A Sildenafil Oral Dissolving Film Formulation, Its Preparation Method and Application

Abstract

This invention discloses a sildenafil orally disintegrating film, its preparation method, and its application. The sildenafil orally disintegrating film comprises the following materials: sildenafil citrate and / or its pharmaceutically acceptable salts, methylamino methacrylate copolymers, a polymeric film-forming material, an anti-adhesive, vitamin C, a plasticizer, and a humectant. The orally disintegrating film of this invention not only effectively masks the bitter taste of sildenafil itself but also has a good taste and a short disintegration time, solving the problem of the bitter taste of traditional sildenafil citrate orally disintegrating films during administration. Furthermore, this orally disintegrating film also has good physical properties and drug stability, meeting the requirements for drug storage, transportation, and clinical use.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical materials technology, specifically to a sildenafil orally disintegrating film formulation, its preparation method, and its application. Background Technology

[0002] Erectile dysfunction (ED) is a common sexual dysfunction characterized by the inability to maintain a full erection for more than three consecutive months during sexual activity. Currently available medications for treating ED include PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil, and avanafil. Sildenafil citrate is currently the first-line drug for treating various types of ED, and is available in tablet form. Traditional tablets have drawbacks such as requiring water for oral administration and low compliance; newly developed oral solid-release formulations offer convenience and rapid dissolution in the mouth.

[0003] Oral solid immediate-release formulations include orally disintegrating tablets, sublingual tablets, dispersible tablets, and orally dissolving films. Orally dissolving films are formulations in which a certain dose of the active ingredients of a chemical drug or traditional Chinese medicine extract is dispersed in a film-forming material. They dissolve rapidly in the oral cavity and have advantages such as being difficult to spit out, rapid absorption, quick onset of action, and easy swallowing. Sildenafil citrate orally disintegrates rapidly in the mouth during administration, allowing its components to fully contact the oral cavity. Because sildenafil citrate has a particularly bitter taste, current processes often use sweeteners or taste masking agents to improve the taste, but this still cannot completely solve the problem of the bitter taste of sildenafil orally disintegrating films during administration. Summary of the Invention

[0004] To overcome the problems existing in the prior art, one objective of the present invention is to provide a sildenafil orally disintegrating film. Another objective of the present invention is to provide a method for preparing the aforementioned sildenafil orally disintegrating film.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] The first aspect of this invention provides a sildenafil oral disintegrating film, comprising the following materials: sildenafil citrate and / or its pharmaceutically acceptable salt, methyl methacrylate copolymer, polymeric film-forming material, anti-adhesive, vitamin C, plasticizer, humectant, and cooling agent; wherein the mass ratio of the methyl methacrylate copolymer, anti-adhesive, and vitamin C is 1:(0.03-0.3):(0.15-0.7).

[0007] Preferably, the mass ratio of the methyl methacrylate copolymer, the anti-adhesive, and vitamin C is 1:(0.05-0.15):(0.2-0.55).

[0008] More preferably, the mass ratio of the methyl methacrylate copolymer, sildenafil citrate and / or its pharmaceutically acceptable salt to the polymeric film-forming material is 1:(0.85-1.8):(3-7.5).

[0009] Preferably, the material comprises the following parts by weight: 14-18 parts of sildenafil citrate and / or its pharmaceutically acceptable salt, 10-16 parts of methyl methacrylate copolymer, 40-75 parts of polymeric film-forming material, 0.5-3 parts of anti-adhesive, 3-7 parts of vitamin C, 2-15 parts of plasticizer, and 2-5 parts of humectant.

[0010] More preferably, the polymer film-forming material has a mass fraction of 50-65 parts.

[0011] More preferably, the plasticizer is present in parts by weight of 3-10 parts.

[0012] Preferably, the polymeric film-forming material is selected from at least one of polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and copovidone.

[0013] More preferably, the polymeric film-forming material is selected from polyvinyl alcohol and hydroxypropyl methylcellulose.

[0014] More preferably, the mass ratio of polyvinyl alcohol to hydroxypropyl methylcellulose is 1:(1-2).

[0015] Preferably, the anti-adhesion agent is selected from at least one of talc, magnesium stearate, and stearic acid.

[0016] Preferably, the plasticizer is selected from at least one of polyethylene glycol, propylene glycol, and triethyl citrate.

[0017] Preferably, the humectant is glycerin.

[0018] Preferably, the cooling agent is selected from at least one of menthol, N,2,3-trimethyl-2-isopropylbutyramide, and menthol.

[0019] Preferably, the methyl methacrylate copolymer is a butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate copolymer.

[0020] More preferably, the ratio of the structural units of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate in the butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate copolymer is 1:2:1.

[0021] More preferably, the methyl methacrylate copolymer is Eutech E100 or Eutech EPO.

[0022] Preferably, the particle size D90 of the sildenafil citrate and / or its pharmaceutically acceptable salt does not exceed 10 μm.

[0023] A second aspect of the present invention provides a method for preparing the sildenafil orally dissolving film agent described in the first aspect, comprising the following steps:

[0024] S1. Sildenafil citrate and / or its pharmaceutically acceptable salts are fluidized and coated with an organic solution containing methyl methacrylate copolymer and an anti-adhesive to obtain sildenafil-masked granules.

[0025] S2. Sildenafil flavor-masking granules, polymer film-forming material, vitamin C, plasticizer, humectant and cooling agent are mixed in water to obtain a slurry, which is then coated to form a film, and then dried and slit to obtain sildenafil oral dissolving film.

[0026] Preferably, the solvent of the organic solution is an aqueous ethanol solution.

[0027] More preferably, the organic solution is prepared by dissolving the methyl methacrylate copolymer in an aqueous ethanol solution, then adding an anti-adhesive agent and mixing to obtain an organic solution containing the methyl methacrylate copolymer and the anti-adhesive agent.

[0028] Preferably, in step S1, the fluidized bed coating is performed using a fluidized bed bottom spray coating machine.

[0029] Preferably, in step S1, the material temperature is 22-25°C during the fluidized coating process.

[0030] Preferably, in step S1, the mass ratio of sildenafil citrate to sildenafil masking particles is 1:(1.7-2.1).

[0031] Preferably, at least one of a sweetener and a flavoring agent is added in step S2.

[0032] More preferably, the sweetener is selected from at least one of steviol, mogroside, sucralose, sugar alcohol, acesulfame potassium, and aspartame.

[0033] More preferably, the flavoring agent is selected from at least one of strawberry flavoring, peach flavoring, pomegranate flavoring, and sweet orange flavoring.

[0034] Preferably, step S2 also includes defoaming.

[0035] More preferably, the defoaming method is static defoaming.

[0036] Preferably, in step S2, during the coating and film-making process, the film thickness is 0.15-0.2 mm and the coating speed is 20-40 cm / min.

[0037] Preferably, in step S2, the drying temperature is 50-70°C.

[0038] The beneficial effects of this invention are:

[0039] This invention provides a sildenafil orally disintegrating film. The coating, composed of a methyl methacrylate copolymer and an anti-adhesive, reduces the bitterness of sildenafil. A cooling agent further reduces bitterness, and vitamin C acts as an acidulant. The methyl methacrylate copolymer, anti-adhesive, and vitamin C are used in a specific ratio to reduce the oral perception of bitterness while promoting saliva secretion, thus shortening the dissolution time of the film-forming polymer in the mouth. This allows the masking particles to enter the gastrointestinal tract more quickly, reducing the contact time between the masking particles and the mouth, thereby preventing the bitterness from being released in the oral cavity. This orally disintegrating film not only effectively masks the bitter taste of sildenafil but also has a good taste and a short disintegration time, solving the problem of the bitter taste of traditional sildenafil citrate orally disintegrating films during administration. Furthermore, this orally disintegrating film also has good physical properties and drug stability, meeting the requirements for drug storage, transportation, and clinical use.

[0040] The present invention also provides a method for preparing the above-mentioned sildenafil oral dissolving film. Adding an anti-adhesion agent during the coating process facilitates the smooth operation of spray coating. The resulting sildenafil oral dissolving film has no gritty feeling or bitter taste during administration and has a good taste, improving the clinical use compliance of existing marketed dosage forms and having clinical development and use value. Detailed Implementation

[0041] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the materials used in the following embodiments can be obtained from conventional commercial sources or prepared and separated through simple synthesis; unless otherwise specified, the processes employed are conventional processes in the art.

[0042] Example 1

[0043] This embodiment provides a sildenafil orally disintegrating film formulation, the specific formula of which is shown in Table 1 and is prepared from the following components:

[0044] Table 1

[0045]

[0046] The preparation method of sildenafil orally dissolving film is as follows:

[0047] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 22-25℃, and the coating weight gain is 98%, resulting in sildenafil taste-masked granules.

[0048] 2. Weigh 160 parts by weight of purified water (approximately 2500g water for 1565g of raw materials), heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, vitamin C, hydroxypropyl methylcellulose, stevioside, and N,2,3-trimethyl-2-isopropylbutyramide prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 60℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0049] Example 2

[0050] This embodiment provides a sildenafil orally disintegrating film formulation, the specific formula of which is shown in Table 2 and is prepared from the following components:

[0051] Table 2

[0052]

[0053]

[0054] The preparation method of sildenafil orally dissolving film is as follows:

[0055] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 22-25℃, and the coating weight gain is 100%, to obtain sildenafil taste-masked granules.

[0056] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, vitamin C, hydroxypropyl methylcellulose, stevioside, and N,2,3-trimethyl-2-isopropylbutyramide prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 70℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0057] Example 3

[0058] This embodiment provides a sildenafil orally disintegrating film formulation, the specific formula of which is shown in Table 3 and is prepared from the following components:

[0059] Table 3

[0060]

[0061] The preparation method of sildenafil orally dissolving film is as follows:

[0062] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 22-25℃, and the coating weight gain is 80%, resulting in sildenafil taste-masked granules.

[0063] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, vitamin C, hydroxypropyl methylcellulose, stevioside, and N,2,3-trimethyl-2-isopropylbutyramide prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 55℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0064] Example 4

[0065] This embodiment provides a sildenafil orally disintegrating film formulation, the specific formula of which is shown in Table 4 and is prepared from the following components:

[0066] Table 4

[0067]

[0068] The preparation method of sildenafil orally dissolving film is as follows:

[0069] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add 20wt% polyethylene glycol 400 of talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 22-25℃, and the coating weight gain is 80%, to obtain sildenafil taste-masked granules.

[0070] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, the remaining polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, vitamin C, hydroxypropyl methylcellulose, stevioside, and N,2,3-trimethyl-2-isopropylbutyramide prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 55℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0071] Comparative Example 1

[0072] This comparative example provides a sildenafil orally disintegrating film formulation, the specific formulation of which is shown in Table 5 and is composed of the following components:

[0073] Table 5

[0074]

[0075] The preparation method of sildenafil orally dissolving film is as follows:

[0076] Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add sildenafil citrate raw material powder, vitamin C, hydroxypropyl methylcellulose, stevioside, and N,2,3-trimethyl-2-isopropylbutyramide, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 55℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0077] Comparative Example 2

[0078] This comparative example provides a sildenafil orally disintegrating film formulation, the specific formulation of which is shown in Table 6 and is composed of the following components:

[0079] Table 6

[0080]

[0081] The preparation method of sildenafil orally dissolving film is as follows:

[0082] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 22-25℃, and the coating weight gain is 80%, resulting in sildenafil taste-masked granules.

[0083] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, hydroxypropyl methylcellulose, stevioside, and N,2,3-trimethyl-2-isopropylbutyramide prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 55℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0084] Comparative Example 3

[0085] This comparative example provides a sildenafil orally disintegrating film formulation, the specific formulation of which is shown in Table 7 and is composed of the following components:

[0086] Table 7

[0087]

[0088] The preparation method of sildenafil orally dissolving film is as follows:

[0089] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add silica and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 22-25℃, and the coating weight gain is 80%, resulting in sildenafil taste-masked granules.

[0090] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, vitamin C, hydroxypropyl methylcellulose, stevioside, and N,2,3-trimethyl-2-isopropylbutyramide prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 55℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0091] Comparative Example 4

[0092] This comparative example provides a sildenafil orally disintegrating film formulation, the specific formulation of which is shown in Table 8 and is composed of the following components:

[0093] Table 8

[0094]

[0095] The preparation method of sildenafil orally dissolving film is as follows:

[0096] 1. Add Eutel L100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 22-25℃, and the coating weight gain is 80%, resulting in sildenafil taste-masked granules.

[0097] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, vitamin C, hydroxypropyl methylcellulose, stevioside, and N,2,3-trimethyl-2-isopropylbutyramide prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 55℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0098] Comparative Example 5

[0099] This comparative example provides a sildenafil orally disintegrating film formulation, the specific formulation of which is shown in Table 9 and is composed of the following components:

[0100] Table 9

[0101]

[0102]

[0103] The preparation method of sildenafil orally dissolving film is as follows:

[0104] 1. Dissolve E100 in 95% ethanol as a binder. Add sildenafil citrate and talc to a wet granulator, mix, and then add the binder. Granulate for 10 minutes. The paddle speed is 1500 rpm and the cutting blade speed is 150 rpm during the granulation process to obtain sildenafil-masked granules.

[0105] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, vitamin C, hydroxypropyl methylcellulose, stevioside, and fragrance prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 55℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0106] Comparative Example 6

[0107] This comparative example provides a sildenafil orally disintegrating film formulation, the specific formulation of which is shown in Table 10 and is composed of the following components:

[0108] Table 10

[0109] Material Name effect Quality Sildenafil citrate raw materials 16 UTEC E100 Odor-masking materials 13 talcum powder Anti-adhesive 2.6 Polyvinyl alcohol Film-forming materials 38.4 Hydroxypropyl methylcellulose Film-forming materials 17 Vitamin C acidulant 5 polyethylene glycol plasticizer 6 glycerin moisturizer 4 Stevia sweeteners 0.2 Sweet orange flavoring Fragrance 0.5

[0110] The preparation method of sildenafil orally dissolving film is as follows:

[0111] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 25-30℃, and the coating weight gain is 98%, resulting in sildenafil taste-masked granules.

[0112] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, hydroxypropyl methylcellulose, stevia, and sweet orange flavoring prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 60℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0113] Comparative Example 7

[0114] This comparative example provides a sildenafil orally disintegrating film formulation, the specific formulation of which is shown in Table 11 and is composed of the following components:

[0115] Table 11

[0116]

[0117] The preparation method of sildenafil orally dissolving film is as follows:

[0118] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 of 25μm. The material temperature during the coating process is 22-25℃, and the coating weight gain is 98%, resulting in sildenafil taste-masked granules.

[0119] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, vitamin C, hydroxypropyl methylcellulose, stevia, and sweet orange flavoring prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 60℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0120] Comparative Example 8

[0121] This comparative example provides a sildenafil orally disintegrating film formulation, the specific formulation of which is shown in Table 12 and is composed of the following components:

[0122] Table 12

[0123]

[0124]

[0125] The preparation method of sildenafil orally dissolving film is as follows:

[0126] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 22-25℃, and the coating weight gain is 50%, to obtain sildenafil taste-masked granules.

[0127] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, hydroxypropyl methylcellulose, stevioside, and N,2,3-trimethyl-2-isopropylbutyramide prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 60℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0128] Comparative Example 9

[0129] This comparative example provides a sildenafil orally disintegrating film formulation, the specific formulation of which is shown in Table 13 and is composed of the following components:

[0130] Table 13

[0131]

[0132] The preparation method of sildenafil orally dissolving film is as follows:

[0133] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 22-25℃, and the coating weight gain is 80%, resulting in sildenafil taste-masked granules.

[0134] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, hydroxypropyl methylcellulose, stevia, and sweet orange flavoring prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 55℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0135] Comparative Example 10

[0136] This comparative example provides a sildenafil orally disintegrating film formulation, the specific formulation of which is shown in Table 14 and is composed of the following components:

[0137] Table 14

[0138]

[0139] The preparation method of sildenafil orally dissolving film is as follows:

[0140] 1. Add E100 of Eureka to 95% ethanol and stir for 40 minutes until dissolved to prepare a 20wt% solution. Add talc powder and stir to disperse evenly to obtain a coating solution. Use a fluidized bed bottom spray coating machine to bottom spray coat sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm. The material temperature during the coating process is 32-36℃, and the coating weight gain is 80%, resulting in sildenafil taste-masked granules.

[0141] 2. Weigh 160 parts by weight of purified water, heat to 50℃, add polyvinyl alcohol, polyethylene glycol 400, and glycerin to the purified water, stir and homogenize, cool to room temperature, add the sildenafil flavor-masking granules, hydroxypropyl methylcellulose, stevia, and sweet orange flavoring prepared above, mix and stir to prepare a solution, let stand overnight to remove air bubbles; install the backing material, set the coating dryer drying temperature to 35℃, start coating and drying, coating speed 0.3 m / min, film thickness 0.17 mm; cut to appropriate size to obtain sildenafil oral dissolving films with a tablet weight of approximately 313 mg; use composite film bags to individually package the sildenafil oral dissolving films.

[0142] Performance Tests and Results

[0143] 1. The samples obtained from Examples 1-4 and Comparative Examples 1-10 were subjected to taste tests.

[0144] Ten male and female volunteers aged 20-45 years were selected. After rinsing their mouths with drinking water at 20-minute intervals, they tried samples from Examples 1-4 and Comparative Examples 1-10, respectively. The scores were averaged, and the bitterness scores are shown in Table 15 below. Scoring criteria: 1 - almost no bitterness throughout; 2 - slight bitterness after 5 seconds; 3 - noticeable bitterness within 5 seconds. The score for each group was the average of all volunteers' scores, rounded to the nearest integer.

[0145] Table 15

[0146]

[0147] 2. The samples obtained from Examples 1-4 and Comparative Examples 1-10 were tested for oral dissolution film appearance, tensile strength, folding endurance, and disintegration time.

[0148] (1) Test method

[0149] Visual inspection: Visual inspection under white light.

[0150] Tensile strength testing method: Use a texture analyzer, set the speed to 100 mm / min, set the test conditions, clamp the sample on the instrument fixture, and start the test after the initial value is zeroed.

[0151] Method for determining folding endurance: Take one piece of this product, fold it and place it on a PVC board, add about 500g of weight on it for 2 seconds, repeat the above operation, and record the number of folds until the sample breaks.

[0152] Disintegration time determination: Add 25 ml of purified water to a 250 ml beaker and maintain the water bath temperature at 37 ± 0.5 °C. Fix a paperclip to the center of the oral disintegrating membrane, place it in the beaker, and start timing until it is completely dissolved. Record the time required for the oral disintegrating membrane to completely dissolve. Repeat the determination three times.

[0153] (2) The test results are shown in Table 16:

[0154] Table 16

[0155]

[0156] As can be seen from Tables 15 and 16, Examples 1-4 tested the feasibility of the product process, product appearance, disintegration time, and taste under different process parameters such as different masking coating weight gain and different coating drying temperatures, and the impact was not significant.

[0157] From Tables 15 and 16, it can be seen that Comparative Example 1, using the traditional taste-masking method with sweeteners and cooling agents, without adding Eutec E100 coating, still exhibited a noticeable bitter taste in the oral film 5 seconds after ingestion; Comparative Example 2, although using a coating process for E100, did not add Vitamin C, and a bitter taste still remained 5 seconds after ingestion; Comparative Examples 3, 4, and 5, by changing the type of anti-adhesion agent, changing the type of taste-masking agent, and using granulation instead of coating, respectively, still showed a slight bitter taste in the oral film 5 seconds after ingestion; In Comparative Example 6, when the coating temperature was too high, the coating material softened, causing the taste-masking particles to stick together, resulting in an unsuccessful coating process and a decrease in the taste-masking effect; Comparative Example 7 examined the effect of the active pharmaceutical ingredient particle size, and when using an active pharmaceutical ingredient particle size of 25 μm, the film appearance was unqualified; Comparative Examples 8 and 9 examined the different proportions of talc in the coating, and compared with the examples, a slight bitter taste still remained 5 seconds after ingestion; In Comparative Example 10, when the coating drying temperature was too low, the film surface was uneven due to insufficient drying.

[0158] In summary, this invention uses E100 and talc to perform fluidized bed bottom spray coating on sildenafil, uses N,2,3-trimethyl-2-isopropylbutyramide as a cooling agent and vitamin C to regulate bitterness, and specifies specific coating and application conditions. The above-mentioned improvement method has a very significant effect on solving the bitterness of sildenafil oral disintegration film.

[0159] 3. Samples from Example 1, Comparative Example 4, and Comparative Examples 8-10 were individually packaged in composite film bags and their stability was investigated under accelerated conditions (40°C, 75% RH). The results are shown in Table 17.

[0160] Table 17

[0161]

[0162] As shown in Table 17, after 6 months of accelerated storage under the conditions of Example 1, the folding endurance, content, and disintegration time of the sildenafil oral dissolving film did not change significantly, indicating that the sildenafil citrate oral dissolving film product prepared by the technology adopted in this invention has good quality stability and meets the requirements. In Comparative Examples 4 and 8-10, the decrease in sildenafil citrate content and the decrease in folding endurance of the film were more significant than in the Examples during the stabilization process.

[0163] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A sildenafil orally dissolving film formulation, characterized in that, The product comprises the following materials: sildenafil citrate and / or its pharmaceutically acceptable salts, methyl methacrylate copolymers, a polymeric film-forming material, an anti-adhesive, vitamin C, a plasticizer, a humectant, and a cooling agent; the mass ratio of the methyl methacrylate copolymers, the anti-adhesive, and vitamin C is 1:(0.03-0.3):(0.15-0.7); the mass ratio of the methyl methacrylate copolymers, sildenafil citrate and / or its pharmaceutically acceptable salts, to the polymeric film-forming material is 1:(0.85-1.8):(3-7.5); the methyl methacrylate copolymer is Eutec E100. The anti-adhesion agent is talc; the cooling agent is N,2,3-trimethyl-2-isopropylbutyramide; The sildenafil orally dissolving film agent is prepared by a method comprising the following steps: S1. Sildenafil citrate and / or its pharmaceutically acceptable salts are fluidized and coated with an organic solution containing methyl methacrylate copolymers and an anti-adhesive to obtain sildenafil-masked granules; the material temperature during the fluidized coating process is 22-25°C. S2. Sildenafil flavor-masking granules, polymer film-forming material, vitamin C, plasticizer, humectant and cooling agent are mixed in water to obtain a slurry, which is then coated to form a film, and then dried and slit to obtain sildenafil oral dissolving film.

2. The sildenafil orally dissolving film agent according to claim 1, characterized in that, The mass ratio of the methyl methacrylate copolymer, the anti-adhesive, and vitamin C is 1:(0.05-0.15):(0.2-0.55).

3. The sildenafil orally dissolving film agent according to claim 1, characterized in that, The material comprises the following parts by weight: 14-18 parts of sildenafil citrate and / or its pharmaceutically acceptable salt, 10-16 parts of methylamino methacrylate copolymer, 40-75 parts of polymeric film-forming material, 0.5-3 parts of anti-adhesive, 3-7 parts of vitamin C, 2-15 parts of plasticizer, 2-5 parts of humectant, and 0.2-1 parts of cooling agent.

4. The sildenafil orally dissolving film agent according to claim 1, characterized in that, The polymeric film-forming material is selected from at least one of polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and copovidone.

5. The sildenafil orally dissolving film agent according to claim 1, characterized in that, The plasticizer is selected from at least one of polyethylene glycol, propylene glycol, and triethyl citrate; And / or, the moisturizer is glycerin.

6. The method for preparing the sildenafil orally dissolving film according to any one of claims 1-5, characterized in that, The steps include: S1. Sildenafil citrate and / or its pharmaceutically acceptable salts are fluidized and coated with an organic solution containing methyl methacrylate copolymers and an anti-adhesive to obtain sildenafil-masked granules; the material temperature during the fluidized coating process is 22-25°C. S2. Sildenafil flavor-masking granules, polymer film-forming material, vitamin C, plasticizer, humectant and cooling agent are mixed in water to obtain a slurry, which is then coated to form a film, and then dried and slit to obtain sildenafil oral dissolving film.

7. The method for preparing the sildenafil orally disintegrating film agent according to claim 6, characterized in that, In step S2, at least one of a sweetener and a flavoring agent is added to the slurry.

8. The method for preparing the sildenafil orally dissolving film agent according to claim 6, characterized in that, During the coating process, the film thickness is 0.15-0.2 mm and the coating speed is 20-40 cm / min.

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