that The weight ratio of atomoxetine hydrochloride: trichlorfon: sorbitol is 1:0.1:6; the particle sizes are: D90 is 40 μm to 49 μm; D50 is 20 μm to 29 μm; and D10 is 12 μm to 19 μm.

3. The capsule according to claim 1, characterized in that The particle size is: D90 is 45μm; D50 is 25μm; D10 is 15μm.

4. The capsule according to claim 1, characterized in that The pharmaceutically acceptable excipient is selected from one or a combination of fillers, disintegrants and lubricants.

5. The capsule according to claim 4, characterized in that The filler is one or more of mannitol, microcrystalline cellulose, sorbitol, lactose, calcium hydrogen phosphate, sorbitol, compressible starch, starch, and pregelatinized starch; the disintegrant is one or more of sodium carboxymethyl starch, alginic acid, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose; the lubricant is one or more of magnesium stearate, micropowder silica gel, talc, magnesium aluminum silicate, polyethylene glycol, and sodium stearyl fumarate.

6. The capsule according to claim 4, characterized in that The capsule contains 10 mg, 18 mg, 25 mg or 40 mg of atomoxetine hydrochloride.

7. The capsule according to claim 4, characterized in that The capsule contains 0.5 mg, 1 mg, 1.8 mg, 2.5 mg, 4 mg or 6 mg of trichlorfon.

8. A capsule containing atomoxetine hydrochloride, characterized in that: The capsule is composed of atomoxetine hydrochloride, trichlorfon and sorbitol, wherein the weight ratio of atomoxetine hydrochloride: trichlorfon: sorbitol is 1:0.1:6; the capsule preparation process is as follows: sorbitol is added into a melt granulator, heated to 90-100°C in a molten state, trichlorfon and atomoxetine hydrochloride are added, strips are extruded and cooled, and the particle size D90 of the dried and crushed material is 45 μm, D50 is 25 μm, and D10 is 15 μm, then pharmaceutically acceptable excipients are added, mixed evenly, microcrystalline cellulose PH101 and magnesium stearate are added and filled into a capsule shell to prepare atomoxetine hydrochloride capsules.

9. The capsule according to claim 8, characterized in that Calculated by weight ratio, the amounts of atomoxetine hydrochloride, microcrystalline cellulose PH101 and magnesium stearate are 1:1-5:0.01-0.

05.

10. The capsule according to claim 8, characterized in that Calculated by weight ratio, the amount of atomoxetine hydrochloride, microcrystalline cellulose PH101 and magnesium stearate is 1:3:0.03.

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