Ramelteon tablet and preparation method thereof

Abstract

The invention provides a ramelteon tablet and a preparation method thereof, the ramelteon tablet 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, ramelteon and copovidone are dissolved in 75-85% ethanol, the mixture is sprayed and added for wet granulation, and the particle size of particles containing ramelteon is 250-355 [mu] m. According to the ramelteon tablet and the preparation method disclosed by the invention, the ramelteon is dissolved in the adhesive solution to be sprayed and added for wet granulation, so that the content uniformity of a small-specification preparation prepared by taking the copovidone as an adhesive can be improved; and segregation and layering of the powder in the hopper in the tabletting process can be effectively inhibited by selecting the particles with the specific particle size, the content uniformity can be further improved compared with other particle size ranges, and the production quality controllability is high.

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 pressure, the number of patients with sleep disorders is increasing. According to data from the World Health Organization, 27% of people globally have sleep problems, and in China, the proportion of people suffering from various sleep disorders is as high as 38.2%.

[0003] At present, the anti-insomnia drugs approved for marketing in China are 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 sleep aids recommended by mainstream guidelines. However, these drugs are addictive and long-term use will reduce deep sleep and disrupt the sleep structure.

[0004] As a melatonin receptor agonist, ramelteon can selectively activate melatonin receptor type 1 and type 2 (MT1, MT2), without acting on MT3 receptor, and can increase slow-wave sleep (SWS) and rapid eye movement sleep (REW) to reduce insomnia. The ramelteon tablet was developed by Takeda Pharmaceutical Company of Japan and was launched in the United States and Japan in 2005 and 2010 respectively, under the trade name "ROZEREM". It is the first non-addictive insomnia treatment drug not listed under special control. Its production process is: mixing hydrated lactose, corn starch and ramelteon, spraying granulation with an aqueous solution of hydroxypropyl cellulose, sizing after granulation, mixing with magnesium stearate and then tabletting, and coating to obtain the product.

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

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

[0007] The problem solved by the present invention is that when copovidone is used as a binder, the mixing uniformity of the materials is poor, and segregation is likely to occur during tabletting, which is not conducive to the quality control of this small-specification preparation of ramelteon tablet.

[0008] To solve the above problems, the present invention provides a ramelteon tablet, comprising the following components: 8 parts of ramelteon, 5 - 7 parts of copovidone, 109 - 112 parts of filler, 0.8 - 1.3 parts of lubricant, and 4.2 - 4.5 parts of coating agent. Among them, ramelteon and copovidone are dissolved in 75 - 85% ethanol and added by spraying for wet granulation. The particle size of the prepared ramelteon-containing granules is 250 - 355 μm.

[0009] Preferably, the filler includes one of lactose, sucrose, mannitol, erythritol, sorbitol, xylitol, and also includes one of corn starch, potato starch, rice starch, and partial 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 stearoyl fumarate, talc powder, and hydrogenated vegetable oil.

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

[0012] Preferably, the coating material includes 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. 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 in a mass ratio of 1:0.8 - 1.2.

[0014] The present invention also provides a preparation method of the ramelteon tablet, comprising the following steps:

[0015] S1. Slowly add the prescribed amount of copovidone to 78% - 85% ethanol at 40°C - 45°C and stir for 10 - 25 min to prepare an adhesive solution containing 5.5% - 6.5%. Then add the prescribed amount of ramelteon and stir for 8 - 12 min to dissolve and set aside.

[0016] S2. Uniformly mix the prescribed amount of lactose and corn starch in a fluidized bed granulator and dryer for 4 - 7 min. Then continuously spray the adhesive and raw material drug solution prepared in S1 for granulation, and then dry.

[0017] S3. Screen with 50 - and 65 - mesh stainless steel sieves respectively to control the particle size of the granules within 250 - 355 μm. Mix the sieved granules with the prescribed amount of lubricant for 4 - 6 min and press into tablets.

[0018] S4. Suspend hydroxypropyl methylcellulose, plasticizer, colorant, and antioxidant in an amount corresponding to the prescription in water, and perform spray coating with a coating weight gain of 3.35% - 3.45%. Obtain the product after drying.

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

[0020] Compared with the prior art, the ramelteon tablets and the preparation method thereof according to the embodiments of the present invention have the following beneficial effects: 1) When preparing tablets with copovidone as the binder, by dissolving ramelteon in the binder solution and spraying it in for wet granulation, the content uniformity of small - specification preparations can be improved; 2) When the particle size of wet granulation is 250 - 355 μm, the particles have a moderate size, a high packing density, and good fluidity themselves, thus effectively suppressing the segregation and layering of the powder in the hopper during the tableting process, and further improving the content uniformity compared with other particle size ranges, and the production quality is highly controllable; 3) For the coating step, selecting propylene glycol as the plasticizer can reduce the degradation of ramelteon, and adding an antioxidant with a specific ratio to the coating agent can produce a synergistic effect with propylene glycol, further improving the stability of ramelteon tablets. Detailed Embodiments

[0021] To make the above - mentioned objects, features, and advantages of the present invention more obvious and understandable, the following provides a detailed description of the specific embodiments of the present invention. The experimental methods in the embodiments of this application that do not specify specific conditions are carried out according to conventional methods and conditions, or selected according to the product instructions. On the premise of no conflict, the technical features of the embodiments of the present invention can be combined with each other.

[0022] Ramelteon mainly induces sleep by guiding the sleep center and inhibits the autonomic nerve by maintaining the parasympathetic nerve. It is a drug that regulates the melatonin effect related to the sleep - wake cycle of the biological rhythm and induces natural drowsiness. Since it has almost no dependence, it is not designated as a psychotropic drug or an addictive drug.

[0023] Since the single tablet weight of ramelteon tablets is 130 mg / tablet, containing 8 mg of ramelteon, it belongs to a small specification preparation, and its content uniformity will affect the final drug efficacy. The applicant found that although using copovidone as a binder can improve the stability of the final tablets, the mixing uniformity of the materials is poor. Therefore, the applicant proposed the following technical solutions:

[0024] Example 1

[0025] A kind of ramelteon tablet, the prescription composition is as follows:

[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 min to prepare a binder solution containing 6%. Then add the prescribed amount of ramelteon and stir for 10 min to dissolve and set aside;

[0029] S2. Uniformly mix the prescribed amounts of lactose and corn starch in a fluidized bed granulator dryer for 5 min, and then continuously spray the binder solution prepared in S1 into the raw material drug solution for granulation and then drying;

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

[0031] S3. Screen with stainless steel sieves of 50 and 65 meshes respectively, control the particle size of the particles at 250 - 355 μm, mix the sieved particles with the prescribed amount of magnesium stearate for 6 min, and press into tablets;

[0032] S4. Suspend the prescribed amounts of hypromellose, polyethylene glycol 6000, iron oxide yellow, and titanium dioxide in water, spray coating, with a coating weight gain of 3.35%, and obtain the product after drying.

[0033] Example 2

[0034] A kind of ramelteon tablet, the prescription composition is as follows:

[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 min to prepare an adhesive solution containing 6.5%. Then add the prescribed amount of ramelteon and stir for 12 min until dissolved for standby.

[0038] S2. Uniformly mix the prescribed amounts of lactose and corn starch in a fluidized bed granulator dryer for 7 min. Then continuously spray the adhesive solution prepared in S1 and the API solution for granulation, and then dry.

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

[0040] S3. Screen with stainless steel sieves of 50 and 65 meshes respectively, control the particle size of the granules at 250 - 355 μm, mix the sieved granules with the prescribed amount of calcium stearate for 4 min, and press into tablets.

[0041] S4. Suspend the prescribed amounts of povidone, glycerin, yellow iron oxide, and titanium dioxide in water for spray coating, with a coating weight gain of 3.35%. Obtain the product after drying.

[0042] Example 3

[0043] A ramelteon tablet, with the following prescription composition:

[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 min to prepare an adhesive solution containing 5.5%. Then add the prescribed amount of ramelteon and stir for 8 min until dissolved for standby.

[0047] S2. Uniformly mix the prescribed amounts of lactose and corn starch in a fluidized bed granulator dryer for 4 min. Then continuously spray the adhesive solution prepared in S1 and the API solution for granulation, and then dry.

[0048] The specific operating parameters of the fluidized bed granulator dryer are as follows: the inlet air volume in the initial preheating stage is 13 m 3 / h, the inlet air temperature is 74°C. When the material rises to 38°C, adjust the inlet air volume to 62 m3 / h, while starting the peristaltic pump at a rotational speed of 13 rpm, the atomization pressure of the spray gun at 0.8 Bar, controlling the inlet air humidity at 10 g / m3, and adjusting the inlet air volume to 78 m 3 / h, the inlet air temperature at 74 °C, and discharging when controlling the moisture content at 3%.

[0049] S3. Screen with stainless steel sieves of 50 and 65 meshes respectively, control the particle size of the particles at 250 - 355 μm, mix the sieved particles with the prescribed amount of colloidal silica for 4 min, and press into tablets;

[0050] S4. Suspend the prescribed amount of hypromellose, hydroxypropyl cellulose, yellow iron oxide, and titanium dioxide in water, spray-coat, with a coating weight gain of 3.35%, and obtain the product after drying.

[0051] Example 4

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

[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 min to prepare a binder solution containing 5.5%, then add the prescribed amount of ramelteon and stir for 8 min to dissolve for standby;

[0056] S2. Uniformly mix the prescribed amount of lactose and corn starch in a fluidized bed granulator dryer for 4 min, then continuously spray the binder solution prepared in S1 into the raw material drug solution for granulation and then dry;

[0057] The specific operating parameters of the fluidized bed granulator dryer are: the inlet air volume in the initial preheating stage is 13 m 3 / h, the inlet air temperature is 74 °C, when the material rises to 38 °C, adjust the inlet air volume to 62 m 3 / h, while starting the peristaltic pump at a rotational speed of 13 rpm, the atomization pressure of the spray gun at 0.8 Bar, controlling the inlet air humidity at 10 g / m3, and adjusting the inlet air volume to 78 m 3 / h, the inlet air temperature at 74 °C, and discharging when controlling the moisture content at 3%.

[0058] S3. Screen with stainless steel sieves of 50 and 65 meshes respectively, control the particle size of the particles at 250 - 355 μm, mix the sieved particles with the prescribed amount of colloidal silica for 4 min, and press into tablets;

[0059] S4. Suspend the prescribed amount of hypromellose, povidone, iron oxide yellow, titanium dioxide, tryptophan, and sodium edetate in water, and perform spray coating with a coating weight gain of 3.42%. After drying, it is obtained.

[0060] Comparative Example 1

[0061] Prepare 8 mg of ramelteon tablets using the components and method of Example 1 in Publication No. CN101247805A.

[0062] Comparative Example 2

[0063] Use the same preparation process as in Example 1, with the difference that the antioxidants in the coating agent in the prescription are 0.05 mg of sodium edetate and 0.05 mg of tryptophan.

[0064] Comparative Example 3

[0065] Use the same preparation process as in Example 4, with the difference that triethyl citrate is used as a plasticizer in the coating agent in the prescription.

[0066] Test Example 1 - Content Uniformity Test

[0067] To study the influence of the granulation process and particle size on segregation during tableting, use the same prescription and components as in Example 4. Through the granulation processes of Comparative Example 1 and Example 4, perform wet granulation and drying, then screen the granules with different sieves, and then mix with lubricants and tableting. Collect 10 tablets of the experimental preparation in each group, determine the content of ramelteon by high performance liquid chromatography, calculate the average content of the main drug, and calculate the standard deviation. The results are shown in Table 1.

[0068] Table 1 Content Uniformity Results of Ramelteon

[0069]

[0070] As can be seen from the above table, compared with the traditional process, spraying and adding the active pharmaceutical ingredient dissolved in the binder solution can further improve the content uniformity of small-scale preparations. The possible reason is that ramelteon is uniformly dispersed in the binder liquid in molecular state, and ramelteon and copovidone are co-cured inside the granules during the spray granulation process, forming a "drug-excipient co-precipitation structure", which makes the drug evenly distributed inside the granules, thus avoiding local concentration fluctuations during mixing; when the particle size of wet granulation is greater than 250 μm, the mixing uniformity of the tableting material can be improved; when the particle size range is 250-355 μm, the segregation of the powder in the hopper during the tableting process can be effectively inhibited, and there is a synergistic effect with spraying and adding the drug dissolved in the binder solution, thus further improving the mixing uniformity of the material. The possible reason for the analysis is that the particle size is appropriate at this time, with good fluidity and high packing density, which can inhibit the layering of the material during the tableting process. In the wet granulation process of Comparative Example 1, ramelteon is dry-mixed with the excipient in the form of solid powder, and the density and particle size differences between the drug particles and the excipient particles easily lead to layering during mixing; in addition, ramelteon adheres to the surface of the particles and is easily detached as the particles roll, resulting in local enrichment of the active pharmaceutical ingredient during tableting, especially for low-dose small-scale 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 measuring the degradation products of ramelteon by HPLC. The specific detection parameters of HPLC are prior art and will not be elaborated here.

[0073] Table 2 Stability Data of Each Group

[0074]

[0075] As can be seen from Table 2, the stability of Examples 1-2 is comparable to that of Comparative Example 1, and they have good storage stability; while in Example 3, by selecting propylene glycol as the plasticizer, the degradation of ramelteon can be effectively inhibited; compared with Comparative Example 2 and Comparative Example 3, in Example 4, propylene glycol is selected as the plasticizer, which can inhibit the reduction of ramelteon; compared with Example 3, in Example 4, after adding sodium edetate and tryptophan with a mass ratio of 1:1 to the coating, the final total impurity content is significantly reduced, and the decrease amplitude of the total impurities is lower than the sum of Comparative Example 2 and Example 3, indicating that adding a specific combination of antioxidants to the coating can synergize with propylene glycol to effectively inhibit the degradation of ramelteon.

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

Claims

1. A ramelteon tablet, characterized in that, It comprises the following components: 8 parts of ramelteon, 5 - 7 parts of copovidone, 109 - 112 parts of filler, 0.8 - 1.3 parts of lubricant, 4.2 - 4.5 parts of coating agent. Among them, ramelteon and copovidone are dissolved in 75 - 85% ethanol and added by spraying for wet granulation. The particle size of the granules containing ramelteon is 250 - 355 μm. The coating agent comprises 3.5 - 4 parts of coating material, 0.5 - 1 part of plasticizer, 0.45 - 0.55 part of light-shielding agent, 0.05 - 0.15 part of antioxidant. The plasticizer is propylene glycol. The antioxidant is composed of tryptophan and sodium edetate in a mass ratio of 1:0.8 - 1.

2.

2. The ramelteon tablets according to claim 1, characterized in that, The filler includes one of lactose, sucrose, mannitol, erythritol, sorbitol, xylitol, trehalose, sucrose, and also includes one of corn starch, potato starch, rice starch, and partial pregelatinized starch.

3. The 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 powder, and hydrogenated vegetable oil.

4. The ramelteon tablets according to claim 1, characterized in that, The coating material includes 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.

5. The preparation method of ramelteon tablets according to any one of claims 1-4, characterized in that, It includes the following steps: S1. Slowly add the prescribed amount of copovidone into 78% - 85% ethanol at 40°C - 45°C and stir for 10 - 25 min to prepare an adhesive solution containing 5.5% - 6.5%. Then add the prescribed amount of ramelteon and stir for 8 - 12 min until dissolved for standby. S2. Uniformly mix the prescribed amount of lactose and corn starch in a fluidized bed granulator dryer for 4 - 7 min, and then continuously spray the adhesive solution prepared in S1 into the raw material drug solution for granulation and then dry. S3. Screen with 50 - and 65 - mesh stainless steel sieves respectively to control the particle size of the granules within 250 - 355 μm. Mix the sieved granules with the prescribed amount of lubricant for 4 - 6 min and compress into tablets. S4. Suspend the prescribed amount of hydroxypropyl methyl cellulose, plasticizer, coloring agent, and antioxidant in water for spray coating. The coating weight gain is 3.35% - 3.45%. After drying, it is obtained.

6. The preparation method of ramelteon tablets according to claim 5, characterized in that, In step S2, the operating parameters of the fluidized bed granulator dryer are as follows: the air intake volume in the initial preheating stage is 13 - 17 m 3 / h, the air intake temperature is 74 - 80 °C. When the material rises to 38 - 42 °C, adjust the air intake volume to 58 - 62 m 3 / h. At the same time, start the peristaltic pump with a rotation speed of 12 - 15 rpm, the atomization pressure of the spray gun is 0.8 - 12 Bar, control the air intake humidity at 8 - 10 g / m3. In the drying stage, adjust the air intake volume to 70 - 78 m 3 / h, the air intake temperature is 70 - 74 °C, and discharge the material when the moisture content is controlled at 3%.

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