Vesloxin hydrochloride sustained-release tablet and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a vinloxin hydrochloride sustained-release tablet and a preparation method thereof. The tablet mainly comprises the following raw materials: a framework material, a filling agent, a lubricating agent and coating powder. The preparation process is simple, the production reproducibility is better, the product is slowly and uniformly released, the burst release phenomenon is avoided, the product is safe and non-toxic, the prepared product is good in stability, and the quality is easy to control.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and relates to viloxazine hydrochloride sustained-release tablets and a preparation method thereof. Background Art

[0002] Viloxacin hydrochloride, chemical name is 2-[(2-ethoxyphenoxy)methyl]morpholine hydrochloride, the structural formula is as follows:

[0003] English name: (±)-2-[(2-ethoxyphenoxy)methyl]morpholine hydrochloride It is a white to off-white powder with a CAS number of 35604-67-2. Viloxazine hydrochloride is soluble in water, 0.1N hydrochloric acid, and aqueous solutions with a pH of 9.5 and lower. Viloxazine hydrochloride is sparingly soluble in methanol, very slightly soluble in acetonitrile, acetic acid, and isopropanol, and almost insoluble in ethyl acetate. Viloxazine hydrochloride is a norepinephrine reuptake inhibitor that binds to the norepinephrine transporter (NET, Ki= 0.63µM) and inhibits the reuptake of norepinephrine (IC50=0.2µM). It has specific serotonin regulatory activity. It is mainly used to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents.

[0004] The only dosage form currently on the market is the sustained-release capsule, the original manufacturer is Supernus Pharmaceuticals, and the specifications are 100mg, 150mg, and 200mg, calculated as viloxazine. The original product name is QELBREE®, which was approved for marketing in the United States on April 2, 2021. It is the first new non-central stimulant treatment for attention deficit hyperactivity disorder (ADHD) in a decade. It is used to treat attention deficit hyperactivity disorder (ADHD) in children aged 6 to 17 years. The capsule shell of the capsule is easy to absorb moisture and soften, affecting the stability of the sample. The tablets have better stability and are easy to store and carry. The preparation process is simple and easy to industrialize. Summary of the invention

[0005] The purpose of the present invention is to provide a viloxazine hydrochloride sustained-release tablet and a preparation method thereof. The viloxazine hydrochloride sustained-release tablet prepared by the method has a sustained-release characteristic, is conducive to maintaining a long-term stable blood drug concentration in the body, and exerts a stable therapeutic effect.

[0006] The acid viloxazine sustained-release tablets of the present invention contain viloxazine or a pharmaceutically acceptable salt thereof, a skeleton material, a filler, a wetting agent, a lubricant, and a coating powder. In terms of weight percentage, viloxazine hydrochloride accounts for 31.94% of the tablet core weight, the skeleton material accounts for 25.1-37.6% of the tablet core weight, the filler accounts for 30-42% of the tablet core weight, and the lubricant accounts for 0.5-1.0% of the tablet core weight. The skeleton material is one or more of ethyl cellulose and hydroxypropyl methyl cellulose. The filler is one or more of corn starch and lactose. The wetting agent is one or more of purified water and ethanol. The lubricant is one or more of magnesium stearate and sodium stearyl fumarate.

[0007] First, weigh the viloxazine hydrochloride, the skeleton material and the filler for use; mix the skeleton material, the filler and the viloxazine hydrochloride evenly, add a proper amount of a wetting agent to prepare a soft material, use a 24-mesh sieve to granulate, then dry the obtained particles in an oven at 40° C. until the moisture content is less than 3%, use a 24-mesh sieve to sieve the particles, add a lubricant, mix evenly, take samples to determine the intermediate content, calculate the tablet weight according to the intermediate content, select a suitable tableting mold for tableting, obtain tablet cores, and coat the obtained tablet cores, with the coating weight gain being between 3.0-5.0%. Specific embodiments

[0008] The following examples further describe the beneficial effects of the present invention. The examples are only for illustrative purposes and do not limit the scope of the present invention.

[0009] Example 1 Prescription composition:

[0010] Preparation process: First, viloxazine hydrochloride, ethyl cellulose, hydroxypropyl cellulose, corn starch and lactose are weighed and set aside; the weighed ethyl cellulose, hydroxypropyl cellulose, corn starch, lactose and viloxazine hydrochloride are sequentially added into a wet granulation pot and stirred for 5 minutes, then an appropriate amount of purified water is added to make a soft material, a 24-mesh sieve is used for granulation, and then the obtained particles are dried in an oven at 40° C. until the moisture content is less than 3%, and magnesium stearate is added after granulation with a 24-mesh sieve, and mixed for 1 minute, and the intermediate content is measured by sampling, and the tablet weight is calculated according to the intermediate content, and a Φ10 shallow concave punch is selected for tableting to obtain a tablet core, and the obtained tablet core is coated, and the coating weight gain is between 3.0-5.0%.

[0011] Example 2 Prescription composition:

[0012] Preparation process: First, weigh viloxazine hydrochloride, ethyl cellulose, hydroxypropyl cellulose, corn starch and lactose for use; add the weighed ethyl cellulose, hydroxypropyl cellulose, corn starch, lactose and viloxazine hydrochloride to a wet granulation pot in turn and stir for 5 minutes, then add an appropriate amount of purified water to make a soft material, use a 24-mesh sieve to granulate, then dry the obtained particles in an oven at 40°C until the moisture content is less than 3%, use a 24-mesh sieve to granulate, then add sodium stearyl fumarate, mix evenly, take samples to determine the intermediate content, calculate the tablet weight according to the intermediate content, select a Φ10 shallow concave punch die for tableting, obtain tablet cores, and coat the obtained tablet cores, and the coating weight gain is between 3.0-5.0%. Example 3

[0013] Prescription composition:

[0014] Preparation process: First, viloxazine hydrochloride, ethyl cellulose, hydroxypropyl cellulose, corn starch and lactose are weighed and set aside, and a 30% ethanol aqueous solution is prepared and set aside; the weighed ethyl cellulose, hydroxypropyl cellulose, corn starch, lactose and viloxazine hydrochloride are added into a wet granulation pot in sequence and stirred for 5 minutes, and then an appropriate amount of 30% ethanol aqueous solution is added to prepare a soft material, and a 24-mesh sieve is used for granulation, and then the obtained particles are dried in an oven at 40° C. until the moisture content is less than 3%, and after being sieved with a 24-mesh sieve, magnesium stearate is added and mixed for 1 minute, and a sample is taken to determine the intermediate content, and the tablet weight is calculated according to the intermediate content, and a Φ10 shallow concave punch is selected for tableting to obtain a tablet core, and the obtained tablet core is coated, and the coating weight gain is between 3.0-5.0%.

[0015] Example 4 Prescription composition:

[0016] Preparation process: First, viloxazine hydrochloride, ethyl cellulose, hydroxypropyl cellulose, corn starch and lactose are weighed and set aside; the weighed ethyl cellulose, hydroxypropyl cellulose, corn starch, lactose and viloxazine hydrochloride are sequentially added into a wet granulation pot and stirred for 5 minutes, then an appropriate amount of purified water is added to make a soft material, a 24-mesh sieve is used for granulation, and then the obtained particles are dried in an oven at 40° C. until the moisture content is less than 3%, and magnesium stearate is added after granulation with a 24-mesh sieve, and mixed for 1 minute, and the intermediate content is measured by sampling, and the tablet weight is calculated according to the intermediate content, and a Φ10 shallow concave punch is selected for tableting to obtain a tablet core, and the obtained tablet core is coated, and the coating weight gain is between 3.0-5.0%.

[0017] Example 5 Prescription composition:

[0018] Preparation process: First, viloxazine hydrochloride, ethyl cellulose, hydroxypropyl cellulose, corn starch and lactose are weighed and set aside; the weighed ethyl cellulose, hydroxypropyl cellulose, corn starch, lactose and viloxazine hydrochloride are sequentially added into a wet granulation pot and stirred for 5 minutes, then an appropriate amount of purified water is added to make a soft material, a 24-mesh sieve is used for granulation, and then the obtained particles are dried in an oven at 40° C. until the moisture content is less than 3%, and magnesium stearate is added after granulation with a 24-mesh sieve, and mixed for 1 minute, and the intermediate content is measured by sampling, and the tablet weight is calculated according to the intermediate content, and a Φ10 shallow concave punch is selected for tableting to obtain a tablet core, and the obtained tablet core is coated, and the coating weight gain is between 3.0-5.0%.

[0019] Comparison of dissolution results: The above-mentioned tablets were tested according to the dissolution test method (Method 2, General Rules 0931 of the 2020 Edition of the Chinese Pharmacopoeia), with 900 ml of pH 1.2 hydrochloric acid solution as the dissolution medium and a rotation speed of 50 rpm, and the dissolution was tested for 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 20 h, and 24 h, respectively.

[0020] Table 1: Dissolution comparison results with the original QELBREE

[0021] Note: The selected points for f2 calculation are 1h, 2h, 4h, and 8h The tablets of Examples 2, 4, and 5 were tested for dissolution in accordance with the dissolution test method (Method 2 of General Rules 0931 of the 2020 edition of the Chinese Pharmacopoeia), using a pH 6.8 medium, a paddle method, and a rotation speed of 50 rpm, and the dissolution was tested for 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 20 h, and 24 h, respectively.

[0022]

[0023] Note: The selected points for f2 calculation are 1h, 4h, 8h, 16h, 24h Comparison of content and related substances: The original QELBREE sample, Example 1, Example 2, Example 3, Example 4, and Example 5 samples were placed at a high temperature of 50° C. and a light of 5000 lx (ultraviolet 90 uW / cm) for 10 days and then the related substances and their contents were detected.

[0024]

[0025] Conclusion: The total impurities of the original QELBREE increased significantly under the conditions of 10 days of light and 10 days of high temperature at 50°C. After the samples of Example 1, Example 2, Example 3, Example 4, and Example 5 were placed under light and high temperature at 50°C for 10 days, the total impurities were basically the same as the 0-day samples, and the sample stability was good.

Claims

1. A viloxazine hydrochloride sustained-release tablet, characterized in that The components of the sustained-release tablet include viloxazine or a pharmaceutically acceptable salt thereof, a skeleton material, a filler, a wetting agent, a lubricant, and a coating powder.

2. The viloxazine hydrochloride sustained-release tablet according to claim 1, characterized in that In terms of weight percentage, viloxazine hydrochloride accounts for 31.94% of the tablet core weight, the skeleton material accounts for 25.1-37.6% of the tablet core weight, the filler accounts for 30-42% of the tablet core weight, and the lubricant accounts for 0.5-1.0% of the tablet core weight.

3. The skeleton material as claimed in claim 1 is selected from one or more of ethyl cellulose and hypromellose.

4. The filler as claimed in claim 1 is selected from one or more of corn starch and lactose.

5. The wetting agent as claimed in claim 1 is selected from one or more of purified water and ethanol.

6. The lubricant as claimed in claim 1 is selected from one or more of magnesium stearate and sodium stearyl fumarate.

7. As claimed in claim 6, characterized in that The lubricant is added after the granules are dried and mixed evenly.

8. A viloxazine hydrochloride sustained-release tablet, characterized in that The preparation method comprises the following steps: 1) Weigh viloxazine hydrochloride, skeleton material, and filler respectively for later use; 2) putting the skeleton material, filler and viloxazine hydrochloride into the wet granulation pot in sequence and mixing them evenly; 3) Turn on the stirring and shearing of the mixer, slowly add an appropriate amount of wetting agent to make a soft material, and granulate through a 24-mesh sieve; 4) drying the obtained particles in an oven at 40°C until the moisture content is less than 3%; 5) The dried particles are sieved through a 24-mesh sieve; 6) Add lubricant to the granulated particles, mix for 1 minute, and take samples to determine the intermediate content; 7) Calculate the tablet weight according to the intermediate content and select a suitable tabletting mold for tableting; 8) Coating with colored coating powder, the coating weight gain is between 3.0-5.0%.

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