Tomoxetine hydrochloride oral preparation

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an atomoxetine hydrochloride oral preparation. The atomoxetine hydrochloride oral preparation is an orally disintegrating tablet and comprises atomoxetine hydrochloride, a coating material and other pharmaceutically acceptable auxiliary materials, and the coating material is glyceryl distearate and chitosan. The atomoxetine hydrochloride is coated by heat generated by high-speed rotation of blades of the crusher and a hot melt coating material generated by friction among particles, so that the atomoxetine hydrochloride coating device is convenient and rapid, simple in process and low in energy consumption. The prepared atomoxetine hydrochloride orally disintegrating tablet is good in taste and high in stability and content uniformity.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and specifically relates to an oral formulation of atomoxetine hydrochloride. Background Technology

[0002] Atomoxetine hydrochloride is a selective norepinephrine reuptake inhibitor used to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents. The chemical name of atomoxetine hydrochloride is (-)-N-methyl-3-phenyl-3-(O-tolyloxy)propylamine hydrochloride, and its molecular formula is C2. 19 H 18 ClN3O5S, molecular weight: 435.89, its structural formula is as follows:

[0003]

[0004] Atomoxetine hydrochloride is slightly soluble in water, soluble in ethanol, and readily soluble in methanol. Currently, the only available dosage forms of atomoxetine hydrochloride in China are capsules and oral solutions. Due to its strong bitter taste, there are no other oral dosage forms available. Given that the target audience for atomoxetine hydrochloride is primarily adolescents, the gelatin capsules pose a risk of swallowing difficulties and choking, while the oral solutions have the drawback of inaccurate dosage. There is an urgent need for other dosage forms to fill the gaps in the existing oral medication options, in order to better cater to different populations, especially improving medication adherence in children.

[0005] Most existing patents for atomoxetine hydrochloride involve solutions. EP3003384, CN106727291B, CN115317445A, CN115721634B, and CN115778895A adjust the taste of the solution by adding different kinds of flavorings, sweeteners, and pH adjusters to increase palatability. However, oral solutions have a large number and variety of additives, which poses a risk of increased related substances.

[0006] CN115089549B addresses the taste issue of atomoxetine hydrochloride by encapsulating it with liposomes and then freeze-drying it to create a formulation. However, the addition of organic solvents chloroform and ethanol during liposome preparation raises safety concerns. Furthermore, the complex processes of liposome preparation and freeze-drying pose a risk of drug leakage. US20060057199A1 discloses an orally disintegrating tablet of atomoxetine hydrochloride, comprising rapidly dispersible microparticles, a taste-masking layer, and a TPR layer, which is a timed pulse release and cannot achieve rapid release; ZL201711379236.0 effectively masks the bitterness of atomoxetine through the inclusion of β-cyclodextrin and the flavoring of sorbitol, but β-cyclodextrin has low solubility in water, only 1.85% at room temperature, and the solubility increases with increasing temperature. The preparation process requires a certain temperature to completely dissolve β-cyclodextrin, but the risk of precipitation increases with decreasing temperature, which poses a certain risk to the stability of the solution; KR20130076529A discloses a chewable tablet of atomoxetine hydrochloride, which effectively masks the bitterness by adding hydrophilic and anionic polymers and dissolves rapidly in the mouth, improving the aftertaste and increasing patient compliance. However, it usually cannot completely dissolve in acidic media such as gastric juice, thus reducing the bioavailability of the drug.

[0007] Therefore, there is a need for an oral formulation of atomoxetine hydrochloride that can effectively mask the bitterness of atomoxetine, achieve complete dissolution in the stomach, and have good stability and uniformity of content. Summary of the Invention

[0008] In view of the shortcomings of the prior art, the purpose of this invention is to provide an oral formulation of atomoxetine hydrochloride and its preparation process. The oral formulation of atomoxetine hydrochloride provided by this invention effectively solves the problem of the drug's high bitterness while maintaining high drug content uniformity and good stability.

[0009] The inventors first attempted to melt the lipid excipients in a water bath and then coat atomoxetine hydrochloride using a fluidized bed. However, it was very difficult to effectively maintain the temperature during the lipid excipient delivery pipeline / nozzle transfer process. After partial melting, the matrix became viscous and difficult to disperse upon cooling, making further processing impossible. The inventors then tried adding atomoxetine hydrochloride to the lipid excipient melt, stirring it evenly to obtain a suspension melt, and adding the remaining pharmaceutical excipients to the above suspension melt, stirring and granulating to obtain preliminary granules. The taste was somewhat improved, but the prepared granules were uneven in size, making it difficult to ensure the uniformity of granule content, and the tableting process was prone to stratification.

[0010] The inventors considered adding lipid excipients and atomoxetine hydrochloride to a high-speed grinder, controlling the stirring and shearing speed and time, and then using the heat generated by the high-speed rotation of the grinder blades and the heat-melting coating material generated by inter-particle friction to coat the atomoxetine hydrochloride, thus preparing uniformly sized coated particles. However, the resulting particles dissolved slowly and could not achieve rapid and complete dissolution. After extensive experiments, the inventors selected a mixture of distearate and chitosan as the coating carrier, which can prepare uniformly sized, highly fluid atomoxetine hydrochloride coated particles, significantly reducing the bitterness of the drug while improving dissolution.

[0011] Specifically, the objective of this invention is achieved through the following technical solution:

[0012] An oral formulation of atomoxetine hydrochloride includes atomoxetine hydrochloride, a coating material, and other pharmaceutically acceptable excipients.

[0013] The coating material is glyceryl distearate.

[0014] Preferably, the coating material further includes chitosan.

[0015] More preferably, the ratio of atomoxetine hydrochloride, glyceryl distearate, and chitosan is 1:1-1.5:0.1-0.25.

[0016] In a preferred embodiment, the ratio of atomoxetine hydrochloride, glyceryl distearate, and chitosan is 1:1.25:0.2.

[0017] Other pharmaceutically acceptable excipients include fillers, lubricants, disintegrants, and flavoring agents.

[0018] Preferably, the filler is one or two of lactose, mannitol, microcrystalline cellulose, and pregelatinized starch.

[0019] More preferably, the filler is lactose.

[0020] Preferably, the disintegrant is one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0021] More preferably, the disintegrant is crospovidone.

[0022] More preferably, the ratio of atomoxetine hydrochloride to disintegrant is 40:15-30.

[0023] Preferably, the lubricant is one or more of magnesium stearate, sodium stearate fumarate, and talc.

[0024] More preferably, the lubricant is magnesium stearate.

[0025] Preferably, the flavoring agent is one or more of sucralose, neotame, monosodium glutamate, and menthol.

[0026] More preferably, the flavoring agent is neotame.

[0027] Preferably, the ratio of atomoxetine hydrochloride to filler, flavoring agent and lubricant is 40:120-180:1-5:1-4.

[0028] The oral preparation is an orally disintegrating tablet.

[0029] In a preferred embodiment, the oral formulation of atomoxetine hydrochloride contains the following components in parts by weight:

[0030]

[0031] This invention also provides a preparation process for an oral formulation of atomoxetine hydrochloride, comprising the following steps: atomoxetine hydrochloride and coating material are mixed evenly and then added to a high-speed traditional Chinese medicine pulverizer. The heat generated by the high-speed rotation of the pulverizer blades and the heat generated by the friction between particles melt the coating material to coat the atomoxetine hydrochloride. The granules are then sieved through a 30-mesh sieve. Other pharmaceutically acceptable excipients are then added, mixed evenly, and tableted to obtain the final product.

[0032] The high-speed Chinese medicine pulverizer has a rotation speed of 20,000-25,000 rpm and a pulverization and coating time of 1-3 minutes.

[0033] Preferably, the high-speed Chinese medicine pulverizer has a rotation speed of 25,000 rpm and a pulverization and coating time of 2 minutes.

[0034] Regarding the speed of the pulverizer, when pulverizing and coating at a speed of 10,000 rpm, the coating is uneven and it is impossible to form coated particles of uniform size.

[0035] Compared with existing technologies, the atomoxetine hydrochloride oral formulation of the present invention not only effectively masks the bitter taste of the drug, but also disintegrates rapidly, has good stability, and good content uniformity. At the same time, the atomoxetine hydrochloride is coated with a coating material generated by the high-speed rotation of the blades during the high-speed shearing process of the traditional Chinese medicine pulverizer and the heat generated by the friction between particles. Compared with traditional melt coating technology, the coating process is convenient, quick, simple, and has low energy consumption. Detailed Implementation

[0036] The present invention will be further described below through specific embodiments. It should be understood that the embodiments of the present invention are merely illustrative and not intended to limit the invention. Therefore, any simple modifications to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0037] All raw materials and reagents used in the examples were commercially available. High-speed Chinese medicine pulverizer 1: YF-150B, speed 25000 rpm; High-speed pulverizer 2: FW80, speed 10000 rpm.

[0038] Example 1

[0039]

[0040] After mixing the prescribed amounts of atomoxetine hydrochloride, glyceryl distearate, and chitosan evenly, add them to a high-speed Chinese medicine pulverizer. The pulverizer rotates at 25,000 rpm and is turned off after running for 1 minute. The granules are then sieved through a 30-mesh sieve to obtain atomoxetine hydrochloride coated granules. Then, the prescribed amounts of lactose, crospovidone, neotame, and magnesium stearate are added, mixed evenly, and compressed into tablets to obtain the final product.

[0041] Example 2

[0042]

[0043]

[0044] After mixing the prescribed amounts of atomoxetine hydrochloride, glyceryl distearate, and chitosan evenly, add them to a high-speed Chinese medicine pulverizer. The pulverizer rotates at 25,000 rpm and runs for 2 minutes before being turned off. The granules are then sieved through a 30-mesh sieve to obtain atomoxetine hydrochloride coated granules. Then, the prescribed amounts of microcrystalline cellulose, low-substituted hydroxypropyl cellulose, menthol, and magnesium stearate are added, mixed evenly, and compressed into tablets to obtain the final product.

[0045] Example 3

[0046]

[0047] After mixing the prescribed amounts of atomoxetine hydrochloride, glyceryl distearate, and chitosan evenly, add them to a high-speed Chinese medicine pulverizer. The pulverizer rotates at 25,000 rpm and runs for 3 minutes before being turned off. The granules are then sieved through a 30-mesh sieve to obtain atomoxetine hydrochloride coated granules. Then, add the prescribed amounts of mannitol, crospovidone, sucralose, and sodium stearate fumarate, mix evenly, and compress into tablets to obtain the final product.

[0048] Example 4

[0049]

[0050] After mixing the prescribed amounts of atomoxetine hydrochloride, glyceryl distearate, and chitosan evenly, add them to a high-speed Chinese medicine pulverizer. The pulverizer rotates at 10,000 rpm and runs for 2 minutes before being turned off. The granules are then sieved through a 30-mesh sieve to obtain atomoxetine hydrochloride coated granules. Then, the prescribed amounts of lactose, crospovidone, neotame, and magnesium stearate are added, mixed evenly, and compressed into tablets to obtain the final product.

[0051] Example 5

[0052]

[0053] After mixing the prescribed amounts of atomoxetine hydrochloride, glyceryl monostearate, and chitosan evenly, add them to a high-speed Chinese medicine pulverizer. The pulverizer rotates at 25,000 rpm and runs for 2 minutes before being turned off. The granules are then sieved through a 30-mesh sieve to obtain atomoxetine hydrochloride coated granules. Then, the prescribed amounts of lactose, crospovidone, neotame, and magnesium stearate are added, mixed evenly, and compressed into tablets to obtain the final product.

[0054] Example 6

[0055]

[0056] After mixing the prescribed amounts of atomoxetine hydrochloride and distearate evenly, add them to a high-speed Chinese medicine pulverizer. The pulverizer rotates at 25,000 rpm and runs for 2 minutes before being turned off. The granules are then sieved through a 30-mesh sieve to obtain atomoxetine hydrochloride coated granules. Then, add the prescribed amounts of lactose, crospovidone, neotame, and magnesium stearate, mix evenly, and compress into tablets to obtain the final product.

[0057] Example 7

[0058]

[0059]

[0060] After mixing the prescribed amounts of atomoxetine hydrochloride, glyceryl distearate, and chitosan evenly, add them to a high-speed Chinese medicine pulverizer. The pulverizer rotates at 25,000 rpm and runs for 2 minutes before being turned off. The granules are then sieved through a 30-mesh sieve to obtain atomoxetine hydrochloride coated granules. Then, the prescribed amounts of lactose, crospovidone, neotame, and magnesium stearate are added, mixed evenly, and compressed into tablets to obtain the final product.

[0061] Example 8

[0062]

[0063] After mixing the prescribed amount of atomoxetine hydrochloride and chitosan evenly, add them to a high-speed Chinese medicine pulverizer. The pulverizer rotates at 25,000 rpm and runs for 2 minutes before being turned off. The granules are then sieved through a 30-mesh sieve to obtain atomoxetine hydrochloride coated granules. Then, the prescribed amounts of lactose, crospovidone, neotame, and magnesium stearate are added, mixed evenly, and compressed into tablets to obtain the final product.

[0064] Example 9

[0065]

[0066] After mixing the prescribed amount of distearate and chitosan evenly, heat and melt them. Then, add atomoxetine hydrochloride to the melt and stir evenly. Add the resulting suspension to a mixture of lactose and crospovidone, stir and granulate. Finally, add neotame and magnesium stearate, mix, and compress into tablets to obtain the final product.

[0067] Example 10

[0068]

[0069]

[0070] After mixing the prescribed amounts of atomoxetine hydrochloride, glyceryl distearate, and chitosan evenly, add them to a high-speed Chinese medicine pulverizer. The pulverizer rotates at 25,000 rpm and runs for 2 minutes before being turned off. The pulverizer is then sieved through a 30-mesh sieve to form granules. Then, the prescribed amounts of lactose, low-substituted hydroxypropyl cellulose, neotame, and magnesium stearate are added, mixed evenly, and compressed into tablets to obtain the final product.

[0071] Comparative Example 1

[0072]

[0073] Accurately weigh the prescribed amounts of atomoxetine hydrochloride and β-cyclodextrin, grind them thoroughly in a mortar, pass them through a 60-mesh sieve, and then put them back into the mortar. Moisten them with the minimum volume of ethanol / water (volume 1:1) mixture, knead them with a pestle for 40 minutes to form a paste, vacuum dry them at room temperature, and pass them through a 60-mesh sieve to obtain the complex of atomoxetine hydrochloride and β-cyclodextrin. Then, add the other excipients in the prescribed amounts in sequence, mix them evenly, and compress them into tablets to obtain the final product.

[0074] Comparative Example 2

[0075]

[0076]

[0077] The prescribed amounts of atomoxetine hydrochloride, gellan gum, and crospovidone I were sieved through a 20-mesh sieve and then added to a wet granulator and mixed for 5 minutes. An appropriate amount of 96% ethanol was added to the powder mixture, and wet granulation was performed. The resulting granules were sieved through a 20-mesh sieve and dried in an oven at 50°C for approximately 1 hour. The dried granules were mixed with mannitol 200, crospovidone II, aspartame, and white chocolate flavoring, and sieved through a 20-mesh sieve. The sieved powder mixture was then mixed in a cubic mixer at 12 rpm for 10 minutes. Magnesium stearate was sieved through a 40-mesh sieve and added to the powder mixture, stirred at 12 rpm for 3 minutes, and then compressed into tablets using an 8 mm round punch.

[0078] Comparative Example 3

[0079]

[0080] The prescribed amounts of atomoxetine hydrochloride, microcrystalline cellulose, and PVP K-30 were mixed in a granulator for 5 minutes, granulated with water, dried, and then passed through a 60-mesh sieve for granulation. The dried granules were spray-granulated with a solution of Eudragit EPO and talc 1 (solvent 60:40 isopropanol:acetone, Eudragit EPO and talc 1 ratio 25% w / w). Then, the other excipients in the prescription were added in sequence, mixed evenly, and then compressed into tablets to obtain the final product.

[0081] Comparative Example 4

[0082]

[0083]

[0084] The prescribed amounts of atomoxetine hydrochloride, fenugreek seed mucilage powder, mannitol, microcrystalline cellulose, magnesium stearate, and talc are mixed evenly and then directly compressed into tablets to obtain the final product.

[0085] Verification of Examples

[0086] 1. Bitterness evaluation

[0087] Ten healthy volunteers rinsed their mouths with saline solution, then each held one orally disintegrating tablet in their mouth until it completely disintegrated. They spat out the remaining powder, rinsed their mouths with saline solution again, and the taste was recorded for each volunteer. The bitterness was rated from 1 to 4, with 1 representing a slightly sweet taste that was acceptable, 2 representing almost no bitterness, 3 representing a slightly bitter taste that was acceptable, and 4 representing a very bitter taste that was unbearable.

[0088] Table 1 Taste Evaluation Results

[0089]

[0090]

[0091] 2. Disintegration time limit check

[0092] The disintegration time limit test method for orally disintegrating tablets was performed in accordance with the 2020 edition of the Chinese Pharmacopoeia (General Chapter 0921).

[0093] Take one tablet of the example or comparative product and test it in an oral disintegration tablet disintegration apparatus. It should completely disintegrate and pass through the sieve within 60 seconds. If a small amount of light matter floats to the top or adheres to the inner wall of the stainless steel tube or the sieve, but there is no hard core, it can be considered compliant. Repeat the test on 6 tablets, and all of them should comply with the requirements. If one tablet does not comply with the requirements, take another 6 tablets for retesting, and all of them should comply with the requirements.

[0094] Table 2 Results of Disintegration Time Measurement

[0095] prescription Disintegration Time Example 1 Completely disintegrates in 10-15 seconds Example 2 Completely disintegrates in 10-15 seconds Example 3 Completely disintegrates in 10-15 seconds Example 4 Completely disintegrates in 10-15 seconds Example 5 Completely disintegrates in 10-15 seconds Example 6 Completely disintegrates in 20-30 seconds Example 7 Completely disintegrates in 15-25 seconds Example 8 Completely disintegrates in 10-15 seconds Example 9 Completely disintegrates in 10-15 seconds Example 10 Completely disintegrates in 30-45 seconds Comparative Example 1 Completely disintegrates in 15-20 seconds Comparative Example 2 Completely disintegrates in 10-15 seconds Comparative Example 3 Completely disintegrated in 160-170 seconds Comparative Example 4 Completely disintegrates in 10-15 seconds

[0096] 3. Examination of content uniformity

[0097] The content uniformity (A+2.2S) was determined according to the content uniformity test method in Part IV of the 2020 edition of the Chinese Pharmacopoeia (0941).

[0098] Take 10 tablets to be tested, place each tablet in a volumetric flask, add an appropriate amount of mobile phase, let stand for 10 minutes, shake for 20 minutes, dilute to the mark with mobile phase to prepare a solution containing approximately 0.1 mg of atomoxetine (free base) per 1 ml, shake well, filter through a 0.45 μm filter membrane, and take the filtrate as the test solution (dilute if necessary). Determine the chromatographic conditions as follows, and it should meet the requirements (Chinese Pharmacopoeia 2020 Edition, Part II, Appendix XE).

[0099] Chromatographic conditions: Octylsilane-bonded silica gel (Zorbax SB-C8, 150×4.6mm, 3.5μm) was used as the stationary phase; potassium dihydrogen phosphate buffer (4.9g sodium decanesulfonate and 6.9g potassium dihydrogen phosphate dissolved in 1000ml water, pH adjusted to 3.1 with phosphoric acid)-acetonitrile (59:41) was used as the mobile phase; the detection wavelength was 215nm; the column temperature was 30℃. The resolution test: The resolution between the main peak and the N-amino compound peak in the chromatogram of the solution should be greater than 2.3.

[0100] 4. Stability test

[0101] Samples from the examples and comparative examples were placed in sealed containers at 40℃±2℃ and 75%±5% relative humidity for 6 months for accelerated testing. Samples were taken on day 0 to investigate the related substances and dissolution of each sample. Samples were taken at the end of 6 months to investigate the related substances and dissolution of each sample.

[0102] 4.1 Related substances

[0103] The determination was performed using high-performance liquid chromatography (HPLC). Chromatographic conditions and system suitability tests were conducted using octylsilane-bonded silica gel as the stationary phase (Zorbax SB-C8, 150×4.6 mm, 3.5 μm column); the mobile phase was potassium dihydrogen phosphate buffer (4.9 g sodium decanesulfonate and 6.9 g potassium dihydrogen phosphate dissolved in 1000 ml of water, with pH adjusted to 3.1 with phosphoric acid)-acetonitrile (59:41); the detection wavelength was 215 nm; and the column temperature was 30 °C. For the limit of quantitation (LOQ) solution, the main peak should be quantitatively detectable in the chromatogram. For the resolution test, the resolution between the main peak and the N-amino compound peak in the chromatogram of the solution should be greater than 2.3.

[0104] Take an appropriate amount of the contents of this product (not less than 5 tablets), place it in a volumetric flask, add an appropriate amount of mobile phase, shake vigorously for 15 minutes, dilute to the mark with mobile phase to prepare a solution containing approximately 1 mg of atomoxetine (free base) per ml. Filter through a 0.45 μm filter membrane and use the filtrate as the test solution (dilute if necessary). Accurately weigh an appropriate amount of atomoxetine hydrochloride reference standard, dissolve it in mobile phase to prepare a solution containing approximately 0.0001 mg of atomoxetine per ml, as the limit of quantitation solution. Separately weigh approximately 30 mg each of atomoxetine hydrochloride reference standard and urea, place them in the same 25 ml volumetric flask, add 5 ml of water, sonicate for 3 minutes, place in an 88.0℃ incubator for 30–40 minutes to generate N-amino compounds, remove, cool, and dilute to the mark with mobile phase to prepare the resolution test solution. Accurately measure 10 μl of each of the above solutions and inject them separately into the liquid chromatograph, and record the chromatograms. Impurity content is calculated based on peak area using the normalization method, excluding chromatographic peaks with a retention time less than 4 minutes. In the chromatogram of the test solution, the peak area of ​​impurities with a relative retention time of 1.00 for atomoxetine and a relative retention time of approximately 0.76 must not exceed 0.3% of the total peak area; the peak areas of all other impurities must not exceed 0.2% of the total peak area; and the total impurity peak area must not exceed 1.0% of the total peak area.

[0105] 4.2 Dissolution

[0106] Take the orally disintegrating tablets from Example 1 and the orally disintegrating tablets from Comparative Example 1 (which showed superior overall performance in terms of taste, stability, and content uniformity), and perform dissolution testing according to the method described in the 2020 edition of the Chinese Pharmacopoeia, Part II, Appendix XC, Method II). Use 1000 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium and a rotation speed of 50 rpm. After 5 and 10 minutes, take 10 ml of the solution, filter it through a 0.45 μm filter membrane, and use the filtrate as the test solution. Separately, accurately weigh approximately 11.5 mg of atomoxetine hydrochloride reference standard, place it in a 100 ml volumetric flask, dissolve and dilute to the mark with the dissolution medium to prepare the reference standard stock solution. Accurately measure 10 ml of the reference standard stock solution, place it in a 25 ml volumetric flask, dilute to the mark with the dissolution medium, and mix well to prepare the reference solution for the sample. Perform the determination under the chromatographic conditions specified in the Assay section. Calculate the dissolution amount per tablet by peak area using the external standard method. Multiply the result by 0.875. The limit is 80% of the labeled amount, and it should comply with the regulations.

[0107] Table 3 Results of stability and content uniformity tests

[0108]

[0109] Table 4 Dissolution test results

[0110]

[0111]

[0112] The test results in Tables 1-4 show that the orally disintegrating tablets obtained in this application, using glyceryl distearate and chitosan as coating materials and crospovidone as a disintegrant, effectively improve the bitterness of the drug, exhibit rapid disintegration, good stability and content uniformity, and can be completely dissolved within 10 minutes. While chitosan as a carrier material also achieves rapid disintegration and dissolution, the improvement in taste is not significant, and the content uniformity and stability are inferior to those of this application. Comparative Example 1 shows good overall taste, stability, and content uniformity of the orally disintegrating tablets, but dissolution is relatively slow. Comparative Example 2, which uses gellan gum as a wet granulation agent, improves the taste but has poor content uniformity. Comparative Example 3, with Eudragit EPO as the coating material, results in slow disintegration. Comparative Example 4, using fenugreek seed mucilage powder as a natural super-disintegrant, disintegrates rapidly, but its taste and stability need improvement.

Claims

1. An oral formulation of atomoxetine hydrochloride, characterized in that, This includes atomoxetine hydrochloride, coating materials, and other pharmaceutically acceptable excipients.

2. The atomoxetine hydrochloride oral formulation as described in claim 1, characterized in that, The coating material is glyceryl distearate.

3. The oral formulation of atomoxetine hydrochloride as described in claim 2, characterized in that, The coating material also includes chitosan.

4. The oral formulation of atomoxetine hydrochloride as described in claim 3, characterized in that, The ratio of atomoxetine hydrochloride, glyceryl distearate, and chitosan is 1:1-1.5:0.1-0.25; preferably 1:1.25:0.

2.

5. The oral formulation of atomoxetine hydrochloride as described in claim 1, characterized in that, Other pharmaceutically acceptable excipients include fillers, lubricants, disintegrants, and flavoring agents.

6. The oral formulation of atomoxetine hydrochloride as described in claim 5, characterized in that, The disintegrant is one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; crospovidone is preferred.

7. The oral formulation of atomoxetine hydrochloride as described in claim 1, characterized in that, The oral preparation is an orally disintegrating tablet.

8. The preparation process of the oral formulation of atomoxetine hydrochloride according to any one of claims 1-7, characterized in that, The process includes the following steps: After mixing atomoxetine hydrochloride and coating material evenly, the mixture is added to a high-speed Chinese medicine pulverizer. The heat generated by the high-speed rotation of the pulverizer blades and the heat generated by the friction between particles melts the coating material to coat atomoxetine hydrochloride. The granules are then sieved through a 30-mesh sieve. Other pharmaceutically acceptable excipients are then added, mixed evenly, and compressed into tablets to obtain the final product.

9. The preparation method according to claim 8, characterized in that, The high-speed Chinese medicine pulverizer has a rotation speed of 20,000-25,000 rpm and a pulverization and coating time of 1-3 minutes.

10. The preparation method according to claim 9, characterized in that, The high-speed Chinese medicine pulverizer has a rotation speed of 25,000 rpm and a pulverization and coating time of 2 minutes.

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