Amlodipine besylate orally disintegrating tablet

Abstract

The application provides amlodipine besylate orally disintegrating tablet and a preparation method. The orally disintegrating tablet has good taste, fast oral disintegration speed and stable quality, can be quickly disintegrated in the oral cavity without drinking water, has no foreign body sensation and residual sensation in the oral cavity basically, and is expected to improve patient medication compliance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an orally disintegrating tablet of amlodipine besylate and its preparation method. Background Technology

[0002] Amlodipine besylate belongs to the dihydropyridine class of calcium channel blockers. It exhibits high vascular selectivity, acting on L-type calcium channels in vascular smooth muscle to inhibit calcium ion influx. This reduces vasoconstrictive reactivity and thus lowers blood pressure, making it a highly effective antihypertensive drug clinically used to treat hypertension and angina. Amlodipine besylate tablets were first approved for marketing in Belgium in 1989 and successfully launched in China in June 1994.

[0003] While commercially available oral amlodipine besylate formulations are effective in managing hypertension, they present significant challenges in administration and have long disintegration times, failing to meet patients' urgent medication needs. Furthermore, traditional tablets are relatively difficult for elderly individuals and children with swallowing difficulties.

[0004] Orally disintegrating tablets disintegrate rapidly in the mouth, providing great convenience for the elderly, children, and patients with swallowing difficulties. They solve the problem of medication administration in situations where access to water is inconvenient or unsuitable, improving patient adherence when traveling or on the go. For patients with chronic diseases such as hypertension, who often experience significant psychological resistance to medication, the "waterless administration" characteristic of orally disintegrating tablets helps reduce their psychological burden. Furthermore, since orally disintegrating tablets disintegrate directly in the mouth, and amlodipine besylate has a bitter and numbing taste, if this taste is not effectively masked, patients may experience strong resistance, affecting medication adherence.

[0005] Chinese patent CN107823153A discloses an orally disintegrating tablet of amlodipine besylate prepared by 3D printing and its preparation method. The 3D printing process can effectively reduce the disintegration time of amlodipine besylate, but the effect on improving the taste is small.

[0006] Chinese patent CN118845681A discloses an orally disintegrating tablet composition of amlodipine besylate and its preparation method. The formulation is shown in the table below. The raw materials of the orally disintegrating tablet composition of amlodipine besylate are mixed, and then compressed into tablets. However, there are limitations in terms of taste. The amlodipine besylate raw material itself has a significant bitter taste, and the active ingredient accounts for 7.71% of the formulation. Adding sucralose, neotame, and peppermint flavoring only through physical mixing to improve the taste is insufficient to completely suppress the rapid release of bitterness after the drug dissolves. This results in noticeable bitter residue during oral disintegration, affecting patient medication adherence.

[0007]

[0008] Chinese patent CN101646461A discloses amlodipine besylate orally disintegrating tablets and their preparation method. The method involves dissolving 80g of hydroxypropyl cellulose (HPC-L, 2% aqueous solution viscosity: 6.0–10.0 mPa·s, manufactured by Nippon Soda Co., Ltd.) in 2320g of purified water to obtain 2400g of adhesive liquid. Then, 69.3g of amlodipine besylate, 936.7g of D-mannitol (β-crystal, average particle size: 43μm, specific surface area: 0.51m² / g), 100g of corn starch (Corn Starch (XX16)W, ​​manufactured by Nippon Food Chemical Co., Ltd.), and polyplasdone are added to a fluidized bed granulator (Multiplex MP-01, manufactured by Powrex Co., Ltd.). 50g of XL-10 (manufactured by ISP) was mixed with 240g of the above-mentioned adhesive liquid, granulated, and dried to obtain approximately 1000g of granulated particles. 1.2g of light anhydrous silica (Aerosil 200, manufactured by Aerosil Corporation of Japan) and 2.4g of sodium stearoyl fumarate (PRUV, manufactured by JRS PHARMA) were added to 116.4g of these granulated particles and mixed to form tableting granules. The obtained tableting granules were compressed using a single-punch tablet press (EK0, manufactured by KORSCH) at a compression force of approximately 7kN to obtain tablets with a diameter of 7mm, a radius of curvature of 10mm, and a weight of 120mg. However, this amlodipine besylate orally disintegrating tablet and its preparation method still have many shortcomings in practical applications. In terms of taste, it cannot effectively mask the bitterness of amlodipine besylate itself, resulting in a poor sensory experience for patients and causing significant discomfort. At the same time, the fluidized bed granulator (Multiplex MP-01, Powrex) used in this patent is a laboratory-grade machine with a small size, suitable only for small-scale research and development, and cannot directly meet the needs of industrial-scale production.

[0009] Therefore, there is a need for an orally disintegrating amlodipine besylate tablet that effectively masks the bitter taste of amlodipine besylate, has a rapid oral disintegration rate, and is convenient and easily accepted by patients. Summary of the Invention

[0010] This invention provides an orally disintegrating tablet of amlodipine besylate, which has a good taste, rapid oral disintegration, and stable quality. It can disintegrate rapidly in the mouth without the need for drinking water, and there is virtually no foreign body sensation or residue in the mouth, which is expected to improve patient medication compliance.

[0011] In a first aspect, the present invention provides an orally disintegrating tablet of amlodipine besylate, comprising an inner part of the granules and an outer part of the granules, wherein the inner part of the granules comprises amlodipine besylate and mannitol.

[0012] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention, based on the total weight of the orally disintegrating tablets, have a weight ratio of amlodipine besylate to mannitol in the granular portion of 1:1 to 1:2.

[0013] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention, based on the total weight of the orally disintegrating tablets, have a weight ratio of amlodipine besylate to mannitol in the granule portion of 1:1 or 1:2.

[0014] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention, based on the total weight of the orally disintegrating tablets, contain 4% to 7% (w / w) amlodipine besylate in the granule portion. In some embodiments, the amlodipine besylate content in the granule portion is 5% to 6% (w / w).

[0015] In some embodiments, the mannitol content in the orally disintegrating tablets of amlodipine besylate, based on the total weight of the orally disintegrating tablets, is 3% to 15% (w / w) in the granule portion. In some embodiments, the mannitol content in the granule portion is 5% to 15% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the mannitol content in the granule portion is 5% to 14% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the mannitol content in the granule portion is 5% to 13% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the mannitol content in the granule portion is 5% to 12% (w / w) based on the total weight of the orally disintegrating tablets.

[0016] In some embodiments, the amlodipine benzyl sulfonate orally disintegrating tablets of the present invention further include a taste-masking composition within the granules. This taste-masking composition comprises a taste-masking agent, a solubilizer, an emulsifier, an anti-adhesion agent, and a defoamer. The taste-masking agent is an amino alkyl methacrylate copolymer. The solubilizer is sodium dodecyl sulfate. The emulsifier is stearic acid. The anti-adhesion agent is talc. The defoamer is simethicone.

[0017] In some embodiments, the content of the flavor masking agent in the flavor masking composition is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the content of the solubilizer in the flavor masking composition is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the content of the emulsifier in the flavor masking composition is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the content of the emulsifier in the flavor masking composition is 0.1% to 0.25% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the content of the anti-sticking agent in the flavor masking composition is 0.6% to 0.7% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the content of the defoamer in the flavor masking composition is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets.

[0018] In some implementations, the amlodipine benzylsulfonate orally disintegrating tablets of the present invention are granulated via fluidized bed granulation.

[0019] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention, wherein the extragranular portion comprises a filler, a disintegrant, a sweetener, a flavoring agent, a colorant, and a lubricant. The filler is selected from microcrystalline cellulose and mannitol; preferably, the filler is a combination of microcrystalline cellulose and mannitol. The disintegrant is crospovidone. The sweetener is sucralose. The flavoring agent is a fragrance. The colorant is ferric oxide. The lubricant is magnesium stearate.

[0020] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention, based on the total weight of the orally disintegrating tablets, have a filler content of 70% to 90% (w / w) in the outer portion. In some embodiments, the filler content in the outer portion is 75% to 85% (w / w) based on the total weight of the orally disintegrating tablets.

[0021] In some embodiments, the orally disintegrating tablets of amlodipine besylate described in this invention have a weight ratio of microcrystalline cellulose to mannitol in the outer portion of the tablets of 1:4 to 1:6 based on the total weight of the orally disintegrating tablets.

[0022] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention, based on the total weight of the orally disintegrating tablets, contain 10% to 15% (w / w) microcrystalline cellulose in the extragranular portion. In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention, based on the total weight of the orally disintegrating tablets, contain 50% to 80% (w / w) mannitol in the extragranular portion. In some embodiments, the mannitol content in the extragranular portion is 55% to 75% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the mannitol content in the extragranular portion is 60% to 70% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the mannitol content in the extragranular portion is 65% to 70% (w / w) based on the total weight of the orally disintegrating tablets.

[0023] In some embodiments, the content of the disintegrant in the extragranular portion is 4.5% to 5.5% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the content of the sweetener in the extragranular portion is 0.05% to 0.1% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the content of the flavoring agent in the extragranular portion is 0.05% to 0.1% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the content of the colorant in the extragranular portion is 0.05% to 0.1% (w / w) based on the total weight of the orally disintegrating tablets. In some embodiments, the content of the lubricant in the extragranular portion is 0.5% to 1.5% (w / w) based on the total weight of the orally disintegrating tablets.

[0024] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention include an inner part and an outer part, wherein the inner part comprises: Amlodipine besylate, with a content of 4% to 7% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content of 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets.

[0025] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention include an inner part and an outer part, wherein the inner part comprises: Amlodipine besylate, with a content of 4% to 7% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content of 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; The weight ratio of amlodipine besylate to mannitol in the internal part of the particles is 1:1 to 1:2.

[0026] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention include an inner part and an outer part, wherein the inner part comprises: Amlodipine besylate, with a content of 4% to 7% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content is 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; The weight ratio of amlodipine besylate and mannitol in the internal part of the particles is 1:1 and 1:2, respectively.

[0027] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention comprise: (1) Internal part of the particle: Amlodipine besylate, with a content of 4% to 7% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content of 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; The weight ratio of amlodipine besylate to mannitol in the granule is 1:1 to 1:2. (2) External part of the particle: Mannitol content is 50% to 80% (w / w) based on the total weight of orally disintegrating tablets; Microcrystalline cellulose with a content of 10% to 15% (w / w) based on the total weight of orally disintegrating tablets; The disintegrant content is 4.5% to 5.5% (w / w) based on the total weight of the orally disintegrating tablets; Sweeteners with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; Flavoring agent with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; The colorant content is 0.05% to 0.1% (w / w) based on the total weight of the orally disintegrating tablets; Lubricant with a content of 0.5% to 1.5% (w / w) based on the total weight of the orally disintegrating tablets.

[0028] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention comprise: (1) Internal part of the particle: Amlodipine besylate, with a content of 4% to 7% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content of 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; The weight ratio of amlodipine besylate and mannitol in the internal part of the particles is 1:1 and 1:2, respectively. (2) External part of the particle: Mannitol content is 50% to 80% (w / w) based on the total weight of orally disintegrating tablets; Microcrystalline cellulose with a content of 10% to 15% (w / w) based on the total weight of orally disintegrating tablets; The disintegrant content is 4.5% to 5.5% (w / w) based on the total weight of the orally disintegrating tablets; Sweeteners with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; Flavoring agent with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; The colorant content is 0.05% to 0.1% (w / w) based on the total weight of the orally disintegrating tablets; Lubricant with a content of 0.5% to 1.5% (w / w) based on the total weight of the orally disintegrating tablets.

[0029] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention include an inner part and an outer part, wherein the inner part comprises: Amlodipine besylate, with a content of 5% to 6% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content of 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesive is 0.6%~0.7% (w / w); Based on the total weight of orally disintegrating tablets, the content of defoaming agent is 0.01%~0.03% (w / w); The weight ratio of amlodipine besylate to mannitol in the internal part of the particles is 1:1 to 1:2.

[0030] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention include an inner part and an outer part, wherein the inner part comprises: Amlodipine besylate content of 5%~6% (w / w) based on the total weight of orally disintegrating tablets. Mannitol content of 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; The weight ratio of amlodipine besylate and mannitol in the internal part of the particles is 1:1 and 1:2, respectively.

[0031] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention comprise: (1) Internal part of the particle: Amlodipine besylate, with a content of 5% to 6% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content of 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; The weight ratio of amlodipine besylate to mannitol in the granule is 1:1 to 1:2. (2) External part of the particle: Mannitol content is 50% to 80% (w / w) based on the total weight of orally disintegrating tablets; Microcrystalline cellulose with a content of 10% to 15% (w / w) based on the total weight of orally disintegrating tablets; The disintegrant content is 4.5% to 5.5% (w / w) based on the total weight of the orally disintegrating tablets; Sweeteners with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; Flavoring agent with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; The colorant content is 0.05% to 0.1% (w / w) based on the total weight of the orally disintegrating tablets; Lubricant with a content of 0.5% to 1.5% (w / w) based on the total weight of the orally disintegrating tablets.

[0032] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention comprise: (1) Internal part of the particle: Amlodipine besylate, with a content of 5% to 6% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content of 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; The weight ratio of amlodipine besylate and mannitol in the internal part of the particles is 1:1 and 1:2, respectively. (2) External part of the particle: Mannitol content is 50% to 80% (w / w) based on the total weight of orally disintegrating tablets; Microcrystalline cellulose with a content of 10% to 15% (w / w) based on the total weight of orally disintegrating tablets; The disintegrant content is 4.5% to 5.5% (w / w) based on the total weight of the orally disintegrating tablets; Sweeteners with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; Flavoring agent with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; The colorant content is 0.05% to 0.1% (w / w) based on the total weight of the orally disintegrating tablets; Lubricant with a content of 0.5% to 1.5% (w / w) based on the total weight of the orally disintegrating tablets.

[0033] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention include an inner part and an outer part, wherein the inner part comprises: Based on the total weight of orally disintegrating tablets, the content of amlodipine besylate is 5.77% (w / w). Mannitol content is 5.83% (w / w) based on the total weight of the orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets.

[0034] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention comprise: (1) Internal part of the particle: Amlodipine besylate, with a content of 5.77% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content is 5.83% (w / w) based on the total weight of the orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; (2) External part of the particle: Mannitol content is 50% to 80% (w / w) based on the total weight of orally disintegrating tablets; Microcrystalline cellulose with a content of 10% to 15% (w / w) based on the total weight of orally disintegrating tablets; The disintegrant content is 4.5% to 5.5% (w / w) based on the total weight of the orally disintegrating tablets; Sweeteners with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; Flavoring agent with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; The colorant content is 0.05% to 0.1% (w / w) based on the total weight of the orally disintegrating tablets; Lubricant with a content of 0.5% to 1.5% (w / w) based on the total weight of the orally disintegrating tablets.

[0035] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention include an inner part and an outer part, wherein the inner part comprises: Based on the total weight of orally disintegrating tablets, the content of amlodipine besylate is 5.77% (w / w). Mannitol content is 11.66% (w / w) based on the total weight of the orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets.

[0036] In some embodiments, the amlodipine besylate orally disintegrating tablets of the present invention comprise: (1) Internal part of the particle: Amlodipine besylate, with a content of 5.77% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content is 11.66% (w / w) based on the total weight of the orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; (2) External part of the particle: Mannitol content is 50% to 80% (w / w) based on the total weight of orally disintegrating tablets; Microcrystalline cellulose with a content of 10% to 15% (w / w) based on the total weight of orally disintegrating tablets; The disintegrant content is 4.5% to 5.5% (w / w) based on the total weight of the orally disintegrating tablets; Sweeteners with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; Flavoring agent with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; The colorant content is 0.05% to 0.1% (w / w) based on the total weight of the orally disintegrating tablets; Lubricant with a content of 0.5% to 1.5% (w / w) based on the total weight of the orally disintegrating tablets.

[0037] Secondly, the present invention provides a method for preparing amlodipine besylate orally disintegrating tablets, comprising: (1) Prepare the odor-masking composition into a suspension for later use; (2) Add amlodipine besylate and a portion of mannitol to a fluidized bed, and spray in a suspension for granulation, drying and sizing; (3) Add the granulated particles and the auxiliary materials outside the particles to the hopper mixer and mix them evenly. After mixing, compress the mixture into tablets.

[0038] In some embodiments, the method for preparing amlodipine besylate orally disintegrating tablets according to the present invention includes: (1) Prepare a suspension by mixing methacrylate alkyl ester copolymer EPO, sodium dodecyl sulfate, stearic acid, talc and simethicone emulsion for later use; (2) Add amlodipine besylate and a portion of mannitol to a fluidized bed, and spray in a suspension for granulation, drying and sizing; (3) After granulation, add the granules, microcrystalline cellulose, mannitol, crospovidone, sucralose, orange powder flavoring, yellow iron oxide and magnesium stearate into the hopper mixer and mix evenly. After mixing, press into tablets.

[0039] The beneficial technical effects of this invention are as follows: (1) The amlodipine besylate orally disintegrating tablets provided by this invention can rapidly disintegrate in the oral cavity. The disintegration time was measured using an orally disintegrating meter, and the disintegration time was less than 60 seconds. (2) The orally disintegrating tablets of amlodipine besylate provided by this invention can effectively mask the bitter and numbing taste of the amlodipine besylate raw material. The palatability was evaluated using the 0-100 point visual analog scale (VAS method), and the evaluation result showed good palatability. (3) The amlodipine benzylsulfonate oral disintegrating tablets provided by the present invention slow down their dissolution in a medium of pH 6.8. Detailed Implementation

[0040] The specific embodiments of the present invention are described in detail below. It should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0041] The equipment and instruments used in the following embodiments are shown in the table below.

[0042]

[0043] The sources of raw materials and excipients used in the following examples are shown in the table below.

[0044]

[0045] Example 1: Preparation of Amlodipine Besylate Orally Disintegrating Tablets prescription:

[0046] *Moisture is removed during the granule drying process, and there is no significant amount of moisture in the final formulation product.

[0047] Preparation method: A suspension was prepared by combining methacrylate amino alkyl copolymer EPO, sodium dodecyl sulfate, stearic acid, talc, and simethicone emulsion. Amlodipine besylate and a portion of mannitol were added to a fluidized bed in an approximately 1:1 ratio, and the suspension was sprayed in for granulation, drying, and sizing. The sized granules and excipients (microcrystalline cellulose, mannitol, crospovidone, sucralose, orange powder flavoring, yellow iron oxide, and magnesium stearate) were added to a hopper mixer and mixed evenly. After mixing, tablets were directly compressed using a 7mm circular punch, with a tablet weight controlled at 120mg.

[0048] Example 2: Preparation of Amlodipine Besylate Orally Disintegrating Tablets prescription:

[0049] *Moisture is removed during the granule drying process, and there is no significant amount of moisture in the final formulation product.

[0050] Preparation method: A suspension was prepared by combining methacrylate amino alkyl copolymer EPO, sodium dodecyl sulfate, stearic acid, talc, and simethicone emulsion. Amlodipine besylate and a portion of mannitol were added to a fluidized bed at a ratio of approximately 1:2. The suspension was then sprayed in for granulation, drying, and sizing. The sized granules and excipients (microcrystalline cellulose, mannitol, crospovidone, sucralose, orange powder flavoring, yellow iron oxide, and magnesium stearate) were added to a hopper mixer and mixed evenly. After mixing, tablets were directly compressed using a 7mm circular punch, with a tablet weight controlled at 120mg.

[0051] Comparative Example 1 prescription:

[0052] Preparation method: Amlodipine besylate, mannitol, microcrystalline cellulose, crospovidone, sucralose, peppermint powder flavoring, yellow iron oxide, and magnesium stearate were added to a hopper mixer and mixed evenly. After mixing, tablets were directly compressed using a 7mm round punch, with a tablet weight controlled at 120mg.

[0053] Comparative Example 2 prescription:

[0054] *Moisture is removed during the granule drying process, and there is no significant amount of moisture in the final formulation product.

[0055] Preparation method: A suspension was prepared by combining methacrylate amino alkyl ester copolymer (EPO), sodium dodecyl sulfate, stearic acid, talc, and simethicone emulsion. Amlodipine besylate and a portion of mannitol were added to a fluidized bed at a ratio of approximately 2:1. The suspension was then sprayed in for granulation, drying, and sizing. The sized granules and excipients (microcrystalline cellulose, mannitol, crospovidone, sucralose, orange powder flavoring, yellow iron oxide, and magnesium stearate) were added to a hopper mixer and mixed evenly. After mixing, tablets were directly compressed using a 7mm circular punch, with a tablet weight controlled at 120mg.

[0056] Comparative Example 3 prescription:

[0057] *Moisture is removed during the granule drying process, and there is no significant amount of moisture in the final formulation product.

[0058] Preparation method: A suspension was prepared by combining methacrylate amino alkyl copolymer EPO, sodium dodecyl sulfate, stearic acid, talc, and dimethicone. Amlodipine benzyl sulfonate was added to a fluidized bed and sprayed into the suspension for granulation, drying, and sizing. The sized granules and excipients (microcrystalline cellulose, mannitol, crospovidone, sucralose, orange powder flavoring, yellow iron oxide, and magnesium stearate) were added to a hopper mixer and mixed evenly. After mixing, tablets were directly compressed using a 7mm round punch, with a tablet weight controlled at 120mg.

[0059] Comparative Example 4 prescription:

[0060] *Moisture is removed during the granule drying process, and there is no significant amount of moisture in the final formulation product.

[0061] A suspension was prepared by mixing methacrylate amino alkyl copolymer EPO, sodium dodecyl sulfate, stearic acid, talc, and dimethicone. Amlodipine benzyl sulfonate and a portion of mannitol were added to a fluidized bed at a ratio of approximately 1:3. The suspension was then sprayed in for granulation, drying, and sizing. The sized granules and excipients (microcrystalline cellulose, mannitol, crospovidone, sucralose, orange powder flavoring, yellow iron oxide, and magnesium stearate) were added to a hopper mixer and mixed evenly. After mixing, tablets were directly compressed using a 7mm circular punch, with a tablet weight controlled at 120mg.

[0062] Preparation method: A suspension was prepared by mixing methacrylate amino alkyl copolymer EPO, sodium dodecyl sulfate, stearic acid, talc, and dimethicone. Amlodipine benzyl sulfonate and a portion of mannitol were added to a fluidized bed at a ratio of approximately 1:3. The suspension was then sprayed in for granulation, drying, and sizing. The sized granules and excipients (microcrystalline cellulose, mannitol, crospovidone, sucralose, orange powder flavoring, yellow iron oxide, and magnesium stearate) were added to a hopper mixer and mixed evenly. After mixing, tablets were directly compressed using a 7mm circular punch, with a tablet weight controlled at 120mg.

[0063] Example 3 Oral Disintegration Time Experimental Method: An orally disintegrating tablet disintegrator conforming to General Chapter 0921 of the 2025 edition of the Chinese Pharmacopoeia was used. The medium was 900 mL of purified water at 37℃±2℃, and the disintegration basket (30 mm × 13 mm, 710 μm sieve) was used. The lifting support moved up and down 9–11 mm at a frequency of 30 times / minute. The water level was adjusted so that when the stainless steel tube was at its lowest position, the sieve was 15 mm ± 1 mm below the water surface. Six tablets of this product were taken and each tablet was placed in the disintegration basket for testing. The tablets should meet the requirements within 60 seconds. If a small amount of light particles floated to the top or adhered to the inner wall of the stainless steel tube or the sieve, but there was no obvious hard core, the tablets were considered completely disintegrated.

[0064] Experimental results: Both Examples 1 and 2 of the present invention can completely disintegrate within 60 seconds in the orally disintegrating apparatus, with no hard core residue, which fully meets the legal disintegration requirements for orally disintegrating tablets. Moreover, the disintegration speed is moderate, which can achieve rapid disintegration in the oral cavity and avoid the feeling of retention when taking the medicine. Comparative Example 1 had a disintegration time of 24-32 seconds, which was the fastest. However, due to its direct compression of mixed powder without masking or coating of the raw materials, it relied solely on flavoring agents and sweeteners to improve the taste, resulting in a noticeable bitterness in the mouth and affecting the user experience. Comparative Example 2 met the disintegration speed requirements, but subsequent dissolution tests showed that its dissolution was relatively fast and not similar to the in vitro dissolution of the reference formulation. Comparative Example 3 exceeded the ideal disintegration range, with some samples having a disintegration time exceeding 60 seconds. The disintegration was slow, resulting in a strong feeling of retention in the mouth after consumption, failing to meet the core requirement of rapid disintegration of orally disintegrating tablets. Comparative Example 4 showed no significant change in the lumps within 1-3 minutes, essentially lacking oral disintegration properties, completely failing to meet legal requirements, and therefore unsuitable for clinical use.

[0065]

[0066] Example 4: Taste evaluation of amlodipine besylate orally disintegrating tablets Experimental method: Take one tablet of each example and comparative sample, place it on the tongue, without water or chewing, record the taste after the tablet disintegrates, evaluate the sweetness, bitterness and aroma of the preparation, and then spit out the powder and rinse your mouth.

[0067] Taste evaluation methods: Palatability was evaluated using the 0-100 point Visual Analogue Scale (VAS). A palatability description was assigned to each score from 0 to 100 to allow evaluators to make relatively accurate choices. The experimental data was collected by 10 evaluators, with a total score divided into five levels: Very Poor (0 points), Poor (20 points), Neutral (50 points), Good (80 points), and Excellent (100 points). For each prescription, a VAS score of 50 or higher by more than 90% of evaluators was considered good palatability, and a VAS score of 50 or higher by more than 70% was considered acceptable palatability.

[0068] The taste rating criteria and acceptable standards are described below:

[0069] Experimental Results: Examples 1 and 2 of this invention exhibit excellent palatability. In Examples 1 and 2, 100% of the evaluators scored ≥50 on the VAS, meeting the good palatability standard. The taste was moderately sweet, with virtually no bitterness, noticeable aftertaste, or gritty texture, resulting in a pleasant mouthfeel and widespread acceptance by the evaluators. In Comparative Examples 1 and 3, less than 70% of the evaluators scored ≥50, indicating unacceptable palatability. The main issues were a severe gritty texture, noticeable bitterness, and a strong aftertaste. In Comparative Example 2, 100% of the evaluators scored ≥50, meeting the good palatability standard, but its rapid dissolution was dissimilar to the in vitro dissolution of the reference formulation. In Comparative Example 4, 80% of the evaluators scored ≥50, meeting the acceptable palatability standard, but the lumps showed no significant change within 1-3 minutes in the oral disintegration apparatus, indicating a lack of oral disintegration performance and failing to meet legal requirements.

[0070] Summary table of taste tester score distribution

[0071] Example 5 Dissolution Behavior Experimental Methods: Dissolution and release were determined according to the method (Chinese Pharmacopoeia General Chapter 0931, Method II, Paddle Method). 900 mL of pH 6.8 phosphate buffer was used as the dissolution medium, at a temperature of 37℃±0.5℃ and a rotation speed of 50 r / min. Six tablets of this product were placed in separate dissolution vessels. The procedure was followed, and 10 mL of solution was collected at 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes. The solution was filtered through a 0.45 μm microporous membrane, and an isothermal blank medium of equal volume was immediately added. The filtrate was used as the test solution. The dissolution was determined according to the prescribed method, and the amount of drug dissolved at each time point was calculated. A dissolution curve was plotted against time using the average dissolution amount. The similarity factor f2 method was used to compare the similarity of the dissolution curves of the test formulation and the reference formulation.

[0072] Experimental results: Examples 1 and 2 of this invention showed slow dissolution, ensuring that patients could hardly taste any bitterness when the drug passed through the oral cavity; Comparative Examples 1-3 dissolved faster, which may have caused the tablets to start releasing bitterness on the tongue surface, affecting patient compliance; Although Comparative Example 4 had a smooth dissolution curve, the lumps did not change significantly within 1-3 minutes in the oral disintegration apparatus, and it basically did not have oral disintegration performance, which did not meet the legal requirements.

[0073]

Claims

1. An orally disintegrating tablet of amlodipine besylate, characterized in that, It includes an inner part and an outer part. The inner part includes amlodipine besylate and mannitol. The weight ratio of amlodipine besylate to mannitol in the inner part is 1:1 to 2 based on the total weight of the orally disintegrating tablets.

2. The amlodipine benzylsulfonate orally disintegrating tablet according to claim 1, characterized in that, Based on the total weight of the orally disintegrating tablets, the weight ratio of amlodipine besylate and mannitol in the granules is 1:1 and 1:

2.

3. The amlodipine benzylsulfonate orally disintegrating tablet according to claim 1, characterized in that, Based on the total weight of the orally disintegrating tablets, the content of amlodipine besylate in the granule portion is 4%~7% (w / w), and the content of mannitol in the granule portion is 3%~15% (w / w).

4. The amlodipine benzylsulfonate orally disintegrating tablet according to claim 1, characterized in that, The granules also include a flavor-masking composition, wherein the flavor-masking composition includes a flavor masking agent, a solubilizer, an emulsifier, an anti-sticking agent, and a defoamer.

5. The amlodipine benzylsulfonate orally disintegrating tablet according to claim 4, characterized in that, Based on the total weight of the orally disintegrating tablets, the content of the flavor masking agent in the flavor masking composition is 1%~2% (w / w); the content of the solubilizer in the flavor masking composition is 0.1%~0.2% (w / w); the content of the emulsifier in the flavor masking composition is 0.1%~0.3% (w / w); the content of the anti-adhesive in the flavor masking composition is 0.6%~0.7% (w / w); and the content of the defoamer in the flavor masking composition is 0.01%~0.03% (w / w).

6. The amlodipine benzylsulfonate orally disintegrating tablet according to claim 1, characterized in that, The internal portion of the particles is granulated using a fluidized bed.

7. The amlodipine benzylsulfonate orally disintegrating tablet according to claim 1, characterized in that, The outer portion of the particles includes fillers, disintegrants, sweeteners, flavoring agents, colorants, and lubricants.

8. The amlodipine benzylsulfonate orally disintegrating tablet according to claim 7, characterized in that, The filler for the outer portion of the particles is a composition of microcrystalline cellulose and mannitol, wherein the weight ratio of microcrystalline cellulose to mannitol is 1:4 to 1:

6.

9. An orally disintegrating tablet of amlodipine benzylsulfonate, characterized in that, It includes an inner part and an outer part, wherein the inner part of the particle comprises: Amlodipine besylate, with a content of 4% to 7% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content of 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; The weight ratio of amlodipine besylate to mannitol in the internal part of the particles is 1:1 to 1:

2.

10. An orally disintegrating tablet of amlodipine benzylsulfonate, characterized in that, include: (1) Internal part of the particle: Amlodipine besylate, with a content of 4% to 7% (w / w) based on the total weight of orally disintegrating tablets; Mannitol content of 3% to 15% (w / w) based on the total weight of orally disintegrating tablets; The content of the masking agent is 1% to 2% (w / w) based on the total weight of the orally disintegrating tablets; The solubilizer content is 0.1% to 0.2% (w / w) based on the total weight of the orally disintegrating tablets; The emulsifier content is 0.1% to 0.3% (w / w) based on the total weight of the orally disintegrating tablets; Based on the total weight of orally disintegrating tablets, the content of anti-adhesion agent is 0.6% to 0.7% (w / w); The defoamer content is 0.01% to 0.03% (w / w) based on the total weight of the orally disintegrating tablets; The weight ratio of amlodipine besylate and mannitol in the internal part of the particles is 1:1 and 1:2, respectively. (2) External part of the particle: Mannitol content is 50% to 80% (w / w) based on the total weight of orally disintegrating tablets; Microcrystalline cellulose with a content of 10% to 15% (w / w) based on the total weight of orally disintegrating tablets; The disintegrant content is 4.5% to 5.5% (w / w) based on the total weight of the orally disintegrating tablets; Sweeteners with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; Flavoring agent with a content of 0.05% to 0.1% (w / w) based on the total weight of orally disintegrating tablets; The colorant content is 0.05% to 0.1% (w / w) based on the total weight of the orally disintegrating tablets; Lubricant with a content of 0.5% to 1.5% (w / w) based on the total weight of the orally disintegrating tablets.

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