A ramelteon tablet and a preparation method thereof

Abstract

The application provides a ramelteon tablet and a preparation method, which comprises the following components: 8 parts of ramelteon, 5-7 parts of copovidone, 109-112 parts of a filler, 0.8-1.3 parts of a lubricant and 4.2-4.5 parts of a coating agent, wherein the ramelteon and the copovidone are dissolved in 75-85% ethanol and are added by spraying to carry out wet granulation, and the particle size of the granules containing the ramelteon is 250-355 mu m. The ramelteon tablet and the preparation method can improve the content uniformity of small-size preparations prepared by taking the copovidone as the binder by dissolving the ramelteon in the binder solution and adding by spraying to carry out wet granulation; the segregation and stratification of the powder in the hopper during the tablet pressing process can be effectively inhibited by selecting the granules with a specific particle size, the content uniformity can be further improved compared to other particle size ranges, and the production quality is controllable.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a ramelteon tablet and a preparation method thereof. Background Art

[0002] With the accelerating pace of life and increasing stress, the number of people suffering from sleep disorders is increasing. According to data from the World Health Organization, 27% of people worldwide have sleep problems, and the proportion of people suffering from various sleep disorders in my country is as high as 38.2%.

[0003] Currently, the number of anti-insomnia drugs approved for marketing in China is relatively limited, mainly including benzodiazepines such as diazepam and clonazepam, and new non-benzodiazepines represented by zolpidem and eszopiclone. Among them, non-benzodiazepines have gradually become the first-line sleeping aids recommended by mainstream guidelines, but this type of drug is addictive and long-term use will reduce deep sleep and destroy sleep structure.

[0004] Ramelteon, a melatonin receptor agonist, selectively activates melatonin type 1 and type 2 receptors (MT1 and MT2) without interacting with MT3 receptors. This increases slow-wave sleep (SWS) and rapid eye movement (REW) sleep, thereby reducing insomnia. Ramelteon tablets, developed by Takeda Pharmaceuticals of Japan, were launched in the United States in 2005 and Japan in 2010 under the trade name "ROZEREM." It is the first non-addictive insomnia treatment not listed as a specially regulated medication. Its production process involves mixing aqueous lactose, corn starch, and ramelteon, spraying the mixture with an aqueous solution of hydroxypropyl cellulose to form granules. The granules are then mixed with magnesium stearate, compressed into tablets, and coated.

[0005] In order to improve the stability of tablets, publication number CN104224741B discloses a ramelteon composition and tablets, comprising 5-8 parts of ramelteon, 0.5-3 parts of copovidone, 80-110 parts of a filler, 3-10 parts of a disintegrant, and 0.5-1.5 parts of a lubricant; the ramelteon tablets of this solution not only have a fast dissolution rate, but also use copovidone to improve the thermal stability and light stability of ramelteon, inhibit its oxidative degradation, and ensure the stability of the ramelteon tablets. However, the applicant found that the mixing uniformity of the mixed materials was poor.

[0006] In view of this, the present invention is proposed. Summary of the Invention

[0007] The problem solved by the present invention is that when copovidone is used as a binder, the material mixing uniformity is poor, segregation is easily generated during tableting, and it is not conducive to the quality control of small-scale preparations such as ramelteon tablets.

[0008] To solve the above problems, the application provides a ramelteon tablet, which comprises the following components: 8 parts of ramelteon, 5-7 parts of copolyvidone, 109-112 parts of a filler, 0.8-1.3 parts of a lubricant and 4.2-4.5 parts of a coating agent, wherein the ramelteon and the copolyvidone are dissolved in 75-85% ethanol and then added into a wet granulation process, and the particle size of the prepared granules containing the ramelteon is 250-355 μm.

[0009] Preferably, the filler comprises one of lactose, sucrose, mannitol, erythritol, sorbitol and xylitol, and further comprises one of corn starch, potato starch, rice starch and partially pregelatinized starch. Preferably, the filler is composed of 92.8-95.1 parts of lactose and 15.1-17.4 parts of corn starch.

[0010] Preferably, the lubricant is one of magnesium stearate, stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearate fumarate, talc and hydrogenated vegetable oil.

[0011] Preferably, the coating agent comprises 3.5-4 parts of a coating material, 0.5-1 part of a plasticizer, 0.45-0.55 part of a light shielding agent and 0.05-0.15 part of an antioxidant.

[0012] Preferably, the coating material comprises any one of polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose, and the plasticizer is any one of polyethylene glycol, propylene glycol, hydroxypropyl methyl cellulose and glycerol.

[0013] Preferably, the antioxidant is composed of tryptophan and sodium edetate according to a mass ratio of 1:0.8-1.2.

[0014] The application further provides a preparation method of the ramelteon tablet, which comprises the following steps:

[0015] S1, slowly adding a prescribed amount of copolyvidone into 78-85% ethanol at 40-45°C and stirring for 10-25 min to prepare a binder solution containing 5.5-6.5%, and then adding a prescribed amount of ramelteon and stirring for 8-12 min for dissolution;

[0016] S2, uniformly mixing a prescribed amount of lactose and corn starch in a fluidized bed granulator dryer for 4-7 min, and then continuously spraying the binder solution prepared in S1 and the raw material solution for granulation and drying;

[0017] S3, screening with 50 and 65 mesh stainless steel screens respectively to control the particle size of the granules in a range of 250-355 μm, mixing the screened granules with a prescribed amount of lubricant for 4-6 min, and then compressing into tablets.

[0018] S4. Use the prescribed amount of hydroxypropyl methylcellulose, plasticizer, colorant and antioxidant to suspend in water, spray coating, and the coating weight gain is 3.35%-3.45%. After drying, the product is obtained.

[0019] Preferably, the operating parameters of the fluidized bed granulation dryer in step S2 are: the air volume in the initial preheating stage is 13-17m 3 / h, the inlet air temperature is 74-80℃, when the material temperature rises to 38-42℃, adjust the inlet air volume to 58-62m 3 / h, and at the same time, start the peristaltic pump speed at 12-15rpm, the spray gun atomization pressure at 0.8-12Bar, control the inlet air humidity at 8-10g / m3, and adjust the inlet air volume to 70-78m3 during the drying stage. 3 / h, the inlet air temperature is 70-74℃, and the discharge is controlled at 3% moisture content.

[0020] Compared with the prior art, the ramelteon tablets and preparation method described in the embodiments of the present invention have the following beneficial effects: 1) when tablets are prepared using copovidone as a binder, wet granulation is performed by dissolving ramelteon in a binder solution and adding it by spraying, thereby improving the content uniformity of small-scale preparations; 2) when the particle size of the wet granulation is 250-355 μm, the particles are of moderate size, have a high filling density, and have good fluidity, thereby effectively suppressing the segregation and stratification of the powder in the hopper during the tableting process, further improving the content uniformity compared with other particle size ranges, and enhancing the controllability of production quality; 3) for the coating step, selecting propylene glycol as a plasticizer can reduce the degradation of ramelteon, and adding a specific ratio of antioxidants to the coating agent can produce a synergistic effect with propylene glycol, further improving the stability of the ramelteon tablets. DETAILED DESCRIPTION

[0021] To make the above-mentioned objectives, features, and advantages of the present invention more readily apparent, the following detailed description of specific embodiments of the present invention is provided. Experimental methods not specifying specific conditions in the examples herein should be performed according to conventional methods and conditions, or according to product specifications. The technical features of the embodiments of the present invention may be combined unless they conflict.

[0022] Ramelteon mainly induces sleep by inducing the sleep center and suppressing the autonomic nervous system by maintaining the parasympathetic nervous system. It is a drug that regulates the action of melatonin related to the sleep-wake cycle of the biological rhythm and induces natural sleepiness. Since it has almost no dependence, it is not designated as a psychotropic or addictive drug.

[0023] Since the weight of a single ramelteon tablet is 130 mg / tablet, containing 8 mg of ramelteon, it is a small-sized preparation. Its content uniformity will affect the final efficacy. The applicant found that although the use of copolyvidone as a binder can improve the stability of the final tablet, the mixing uniformity of the materials is poor. Therefore, the applicant proposed the following technical solution:

[0024] Example 1

[0025] A ramelteon tablet, the prescription composition is:

[0026]

[0027] Prepared by the following method:

[0028] S1. Slowly add the prescribed amount of copovidone to 80% ethanol at 45°C and stir for 30 minutes to prepare a 6% adhesive solution, then add the prescribed amount of ramelteon and stir for 10 minutes to dissolve;

[0029] S2. Evenly mix the prescribed amount of lactose and corn starch in a fluidized bed granulation dryer for 5 minutes, then continuously spray the binder prepared in S1 and the API solution into the mixture for granulation, followed by drying.

[0030] The specific operating parameters of the fluidized bed granulation dryer are: the air volume in the initial preheating stage is 15m 3 / h, the inlet air temperature is 80℃, when the material temperature rises to 40℃, adjust the inlet air volume to 60m 3 / h, and at the same time, start the peristaltic pump at 12rpm, the spray gun atomization pressure at 0.9Bar, control the inlet air humidity at 8g / m3, and adjust the inlet air volume to 70m3 during the drying stage. 3 / h, the inlet air temperature is 70℃, and the discharge is controlled at 3% moisture content.

[0031] S3. Sieve the granules using 50 and 65 mesh stainless steel sieves respectively to control the particle size of the granules to 250-355 μm, mix the sieved granules with the prescribed amount of magnesium stearate for 6 minutes, and press into tablets;

[0032] S4. Use the prescribed amount of hypromellose, polyethylene glycol 6000, yellow iron oxide and titanium dioxide to suspend in water, spray coating, the coating weight gain is 3.35%, and then dry to obtain the product.

[0033] Example 2

[0034] A ramelteon tablet, the prescription composition is:

[0035]

[0036] Prepared by the following method:

[0037] S1. Slowly add the prescribed amount of copovidone to 85% ethanol at 40°C and stir for 25 minutes to prepare a 6.5% adhesive solution, then add the prescribed amount of ramelteon and stir for 12 minutes to dissolve;

[0038] S2. Evenly mix the prescribed amount of lactose and corn starch in a fluidized bed granulation dryer for 7 minutes, then continuously spray the binder prepared in S1 and the API solution into the granules for granulation, followed by drying.

[0039] The specific operating parameters of the fluidized bed granulation dryer are: the air volume in the initial preheating stage is 17m 3 / h, the inlet air temperature is 75℃, when the material temperature rises to 42℃, adjust the inlet air volume to 58m 3 / h, and at the same time, start the peristaltic pump at 15rpm, the spray gun atomization pressure at 1.2Bar, control the inlet air humidity at 9g / m3, and adjust the inlet air volume to 75m3 during the drying stage. 3 / h, the inlet air temperature is 72℃, and the discharge is controlled at 3% moisture content.

[0040] S3. Sieve the granules using 50 and 65 mesh stainless steel sieves respectively to control the particle size of the granules to 250-355 μm, mix the sieved granules with the prescribed amount of calcium stearate for 4 minutes, and press into tablets;

[0041] S4. Suspend the prescribed amount of povidone, glycerin, yellow iron oxide and titanium dioxide in water, spray coating, and increase the coating weight by 3.35%. After drying, the product is obtained.

[0042] Example 3

[0043] A ramelteon tablet, the prescription composition is:

[0044]

[0045] Prepared by the following method:

[0046] S1. Slowly add the prescribed amount of copovidone to 78% ethanol at 42°C and stir for 20 minutes to prepare a 5.5% adhesive solution, then add the prescribed amount of ramelteon and stir for 8 minutes to dissolve;

[0047] S2. Evenly mix the prescribed amount of lactose and corn starch in a fluidized bed granulation dryer for 4 minutes, then continuously spray the binder prepared in S1 and the API solution into the granules for granulation, followed by drying.

[0048] The specific operating parameters of the fluidized bed granulation dryer are: the air volume in the initial preheating stage is 13m 3 / h, the inlet air temperature is 74℃, when the material temperature rises to 38℃, adjust the inlet air volume to 62m3 / h, and at the same time, start the peristaltic pump at 13rpm, the spray gun atomization pressure at 0.8Bar, control the inlet air humidity at 10g / m3, and adjust the inlet air volume to 78m3 during the drying stage. 3 / h, the inlet air temperature is 74℃, and the discharge is controlled at 3% moisture content.

[0049] S3. Sieve the particles using 50-mesh and 65-mesh stainless steel sieves to control the particle size to 250-355 μm, mix the sieved particles with the prescribed amount of colloidal silicon dioxide for 4 minutes, and press into tablets;

[0050] S4. Use the prescribed amount of hydroxypropyl methylcellulose, hydroxypropyl cellulose, yellow iron oxide and titanium dioxide to suspend in water, spray coating, the coating weight gain is 3.35%, and the product is obtained after drying.

[0051] Example 4

[0052] A ramelteon tablet, the prescription composition is:

[0053]

[0054] Prepared by the following method:

[0055] S1. Slowly add the prescribed amount of copovidone to 78% ethanol at 42°C and stir for 20 minutes to prepare a 5.5% adhesive solution, then add the prescribed amount of ramelteon and stir for 8 minutes to dissolve;

[0056] S2. Evenly mix the prescribed amount of lactose and corn starch in a fluidized bed granulation dryer for 4 minutes, then continuously spray the binder prepared in S1 and the API solution into the granules for granulation, followed by drying.

[0057] The specific operating parameters of the fluidized bed granulation dryer are: the air volume in the initial preheating stage is 13m 3 / h, the inlet air temperature is 74℃, when the material temperature rises to 38℃, adjust the inlet air volume to 62m 3 / h, and at the same time, start the peristaltic pump at 13rpm, the spray gun atomization pressure at 0.8Bar, control the inlet air humidity at 10g / m3, and adjust the inlet air volume to 78m3 during the drying stage. 3 / h, the inlet air temperature is 74℃, and the discharge is controlled at 3% moisture content.

[0058] S3. Sieve the particles using 50-mesh and 65-mesh stainless steel sieves to control the particle size to 250-355 μm, mix the sieved particles with the prescribed amount of colloidal silicon dioxide for 4 minutes, and press into tablets;

[0059] S4. Use the prescribed amount of hydroxypropyl methylcellulose, povidone, yellow iron oxide, titanium dioxide, tryptophan, and sodium edetate to suspend in water, spray coating, and the coating weight gain is 3.42%. After drying, the product is obtained.

[0060] Comparative Example 1

[0061] 8 mg ramelteon tablets were prepared using the components and method of Example 1 in publication number CN101247805A.

[0062] Comparative Example 2

[0063] The same preparation process as in Example 1 was adopted, except that the antioxidants in the coating agent in the formulation were 0.05 mg of sodium edetate and 0.05 mg of tryptophan.

[0064] Comparative Example 3

[0065] The same preparation process as in Example 4 was adopted, except that triethyl citrate was used as a plasticizer in the coating agent in the formulation.

[0066] Test Example 1-Content Uniformity Test

[0067] In order to study the effect of granulation process and particle size on segregation in the tableting process, the same prescription and ingredients as in Example 4 were used, and wet granulation and drying were performed by the granulation process of Comparative Example 1 and Example 4. The particles were then sieved with different sieves and then tableted after mixing with a lubricant. Ten tablets of the experimental preparation were collected from each group, and the content of ramelteon was determined by high performance liquid chromatography. The average content of the main drug was calculated, and the standard deviation was calculated. The results are shown in Table 1.

[0068] Table 1 Content uniformity results of ramelteon

[0069]

[0070] From the above table, compared with the traditional process, the content uniformity of small size preparation can be further improved by adding the raw material into the binder solution, the possible reason is that ramelteon is uniformly dispersed in the binder liquid in a molecular state, and ramelteon and copovidone are solidified together in the interior of the granules during the spray granulation process, forming a "drug-excipient co-precipitation structure", so that the drug is uniformly distributed in the interior of the granules, thereby avoiding local concentration fluctuation during mixing; when the particle size of the wet granulation is greater than 250 μm, the mixing uniformity of the tabletting material can be improved; when the particle size range is 250-355 μm, the segregation of the powder in the hopper during the tabletting process is effectively inhibited, and at the same time, there is a synergistic effect between the drug dissolved in the binder solution and the spray addition, thereby further improving the mixing uniformity of the material. The possible reason is that the particle size is moderate at this time, the flowability is good, and the packing density is high, thereby inhibiting the stratification of the material during tabletting. In the wet granulation process of Comparative Example 1, ramelteon is mixed with excipients in the form of solid powder, and the density and particle size difference between the drug particles and the excipient particles leads to stratification during mixing; in addition, ramelteon adheres to the surface of the granules, and is easily detached with the rolling of the granules, leading to local enrichment of the raw material during tabletting, especially for low-dose small-size drug preparations.

[0071] Test Example 2 Storage stability

[0072] The coated tablets prepared in Examples 1-4 and Comparative Example 1 were stored at 60°C for 1 month, and the stability was evaluated by determining the ramelteon degradation product by HPLC, and the results are shown in Table 2. The specific detection parameters of HPLC are prior art, and are not described here.

[0073] Table 2 Stability data of each group

[0074]

[0075] From Table 2, the stability of Examples 1-2 is comparable to that of Comparative Example 1, and has good storage stability; by selecting propylene glycol as a plasticizer, the degradation of ramelteon can be effectively inhibited in Example 3; compared with Comparative Examples 2 and 3, by selecting propylene glycol as a plasticizer in Example 4, the decrease of ramelteon can be inhibited; compared with Example 3, by adding sodium edetate and tryptophan in a mass ratio of 1:1 into the coating in Example 4, the total impurity content is significantly reduced, and the decrease amplitude of the total impurity is lower than the sum of Comparative Example 2 and Example 3, indicating that the addition of a specific combination of antioxidants in the coating can produce synergy with propylene glycol, effectively inhibiting the degradation of ramelteon.

[0076] Although the present application is disclosed as above, the present application is not limited thereto. Any person skilled in the art, without departing from the spirit and scope of the present application, can make various changes and modifications, therefore the protection scope of the present application should be subject to the scope defined by the claims.

Claims

1. A ramelteon tablet, characterized in that, The invention comprises the following components: 8 parts of ramelteon, 5-7 parts of copovidone, 109-112 parts of a filler, 0.8-1.3 parts of a lubricant, and 4.2-4.5 parts of a coating agent, wherein ramelteon and copovidone are dissolved in 75-85% ethanol and added by spraying for wet granulation, and the particle size of the prepared ramelteon-containing particles is 250-355 μm. The coating agent comprises 3.5-4 parts of a coating material, 0.5-1 part of a plasticizer, 0.45-0.55 parts of a sunscreen, and 0.05-0.15 parts of an antioxidant, wherein the coating material is hypromellose, the plasticizer is propylene glycol, the antioxidant is composed of tryptophan and sodium edetate in a mass ratio of 1:0.8-1.2, and the filler is composed of 92.8-95.1 parts of lactose and 15.1-17.4 parts of corn starch.

2. Ramelteon tablets according to claim 1, characterized in that, The lubricant is one of magnesium stearate, stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearyl fumarate, talc, and hydrogenated vegetable oil.

3. The method for preparing the ramelteon tablets according to any one of claims 1 to 2, wherein The steps include: S1. Slowly add the prescribed amount of copovidone to 78%-85% ethanol at 40°C-45°C and stir for 10-25 minutes to prepare a 5.5%-6.5% adhesive solution. Then add the prescribed amount of ramelteon and stir for 8-12 minutes to dissolve. S2. Evenly mix the prescribed amount of lactose and corn starch in a fluidized bed granulation dryer for 4-7 minutes, then continuously spray the binder prepared in S1 and the API solution into the granules for granulation, followed by drying. S3. Sieve the particles using 50-mesh and 65-mesh stainless steel sieves to control the particle size to 250-355 μm, mix the sieved particles with the prescribed amount of lubricant for 4-6 minutes, and press into tablets; S4. Use the prescribed amount of hydroxypropyl methylcellulose, plasticizer, sunscreen and antioxidant to suspend in water, spray coating, and the coating weight gain is 3.35%-3.45%. After drying, the product is obtained.

4. The method for preparing ramelteon tablets according to claim 3, wherein The operating parameters of the fluidized bed granulation dryer in step S2 are: the air volume in the initial preheating stage is 13-17m 3 / h, the inlet air temperature is 74-80℃, when the material temperature rises to 38-42℃, adjust the inlet air volume to 58-62m 3 / h, and at the same time, start the peristaltic pump speed at 12-15rpm, the spray gun atomization pressure at 0.8-12Bar, control the inlet air humidity at 8-10g / m3, and adjust the inlet air volume to 70-78m3 during the drying stage. 3 / h, the inlet air temperature is 70-74℃, and the discharge is controlled at 3% moisture content.

Images