A ramelteon buccal microtablet and a preparation method and application thereof

Abstract

The application belongs to the technical field of medicine preparation, and specifically discloses a ramelteon buccal microtablet which is prepared from the following raw materials in parts by weight: 3.33-26.67 parts of ramelteon, 66.33-89.67 parts of diluent, 5 parts of disintegrant, 1 part of binder and 1 part of lubricant, and the sum of the parts by weight of the above raw materials is 100 parts. The ramelteon buccal microtablet of the application is placed in the buccal mucosa area, directly absorbed into the superior vena cava by relying on the rich capillary vessels of the buccal mucosa, bypasses the gastrointestinal tract and the liver for the first round of metabolism, greatly reduces the first-pass elimination loss, greatly reduces the dosage required for the same total drug effect, and realizes rapid induction of sleep. Moreover, the preparation process of the application is simple and convenient for popularization and application.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a rametamide buccal microplate, its preparation method, and its application. Background Technology

[0002] Rametamide has a chemical structure similar to melatonin. It can selectively bind to melatonin MT1 and MT2 receptors, mimicking the effects of melatonin to regulate the human sleep-wake cycle, thereby inducing sleep, improving sleep efficiency, and enhancing sleep quality. Moreover, it does not act on γ-aminobutyric acid (GABA) receptors, thus avoiding some of the adverse reactions of traditional sedative-hypnotic drugs, such as addiction and tolerance.

[0003] Ramelteon, developed by Takeda Pharmaceutical Company of Japan, was approved by the US FDA in July 2005. The approved tablet strength is 8mg, marketed under the brand name Rozerem. It was the first melatonin receptor agonist clinically used to treat insomnia, primarily for difficulty falling asleep, and also effective for chronic and short-term insomnia. Ramelteon tablets are absorbed into the stomach via the esophagus, dissolved in the intestines, and enter the liver via the portal vein. Ramelteon undergoes strong first-pass metabolism by the liver's CYP1A2, resulting in a bioavailability of only about 1.8%. A large amount of the drug is prematurely degraded in the liver, requiring a high dose of 8mg to achieve an effective brain concentration. However, the 8mg strength of ramelteon has significant side effects. Sensitive individuals, the elderly, and those with mild to moderate insomnia are highly susceptible to overdose when taking 8mg directly. After oral administration, it rapidly disintegrates and is absorbed, resulting in a very high peak plasma concentration (Cmax). This leads to a large short-term exposure, easily causing symptoms such as hangover (dizziness, drowsiness, fatigue), headache, and daytime sleepiness.

[0004] Therefore, it is essential to develop a rametamide drug formulation that can bypass the first-pass metabolism in the gastrointestinal tract and liver and effectively reduce first-pass elimination loss. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention aims to provide a rametamide buccal microplate and its preparation method. The rametamide buccal microplate of this invention can significantly reduce the first-pass effect and be directly absorbed into the bloodstream through the rich capillaries of the buccal mucosa.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] A ramelteamide buccal microplate is made from the following raw materials in parts by weight: ramelteamide 3.33-26.67 parts, diluent 66.33-89.67 parts, disintegrant 5 parts, binder 1 part, lubricant 1 part, the sum of the above raw material parts is 100 parts.

[0008] Preferably, the diluent is selected from one or more of mannitol, microcrystalline cellulose, and lactose; the disintegrant is crospovidone; the binder is selected from one or two of hydroxypropyl methylcellulose and gelatin; and the lubricant is magnesium stearate.

[0009] Preferably, the diluent is a composition of mannitol and microcrystalline cellulose; the binder is hydroxypropyl methylcellulose.

[0010] Preferably, the mannitol is of type 25C, the microcrystalline cellulose is of type pH101, and the hydroxypropyl methylcellulose is of type E5.

[0011] Based on the same inventive concept, the method for preparing rameltethan buccal microplates includes the following steps:

[0012] S1. Mixing: Add rameltetinamide, diluent, and disintegrant to a wet mixer and stir for 12-18 minutes at a stirring speed of 450-550 rpm and a cutting speed of 280-320 rpm.

[0013] S2. Preparation of the adhesive: Weigh the prescribed amount of adhesive and slowly add it to water while stirring. Stir until completely dissolved to prepare an adhesive aqueous solution. The mass concentration of the adhesive aqueous solution is 4-6%.

[0014] S3. Wet granulation: The adhesive aqueous solution is sprayed into the mixture in S1 at a spraying speed of 5-10 rpm and a spraying pressure of 0.8 bar. The stirring speed during spraying is 450-550 rpm and the cutting speed is 750-850 rpm. After spraying, the granulation is completed in 25-35 seconds and wet granulation is performed through a 20-40 mesh sieve.

[0015] S4. Drying: Dry at 55-65℃ with forced air for 1-3 hours, moisture content ≤2.0%, then sieve through 20-25 mesh and granulate.

[0016] S5. Mix the lubricant and the prepared dry granules in a mixer at a speed of 10 rpm for 3 minutes.

[0017] S6. The tablets can be pressed into micro-tablets using a tableting mold.

[0018] The application of the rameltethan buccal microplates in the preparation of drugs for achieving rapid sleep induction.

[0019] This invention further discloses the application of the rameltetin-doxepin compound buccal microparticles in the preparation of drugs for achieving rapid sleep induction and sustained sleep maintenance. Rameltetin, as a melatonin receptor agonist, can regulate the sleep-wake cycle and rapidly improve difficulty falling asleep. When prepared as buccal microparticles and placed in the buccal mucosa, it is directly absorbed into the superior vena cava via the rich capillaries of the buccal mucosa, thus bypassing the first-pass metabolism in the gastrointestinal tract and liver, significantly reducing first-pass elimination loss, and drastically lowering the dosage required for the same total efficacy. Furthermore, the rameltetin-based microparticles of this invention are only 3mm in size, causing no discomfort when placed in the buccal area, and can dissolve and be absorbed rapidly. Attached Figure Description

[0020] Figure 1 The dissolution curve of the buccal microplates of formulation 3 rametamide of this invention;

[0021] Figure 2 The dissolution curve of the buccal microplates of formulation 8, rametamide, is shown in this invention. Detailed Implementation

[0022] The technical solutions of the present invention will be clearly and completely described below with reference to specific embodiments.

[0023] Example 1: The Influence of Different Preparation Processes on the Invention

[0024] This embodiment presents two preparation processes for rameltetinide buccal microtablets, namely Formula 1 and Formula 2, and their raw material composition, preparation process and tableting results are shown in Table 1.

[0025] Table 1. Raw material composition, preparation process, and tableting results of Formula 1 and Formula 2

[0026]

[0027] Among them, the preparation process of Formula 1 is to directly compress the formula components into powder without adding binders.

[0028] The preparation process of Formula 2 involves wet granulation, using a 5% hydroxypropyl methylcellulose E5 aqueous solution as the binder. The preparation method includes the following steps:

[0029] S1, Mix

[0030] Weigh ramelteamide, diluent, and disintegrant in sequence according to the prescription. Add the materials to a wet mixer and stir for 15 minutes at a stirring speed of 500 rpm and a cutting speed of 300 rpm.

[0031] S2, Adhesive formulation

[0032] To prepare a 5% (w / w) aqueous solution of adhesive, weigh out the prescribed amount of adhesive and slowly add it to the aqueous solution while stirring until completely dissolved.

[0033] S3, Wet Granulation

[0034] The adhesive is sprayed into the mixed material at a spraying speed of 8 rpm and a spraying pressure of 0.8 bar. The stirring speed during spraying is 500 rpm, and the cutting speed is 800 rpm. After spraying, the material is granulated for 30 seconds and then wet-granulated through a 30-mesh sieve.

[0035] S4, Drying

[0036] Dry at 60℃ with forced air for 1 hour, moisture content ≤2.0%, then sieve dry and granulate through a 24-mesh sieve;

[0037] S5, General Mixing

[0038] Weigh the lubricant according to the prescription, mix the dry granules with the lubricant in a mixer at 10 rpm for 3 minutes;

[0039] S6, tableting

[0040] Microsheets are pressed using a 3mm mold.

[0041] As shown in Table 1, when using direct powder compression, the material has poor flowability and cannot be directly compressed into tablets. Therefore, this invention uses a wet granulation process for sample preparation.

[0042] It should be noted that in other implementation methods,

[0043] S1. Mixing: Add ramelteinamide, diluent, and disintegrant to a wet mixer and stir for 12-18 minutes, for example, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, or 18 minutes; stirring speed 450-550 rpm, for example, 450 rpm, 500 rpm, or 550 rpm; cutting speed 280-320 rpm, for example, 280 rpm, 300 rpm, or 320 rpm; the diluent is selected from one or more of mannitol, microcrystalline cellulose, and lactose; the disintegrant is crospovidone.

[0044] S2. Adhesive Preparation: The mass concentration of the adhesive aqueous solution is 4-6%, for example, it can be 4%, 5%, or 6%; the adhesive is selected from one or two of hydroxypropyl methylcellulose and gelatin; for example, it can be hydroxypropyl methylcellulose or gelatin or a combination of both;

[0045] S3. In wet granulation, the spraying speed is 5-10 rpm, for example, 5 rpm, 6 rpm, 7 rpm, 8 rpm, 9 rpm, or 10 rpm; the spraying pressure is 0.8 bar; the stirring speed during spraying is 450-550 rpm, for example, 450 rpm, 500 rpm, or 550 rpm; the cutting speed is 750-850 rpm, for example, 750 rpm, 800 rpm, or 850 rpm; after spraying, granulation takes 25-35 seconds, for example, 25 seconds, 30 seconds, or 35 seconds; wet granulation is performed using a 20-40 mesh sieve, for example, 20 mesh, 30 mesh, or 40 mesh.

[0046] S4. Drying: Dry at 55-65℃ with forced air for 1-3 hours, for example, 65℃ with forced air for 1 hour, 55℃ with forced air for 3 hours, moisture content ≤2.0%, then sieve through 20-25 mesh for granulation, for example, 20 mesh or 25 mesh.

[0047] Example 2: Effect of different types of diluents on the buccal microplates of the present invention

[0048] This embodiment provides buccal microplates with different diluents, namely Formula 3, Formula 4 and Formula 5, and their raw material composition, preparation process and tableting results are shown in Table 2.

[0049] Table 2. Raw material composition, preparation process and tableting results of prescriptions 3-5

[0050]

[0051] As can be seen from Table 2, when lactose G200US and mannitol 25C are selected as diluents, the tablets have poor formability during compression. When microcrystalline cellulose pH101 is combined with mannitol 25C or microcrystalline cellulose pH101 is combined with lactose G200US, the compressibility is good. However, considering the disintegration time, the combination of microcrystalline cellulose pH101 and mannitol 25C is better than the combination of microcrystalline cellulose pH101 and lactose G200US.

[0052] Example 3: The effect of different types and models of adhesives on the buccal microplates of the present invention

[0053] This embodiment provides buccal microplates with different flavoring agents, namely prescription 3, prescription 6 and prescription 7, and their raw material composition, preparation process and tableting results are shown in Table 3.

[0054] Table 3. Raw material composition, preparation process, and tableting results of prescriptions 2 and 3, and prescriptions 6-7.

[0055]

[0056] As shown in Table 3, when the adhesive is a 5% aqueous solution of hydroxypropyl methylcellulose E5, it has good compressibility and short tablet disintegration time (4s). Changing the type or type of adhesive results in a longer tablet disintegration time or uneven particle size and clumping during tableting. Therefore, hydroxypropyl methylcellulose E5 is preferred as the adhesive of this invention.

[0057] Example 4: Effect of different specifications on the buccal microplate of the present invention

[0058] This embodiment provides buccal microplates of different specifications, namely prescriptions 3 and 8, and their raw material composition, preparation process and tableting results are shown in Table 5.

[0059] Table 4. Raw material composition, preparation process and tableting results of prescriptions 3 and 8

[0060]

[0061] As shown in Table 5, regardless of whether the tablet is 4mg or 0.5mg, its compressibility is good, and the tablet disintegration time is short, reaching 4s.

[0062] Performance testing: Dissolution test

[0063] Taking prescriptions 3 and 8 as examples, dissolution experiments were conducted on the obtained buccal microplates. The results are shown in Table 5 and 6. Figure 1 , Figure 2 As shown.

[0064] Table 5 Dissolution Experiment and Results

[0065]

[0066] The dissolution results of Formula 3 and Formula 8 samples in pH 6.8 phosphate buffer show that the buccal microparticles of the present invention were completely dissolved within 1 minute. Since the pH value of the human oral cavity is 6.5-7.5, the buccal microparticles can rapidly disintegrate and dissolve in the oral cavity to achieve rapid absorption.

[0067] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any simple modifications, alterations, and equivalent changes made by those skilled in the art to the above embodiments based on the technical essence of the present invention within the scope of the technology disclosed in the present invention shall still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A rameltetinamide buccal microplate, characterized in that, It is made from the following raw materials in parts by weight: 3.33-26.67 parts of ramelteamide, 66.33-89.67 parts of diluent, 5 parts of disintegrant, 1 part of binder, and 1 part of lubricant, with the sum of the above raw material parts being 100 parts.

2. The rameltetin buccal microplate according to claim 1, characterized in that, The diluent is selected from one or more of mannitol, microcrystalline cellulose, and lactose; the disintegrant is crospovidone; the binder is selected from one or two of hydroxypropyl methylcellulose and gelatin; and the lubricant is magnesium stearate.

3. The rameltetin buccal microplate according to claim 2, characterized in that, The diluent is a combination of mannitol and microcrystalline cellulose; the binder is hydroxypropyl methylcellulose.

4. The rameltetin-doxepin compound buccal microplate according to claim 3, characterized in that, The mannitol is designated as 25C, the microcrystalline cellulose as pH101, and the hydroxypropyl methylcellulose as E5.

5. The method for preparing rameltetinamide buccal microplates according to any one of claims 1-4, characterized in that, Includes the following steps: S1. Mixing: Add rameltetinamide, diluent, and disintegrant to a wet mixer and stir for 12-18 minutes at a stirring speed of 450-550 rpm and a cutting speed of 280-320 rpm. S2. Preparation of the adhesive: Weigh the prescribed amount of adhesive and slowly add it to water while stirring. Stir until completely dissolved to prepare an adhesive aqueous solution. The mass concentration of the adhesive aqueous solution is 4-6%. S3. Wet granulation: The adhesive aqueous solution is sprayed into the mixture in S1 at a spraying speed of 5-10 rpm and a spraying pressure of 0.8 bar. The stirring speed during spraying is 450-550 rpm and the cutting speed is 750-850 rpm. After spraying, the granulation is completed in 25-35 seconds and wet granulation is performed through a 20-40 mesh sieve. S4. Drying: Dry at 55-65℃ with forced air for 1-3 hours, moisture content ≤2.0%, then sieve through 20-25 mesh and granulate. S5. Mix the lubricant and the prepared dry granules in a mixer at a speed of 10 rpm for 3 minutes. S6. The tablets can be pressed into micro-tablets using a tableting mold.

6. The use of rameltetinide buccal microplates according to any one of claims 1-4 in the preparation of a medicament for achieving rapid sleep induction.

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