A rapidly disintegrating naloxone hydrochloride sublingual tablet and a method of preparing the same

Abstract

The application discloses a fast-disintegrating naloxone hydrochloride sublingual tablet and a preparation method thereof, and belongs to the technical field of pharmaceutical compositions. The technical solution points of the fast-disintegrating naloxone hydrochloride sublingual tablet are as follows: the sublingual tablet is composed of naloxone hydrochloride, corn starch, microcrystalline cellulose, sucrose, a binder, a disintegrating agent and a lubricant. The amount of naloxone hydrochloride is 0.4-0.6 wt%, the amount of corn starch is 8-12 wt%, the amount of microcrystalline cellulose is 18-21 wt%, the amount of sucrose is 60-65 wt%, the amount of the binder is 1.5-2.5 wt%, the amount of the disintegrating agent is 2.5-3.5 wt%, and the amount of the lubricant is 0.5-1.5 wt%. The application can make the naloxone hydrochloride sublingual tablet disintegrate within 2 min and improve the bioavailability of the naloxone hydrochloride sublingual tablet by the proportioning of the raw materials and the selection of the disintegrating agent.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical composition technology, and in particular to a rapidly disintegrating naloxone hydrochloride sublingual tablet and its preparation method. Background Technology

[0002] In the medical field, research on human alcohol metabolism and related poisoning treatments has always been an important topic. The breakdown and metabolism of alcohol in the human body mainly relies on alcohol dehydrogenase and aldehyde dehydrogenase in the liver enzyme system. This process ultimately breaks down alcohol into carbon dioxide and water. With improved living standards and more drinking occasions, intoxication is becoming increasingly common. The cause of intoxication mainly depends on the concentration of ethanol in the blood. When it reaches a certain level, a person may experience slurred speech and unsteady gait. Furthermore, the content of aldehyde dehydrogenase varies greatly among individuals. Acetaldehyde accumulation can cause symptoms such as facial flushing, throbbing headache, palpitations, and nausea. Therefore, the development of drugs to treat acute alcohol poisoning is of great significance and plays an indispensable role in protecting people's health and safety.

[0003] In clinical practice, existing injectable treatments for acute alcohol poisoning primarily aim to rapidly reduce blood alcohol concentration. Meanwhile, naloxone hydrochloride preparations are widely used to treat conditions such as anesthetic overdose, alcohol poisoning, shock, cerebral infarction, and cardiac and respiratory arrest, gaining attention due to their proven efficacy and few side effects. Naloxone hydrochloride preparations are commonly available in sublingual tablet form, a relatively convenient method of administration that facilitates patient use.

[0004] However, existing naloxone hydrochloride sublingual tablets have significant drawbacks. Their low bioavailability and slow disintegration rate directly affect the onset time of naloxone hydrochloride formulations, preventing them from acting promptly in treating conditions such as acute alcohol poisoning and failing to meet the need for rapid treatment. Summary of the Invention

[0005] To address the problems in the prior art, this invention provides a rapidly disintegrating naloxone hydrochloride sublingual tablet and its preparation method. By adjusting the proportions of the raw materials and selecting the disintegrant, this application enables the naloxone hydrochloride sublingual tablet to disintegrate within 2 minutes, thereby improving the bioavailability of the naloxone hydrochloride sublingual tablet.

[0006] The first aspect of this invention is to provide a rapidly disintegrating naloxone hydrochloride sublingual tablet, which adopts the following technical solution: A rapidly disintegrating naloxone hydrochloride sublingual tablet, the sublingual tablet being composed of naloxone hydrochloride, corn starch, microcrystalline cellulose, sucrose, binder, disintegrant and lubricant, wherein the content of naloxone hydrochloride is 0.4-0.6 wt%.

[0007] In a preferred embodiment, the amount of corn starch is 8-12 wt%, the amount of microcrystalline cellulose is 18-21 wt%, the amount of sucrose is 60-65 wt%, the amount of binder is 1.5-2.5 wt%, the amount of disintegrant is 2.5-3.5 wt%, and the amount of lubricant is 0.5-1.5 wt%.

[0008] By adopting the above technical solution, the amounts of corn starch, microcrystalline cellulose, sucrose, binder, disintegrant, and lubricant are controlled at 8-12 wt%, 18-21 wt%, 60-65 wt%, 1.5-2.5 wt%, 2.5-3.5 wt%, and 0.5-1.5 wt%, respectively, with each component working synergistically. Corn starch has good swelling properties and expands rapidly upon contact with water, which helps with tablet disintegration; microcrystalline cellulose increases the hardness and compressibility of tablets and has a certain water-absorbing effect, promoting water penetration into the tablet interior; sucrose improves the taste and, to some extent, regulates the physical properties of the tablet, facilitating the function of other components; an appropriate amount of binder ensures tablet formation without affecting disintegration due to excess; the disintegrant rapidly breaks down the tablet structure under the action of water; and the lubricant prevents material from sticking to the mold, ensuring smooth tableting. The rational combination of these components allows for rapid tablet disintegration, thereby increasing the dissolution rate of naloxone hydrochloride and ultimately improving bioavailability.

[0009] In a preferred embodiment, the adhesive is polyvinyl chloride.

[0010] In a preferred embodiment, the disintegrant is sodium carboxymethyl starch.

[0011] By adopting the above technical solution, when sodium carboxymethyl starch is used as the disintegrant, sodium carboxymethyl starch mainly disintegrates through a swelling mechanism. Its molecular chain has good flexibility and can quickly and massively absorb water after contact with water, thus expanding the tablet structure from the inside and achieving extremely high disintegration efficiency, thereby effectively improving the dissolution efficiency of naloxone hydrochloride sublingual tablets.

[0012] In a preferred embodiment, the lubricant is magnesium stearate.

[0013] By adopting the above technical solution, selecting povidone as a binder, sodium carboxymethyl starch as a disintegrant, and magnesium stearate as a lubricant, the three work synergistically to effectively improve the disintegration efficiency of naloxone hydrochloride sublingual tablets and accelerate the onset of drug action.

[0014] A second aspect of this application is to provide a method for preparing rapidly disintegrating naloxone hydrochloride sublingual tablets as described above, comprising the following steps: S1. Add naloxone hydrochloride, corn starch, microcrystalline cellulose and sucrose into the granulator and mix well; S2. Under stirring, add polyvinyl ketone solution into the granulator to make soft material; S3. Use a gyratory pellet mill to pass the soft material through an 18-mesh sieve to make wet pellets; S4. After drying the wet granules, pass them through an 18-mesh sieve. S5. Add half of the dry granules and disintegrant into the mixer and mix. S6. After mixing the dry granules with the remaining dry granules and lubricant, compress and package the mixture to obtain naloxone hydrochloride sublingual tablets.

[0015] In a preferred embodiment, the povidone solution in step S2 is prepared by adding povidone to water to form a solution with a concentration of 2 wt%.

[0016] In a preferred embodiment, during the stirring process in steps S1 and S2, the stirring blade speed is 100±20 rpm and the cutting blade speed is 1200±200 rpm.

[0017] In a preferred embodiment, the drying conditions in step S4 are an inlet air temperature of 60±5℃ and an air volume of 1800±200m³. 3 / h.

[0018] In a preferred embodiment, the tableting speed is 60-100 KT / h.

[0019] By adopting the above technical solution, step S1 involves mixing naloxone hydrochloride, corn starch, microcrystalline cellulose, and sucrose evenly in a granulator, ensuring thorough dispersion of the components and providing a good foundation for subsequent granulation. Step S2 involves adding a 2wt% povidone solution while stirring to create a soft material, which provides suitable viscosity for subsequent granulation. Step S3 uses a vibrating pellet mill to produce wet pellets through an 18-mesh sieve, ensuring uniform pellet size. Step S4 involves drying the wet pellets under the following conditions: inlet air temperature 60±5℃ and airflow 18... The flow rate is 00±200m³ / h, which can effectively remove moisture, and the appropriate temperature and air volume can avoid overheating of the granules or insufficient drying; in step S5, half of the dry granules and disintegrant are added to the mixer and mixed, so that the disintegrant is evenly distributed in some of the granules, which is conducive to rapid disintegration of the tablets; in step S6, the mixed dry granules are mixed with the remaining dry granules and lubricant, then tableted and packaged. The tableting speed is 60-100KT / h. The appropriate tableting speed can ensure the quality of the tablets, and finally obtain rapidly disintegrating naloxone hydrochloride sublingual tablets, improve bioavailability, and accelerate the onset of action.

[0020] In summary, the present invention has the following beneficial effects: 1. Naloxone hydrochloride sublingual tablets formulated with specific ingredients and dosages can improve bioavailability; 2. Rapidly disintegrating naloxone hydrochloride sublingual tablets can shorten disintegration time; 3. Naloxone hydrochloride sublingual tablets have a rapid onset of action, meeting the need for rapid treatment of conditions such as acute alcohol poisoning. Detailed Implementation

[0021] The present invention will be further described in detail below with reference to the embodiments. All reagents, unless otherwise specified, are commercially available conventional reagent products.

[0022] Example 1 A rapidly disintegrating naloxone hydrochloride sublingual tablet comprises the following ingredients: 0.53 wt% naloxone hydrochloride, 10 wt% corn starch, 20 wt% microcrystalline cellulose, 63.47 wt% sucrose, 2 wt% povidone, 3 wt% sodium carboxymethyl starch, and 1 wt% magnesium stearate; Its preparation method includes the following steps: S1. Add naloxone hydrochloride, corn starch, microcrystalline cellulose and sucrose to the pellet mill and mix for 5 minutes, with the stirring speed at 100 rpm and the cutting speed at 1200 rpm. S2. Add povidone to water to prepare a 2wt% povidone solution. Under the conditions of stirring speed of 100rpm and cutting speed of 1200rpm, add the povidone solution into the granulator and mix for 10min to make soft material. The atomization pressure is 0.5MPa. S3. Use a gyratory pellet mill to pass the soft material through an 18-mesh sieve to make wet pellets; S4. After drying the wet granules, pass them through an 18-mesh sieve. The drying conditions are: inlet air temperature 60℃ and air volume 1800 m³ / h. 3 / h; S5. Add half of the dry granules and sodium carboxymethyl starch into the mixer and mix for 15 minutes at a speed of 15 rpm. S6. Mix the mixed dry granules with the remaining dry granules and magnesium stearate for 5 minutes at a mixing speed of 15 rpm, then compress the tablets at a compression speed of 60 KT / h, and then package them to obtain naloxone hydrochloride sublingual tablets.

[0023] Example 2 A rapidly disintegrating naloxone hydrochloride sublingual tablet comprises the following ingredients: 0.4 wt% naloxone hydrochloride, 10.1 wt% corn starch, 18 wt% microcrystalline cellulose, 65 wt% sucrose, 2.5 wt% povidone, 3.5 wt% sodium carboxymethyl starch, and 0.5 wt% magnesium stearate; Its preparation method includes the following steps: S1. Add naloxone hydrochloride, corn starch, microcrystalline cellulose and sucrose to the pellet mill and mix for 5 minutes, with the stirring speed at 100 rpm and the cutting speed at 1200 rpm. S2. Add povidone to water to prepare a 2wt% povidone solution. Under the conditions of stirring speed of 100rpm and cutting speed of 1200rpm, add the povidone solution into the granulator and mix for 10min to make soft material. The atomization pressure is 0.5MPa. S3. Use a gyratory pellet mill to pass the soft material through an 18-mesh sieve to make wet pellets; S4. After drying the wet granules, pass them through an 18-mesh sieve. The drying conditions are: inlet air temperature 60℃ and air volume 1800 m³ / h. 3 / h; S5. Add half of the dry granules and sodium carboxymethyl starch into the mixer and mix for 15 minutes at a speed of 15 rpm. S6. Mix the mixed dry granules with the remaining dry granules and magnesium stearate for 5 minutes at a mixing speed of 15 rpm, then compress the tablets at a compression speed of 60 KT / h, and then package them to obtain naloxone hydrochloride sublingual tablets.

[0024] Example 3 A rapidly disintegrating naloxone hydrochloride sublingual tablet comprises the following ingredients: 0.6 wt% naloxone hydrochloride, 12 wt% corn starch, 21 wt% microcrystalline cellulose, 60.9 wt% sucrose, 1.5 wt% povidone, 2.5 wt% sodium carboxymethyl starch, and 1.5 wt% magnesium stearate; Its preparation method includes the following steps: S1. Add naloxone hydrochloride, corn starch, microcrystalline cellulose and sucrose to the pellet mill and mix for 5 minutes, with the stirring speed at 100 rpm and the cutting speed at 1200 rpm. S2. Add povidone to water to prepare a 2wt% povidone solution. Under the conditions of stirring speed of 100rpm and cutting speed of 1200rpm, add the povidone solution into the granulator and mix for 10min to make soft material. The atomization pressure is 0.5MPa. S3. Use a gyratory pellet mill to pass the soft material through an 18-mesh sieve to make wet pellets; S4. After drying the wet granules, pass them through an 18-mesh sieve. The drying conditions are: inlet air temperature 60℃ and air volume 1800 m³ / h. 3 / h; S5. Add half of the dry granules and sodium carboxymethyl starch into the mixer and mix for 15 minutes at a speed of 15 rpm. S6. Mix the mixed dry granules with the remaining dry granules and magnesium stearate for 5 minutes at a mixing speed of 15 rpm, then compress the tablets at a compression speed of 60 KT / h, and then package them to obtain naloxone hydrochloride sublingual tablets.

[0025] Example 4 A rapidly disintegrating naloxone hydrochloride sublingual tablet comprises the following ingredients: 0.5 wt% naloxone hydrochloride, 8 wt% corn starch, 20 wt% microcrystalline cellulose, 65 wt% sucrose, 2 wt% povidone, 3 wt% sodium carboxymethyl starch, and 1.5 wt% magnesium stearate; Its preparation method includes the following steps: S1. Add naloxone hydrochloride, corn starch, microcrystalline cellulose and sucrose to the pellet mill and mix for 5 minutes, with the stirring speed at 100 rpm and the cutting speed at 1200 rpm. S2. Add povidone to water to prepare a 2wt% povidone solution. Under the conditions of stirring speed of 100rpm and cutting speed of 1200rpm, add the povidone solution into the granulator and mix for 10min to make soft material. The atomization pressure is 0.5MPa. S3. Use a gyratory pellet mill to pass the soft material through an 18-mesh sieve to make wet pellets; S4. After drying the wet granules, pass them through an 18-mesh sieve. The drying conditions are: inlet air temperature 60℃ and air volume 1800 m³ / h. 3 / h; S5. Add half of the dry granules and sodium carboxymethyl starch into the mixer and mix for 15 minutes at a speed of 15 rpm. S6. Mix the mixed dry granules with the remaining dry granules and magnesium stearate for 5 minutes at a mixing speed of 15 rpm, then compress the tablets at a compression speed of 60 KT / h, and then package them to obtain naloxone hydrochloride sublingual tablets.

[0026] Example 5 A method for preparing rapidly disintegrating naloxone hydrochloride sublingual tablets, the process parameters of which differ from those of Example 1, but the formulation is the same as that of Example 1, is as follows: S1. Add naloxone hydrochloride, corn starch, microcrystalline cellulose and sucrose to the pellet mill and mix for 5 minutes, with the mixing blade speed at 80 rpm and the cutting blade speed at 1000 rpm. S2. Add povidone to water to prepare a 2wt% povidone solution. Under the conditions of stirring speed of 80 rpm and cutting speed of 1000 rpm, add the povidone solution into the granulator and mix for 10 minutes to make a soft material. The atomization pressure is 0.6 MPa. S3. Use a gyratory pellet mill to pass the soft material through an 18-mesh sieve to make wet pellets; S4. After drying the wet granules, pass them through an 18-mesh sieve. The drying conditions are: inlet air temperature 55℃ and air volume 1600 m³ / h. 3 / h; S5. Add half of the dry granules and sodium carboxymethyl starch into the mixer and mix for 15 minutes at a speed of 15 rpm. S6. Mix the mixed dry granules with the remaining dry granules and magnesium stearate for 5 minutes at a mixing speed of 15 rpm, then compress the tablets at a compression speed of 80 KT / h, and then package them to obtain naloxone hydrochloride sublingual tablets.

[0027] Example 6 A method for preparing rapidly disintegrating naloxone hydrochloride sublingual tablets, the process parameters of which differ from those of Example 1, but the formulation is the same as that of Example 1, is as follows: S1. Add naloxone hydrochloride, corn starch, microcrystalline cellulose and sucrose to the pellet mill and mix for 5 minutes, with the mixing blade speed at 120 rpm and the cutting blade speed at 1400 rpm. S2. Add povidone to water to prepare a 2wt% povidone solution. Under the conditions of stirring speed of 120rpm and cutting speed of 1400rpm, add the povidone solution into the granulator and mix for 10min to make soft material. The atomization pressure is 0.7MPa. S3. Use a gyratory pellet mill to pass the soft material through an 18-mesh sieve to make wet pellets; S4. After drying the wet granules, pass them through an 18-mesh sieve. The drying conditions are: inlet air temperature 65℃ and air volume 2000 m³ / h. 3 / h; S5. Add half of the dry granules and sodium carboxymethyl starch into the mixer and mix for 15 minutes at a speed of 15 rpm. S6. Mix the mixed dry granules with the remaining dry granules and magnesium stearate for 5 minutes at a mixing speed of 15 rpm, then compress the tablets at a compression speed of 100 KT / h, and then package them to obtain naloxone hydrochloride sublingual tablets.

[0028] Comparative Example 1 A sublingual naloxone hydrochloride tablet differs from Example 1 in that an equal amount of cross-linked sodium carboxymethyl cellulose is used instead of sodium carboxymethyl starch; otherwise, they are the same as in Example 1.

[0029] Comparative Example 2 A sublingual naloxone hydrochloride tablet differs from Example 1 in that an equal amount of calcium carboxymethyl cellulose is used instead of sodium carboxymethyl starch, while all other aspects are the same as in Example 1.

[0030] Performance testing The dissolution effect of the products obtained in the above embodiments was tested, and the test results are shown in Table 1.

[0031] The specific experimental conditions are as follows: Method 1 (basket method) of General Chapter 0931 of Part IV of the 2020 edition of the Chinese Pharmacopoeia was adopted. The temperature was 37℃, the rotation speed was 100rpm, the medium volume was 900mL, the sample was taken into the injection vial, injected into the high performance liquid chromatograph, the chromatogram was recorded, and the cumulative dissolution rate of the sample at each sampling point was calculated.

[0032] Table 1. Dissolution test results of naloxone hydrochloride sublingual tablets

[0033] Based on the test results in Table 1: The naloxone hydrochloride sublingual tablets obtained in Examples 1-6 of this application completely disintegrated and dissolved within 2 minutes, indicating that the naloxone hydrochloride sublingual tablets obtained in this application have excellent disintegration effect, thereby enabling faster onset of action and improving bioavailability.

[0034] Compared with Example 1, when an equal amount of cross-linked sodium carboxymethyl cellulose was used to replace sodium carboxymethyl starch, the disintegration efficiency of the naloxone hydrochloride sublingual tablets obtained in Comparative Example 1 was significantly lower than that in Example 1. Compared with Example 1, when an equal amount of calcium carboxymethyl cellulose was used to replace sodium carboxymethyl starch, the disintegration efficiency of the naloxone hydrochloride sublingual tablets obtained in Comparative Example 2 was also significantly lower than that in Example 1. The main reasons are: Sodium carboxymethyl starch mainly disintegrates through a swelling mechanism. Its molecular chain has good flexibility and can quickly and massively absorb water after contact with water, expanding the tablet structure from the inside, resulting in extremely high disintegration efficiency. Although cross-linked sodium carboxymethyl cellulose also mainly disintegrates through a swelling mechanism, its molecular chain is a cross-linked structure. After contact with water, the chain segment activity is limited, and its water absorption and swelling capacity is lower than that of sodium carboxymethyl starch. It is also sensitive to the pH value of the medium, and its swelling capacity will further decrease under certain environments. While calcium carboxymethyl cellulose absorbs water and swells, it may form a viscous gel layer inside the tablet. This gel layer will hinder water from further penetrating into the tablet core, resulting in slower disintegration.

[0035] The embodiments described herein are merely illustrative of preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Therefore, all equivalent changes made in accordance with the structure, shape, and principle of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A rapidly disintegrating naloxone hydrochloride sublingual tablet, characterized in that: The sublingual tablet is composed of naloxone hydrochloride, corn starch, microcrystalline cellulose, sucrose, binder, disintegrant and lubricant, wherein the content of naloxone hydrochloride is 0.4-0.6 wt%.

2. The rapidly disintegrating naloxone hydrochloride sublingual tablet according to claim 1, characterized in that: The amount of corn starch used is 8-12 wt%, the amount of microcrystalline cellulose is 18-21 wt%, the amount of sucrose is 60-65 wt%, the amount of binder is 1.5-2.5 wt%, the amount of disintegrant is 2.5-3.5 wt%, and the amount of lubricant is 0.5-1.5 wt%.

3. The rapidly disintegrating naloxone hydrochloride sublingual tablet according to claim 1, characterized in that: The adhesive used is polyvinyl chloride.

4. The rapidly disintegrating naloxone hydrochloride sublingual tablet according to claim 1, characterized in that: The disintegrant is sodium carboxymethyl starch.

5. The rapidly disintegrating naloxone hydrochloride sublingual tablet according to claim 1, characterized in that: The lubricant used is magnesium stearate.

6. A method for preparing rapidly disintegrating naloxone hydrochloride sublingual tablets as described in any one of claims 1-5, characterized in that, Includes the following steps: S1. Add naloxone hydrochloride, corn starch, microcrystalline cellulose and sucrose into the granulator and mix well; S2. Under stirring, add polyvinyl ketone solution into the granulator to make soft material; S3. Use a gyratory pellet mill to pass the soft material through an 18-mesh sieve to make wet pellets; S4. After drying the wet granules, pass them through an 18-mesh sieve. S5. Add half of the dry granules and disintegrant into the mixer and mix. S6. After mixing the dry granules with the remaining dry granules and lubricant, compress and package the mixture to obtain naloxone hydrochloride sublingual tablets.

7. The method for preparing a rapidly disintegrating naloxone hydrochloride sublingual tablet according to claim 6, characterized in that: In step S2, the povidone solution is prepared by adding povidone to water to form a solution with a concentration of 2 wt%.

8. The method for preparing a rapidly disintegrating naloxone hydrochloride sublingual tablet according to claim 6, characterized in that: During the stirring process in steps S1 and S2: the stirring blade speed is 100±20 rpm, and the cutting blade speed is 1200±200 rpm.

9. The method for preparing a rapidly disintegrating naloxone hydrochloride sublingual tablet according to claim 6, characterized in that: The drying conditions in step S4 are: inlet air temperature 60±5℃ and air volume 1800±200m³. 3 / h.

10. The method for preparing a rapidly disintegrating naloxone hydrochloride sublingual tablet according to claim 6, characterized in that: The tableting speed is 60-100 KT / h.

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