Sildenafil oral dissolving film agent as well as preparation method and application thereof

Abstract

The invention discloses a sildenafil oral soluble film agent as well as a preparation method and application thereof. The sildenafil oral soluble film agent is prepared from the following materials: sildenafil citrate and / or pharmaceutically acceptable salt thereof, a methylacrylic acid methylamino ester copolymer, a macromolecular film-forming material, an anti-sticking agent, vitamin C, a plasticizer and a humectant. The oral soluble film agent not only can effectively cover the bitter peculiar smell of sildenafil, but also has good taste and short disintegration time, and solves the problem that a traditional sildenafil citrate oral soluble film is bitter in taste in the taking process. In addition, the oral soluble film agent also has good physical properties and drug stability, and can meet the requirements of storage, transportation, clinical use and the like of drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation materials, and in particular to a sildenafil orodispersible film preparation and a preparation method and application thereof. Background Art

[0002] Erectile dysfunction (ED) is a common sexual dysfunction disease, and its clinical feature is the inability of the penis to maintain a full erection during sexual activity for more than 3 consecutive months. The drugs currently on the market for the treatment of erectile dysfunction include PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil and avanafil. Among them, sildenafil citrate is currently the first choice for the clinical treatment of various types of erectile dysfunction, and the marketed dosage form is tablets. Traditional tablets have problems such as oral water requirement and low compliance. Now the newly developed oral solid rapid-release preparations can be taken easily and dissolve quickly in the mouth.

[0003] Oral solid rapid-release preparations include orally disintegrating tablets, sublingual tablets, dispersible tablets and orally disintegrating films. Among them, the orally disintegrating film is a preparation made by dispersing a certain dose of the active ingredients of chemical drugs or Chinese medicine extracts in a film-forming material. It can be quickly dissolved in the mouth and has the advantages of being difficult to spit out, fast absorption, rapid onset of effect, and easy swallowing. The sildenafil citrate orally disintegrating film quickly disintegrates in the mouth during the administration process, and its related ingredients will be in full contact with the mouth. Since sildenafil citrate tastes particularly bitter, sweeteners or masking agents are often used in existing processes to improve the taste, but it is still difficult to solve the problem that the sildenafil orally disintegrating film tastes bitter during the administration process. Summary of the invention

[0004] In order to overcome the problems existing in the prior art, one of the purposes of the present invention is to provide a sildenafil orodispersible film preparation. Another purpose of the present invention is to provide a method for preparing the sildenafil orodispersible film preparation.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

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

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

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

[0009] Preferably, the following materials are included in parts by mass: 14-18 parts of sildenafil citrate and / or a pharmaceutically acceptable salt thereof, 10-16 parts of methyl methacrylate copolymer, 40-75 parts of polymer film-forming material, 0.5-3 parts of anti-adhesive agent, 3-7 parts of vitamin C, 2-15 parts of plasticizer and 2-5 parts of moisturizer.

[0010] More preferably, the mass proportion of the polymer film-forming material is 50-65 parts.

[0011] More preferably, the mass fraction of the plasticizer is 3-10 parts.

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

[0013] More preferably, the polymer film-forming material is selected from polyvinyl alcohol and hypromellose.

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

[0015] Preferably, the anti-sticking 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 menthyl amide, N,2,3-trimethyl-2-isopropylbutyramide and menthol.

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

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

[0021] Further preferably, the methylamino methacrylate copolymer is Eudragit E100 or Eudragit EPO.

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

[0023] The second aspect of the present invention provides a method for preparing the sildenafil orodispersible film-forming agent described in the first aspect, comprising the following steps:

[0024] S1. Fluidizing and coating sildenafil citrate and / or a pharmaceutically acceptable salt thereof with an organic solution containing methylamino methacrylate copolymer and an anti-adhesive agent to prepare sildenafil taste-masked particles;

[0025] S2. Mix the sildenafil taste-masking particles, polymer film-forming material, vitamin C, plasticizer, humectant and cooling agent in water to obtain a slurry, apply the slurry to form a film, and then dry and cut the slurry to obtain the sildenafil orodispersible film.

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

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

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

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

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

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

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

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

[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-forming 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 the present invention are:

[0039] The invention provides a sildenafil oral dissolving film, wherein the coating composed of methyl methacrylate amino copolymer and anti-adhesive agent can reduce the bitterness of sildenafil, the cooling agent further reduces the bitterness, and vitamin C has the effect of an acidulant, and the methyl methacrylate amino copolymer, anti-adhesive agent and vitamin C are in a specific ratio, which can reduce the bitterness of the oral cavity, promote the secretion of saliva, and shorten the dissolution time of the film polymer film-forming material in the oral cavity, accelerate the entry of taste-masking particles into the gastrointestinal tract, and reduce the contact time between the taste-masking particles and the oral cavity, thereby realizing that the bitterness is not released in the oral cavity. The oral dissolving film can not only effectively cover the bitter taste of sildenafil itself, but also has a good taste and a shorter disintegration time, and solves the problem that the traditional sildenafil citrate oral dissolving film has a bitter taste during the taking process. In addition, the oral dissolving film also has good physical properties and drug stability, and can meet the needs of drug storage, transportation and clinical use.

[0040] The present invention also provides a method for preparing the above-mentioned sildenafil orodispersible film preparation. Adding an anti-adhesive agent during the coating process is conducive to the smooth spray coating operation. The prepared sildenafil orodispersible film preparation has no grittiness and bitterness during the taking process and has a good taste, thereby improving the clinical use compliance of existing marketed dosage forms and having clinical development and use value. DETAILED DESCRIPTION

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

[0042] Example 1

[0043] This embodiment provides a sildenafil orodispersible film, 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 orodispersible film is as follows:

[0047] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 22-25°C, the coating weight gain is 98%, and the sildenafil taste-masked particles are obtained;

[0048] 2. Weigh 160 parts by mass of purified water (about 1565g of raw materials and auxiliary materials correspond to 2500g of water), heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, vitamin C, hydroxypropyl methylcellulose, stevioside, N,2,3.trimethyl-2-isopropylbutyramide, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the drying temperature of the coating dryer to 60°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0049] Example 2

[0050] This embodiment provides a sildenafil orodispersible film, 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 orodispersible film is as follows:

[0055] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 22-25°C, the coating weight gain is 100%, and the sildenafil taste-masked particles are obtained;

[0056] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, vitamin C, hydroxypropyl methylcellulose, stevioside, N,2,3.trimethyl-2-isopropylbutyramide, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer drying temperature to 70°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0057] Example 3

[0058] This embodiment provides a sildenafil orodispersible film, 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 orodispersible film is as follows:

[0062] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 22-25°C, the coating weight gain is 80%, and the sildenafil taste-masked particles are obtained;

[0063] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, vitamin C, hydroxypropyl methylcellulose, stevioside, N,2,3.trimethyl-2-isopropylbutyramide, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer to a drying temperature of 55°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0064] Example 4

[0065] This embodiment provides a sildenafil orodispersible film, 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 orodispersible film is as follows:

[0069] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add 20%wt polyethylene glycol 400 of talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 22-25°C, the coating weight gain is 80%, and the sildenafil taste-masked particles are obtained;

[0070] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, remaining polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, vitamin C, hydroxypropyl methylcellulose, stevioside, N,2,3.trimethyl-2-isopropylbutyramide, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer drying temperature to 55°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0071] Comparative Example 1

[0072] This comparative example provides a sildenafil orodispersible film preparation, the specific formula of which is shown in Table 5, and is prepared from the following components:

[0073] Table 5

[0074]

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

[0076] Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add sildenafil citrate bulk drug powder, vitamin C, hydroxypropyl methylcellulose, stevioside, N,2,3.trimethyl-2-isopropylbutyramide, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the drying temperature of the coating dryer to 55°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0077] Comparative Example 2

[0078] This comparative example provides a sildenafil orodispersible film preparation, the specific formula of which is shown in Table 6, and is prepared from the following components:

[0079] Table 6

[0080]

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

[0082] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 22-25°C, the coating weight gain is 80%, and the sildenafil taste-masked particles are obtained;

[0083] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, hydroxypropyl methylcellulose, stevioside, N,2,3.trimethyl-2-isopropylbutyramide, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer to a drying temperature of 55°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0084] Comparative Example 3

[0085] This comparative example provides a sildenafil orodispersible film preparation, the specific formula of which is shown in Table 7, and is prepared from the following components:

[0086] Table 7

[0087]

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

[0089] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add silicon dioxide, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 22-25°C, the coating weight gain is 80%, and the sildenafil taste-masked particles are obtained;

[0090] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, vitamin C, hydroxypropyl methylcellulose, stevioside, N,2,3.trimethyl-2-isopropylbutyramide, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer to a drying temperature of 55°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0091] Comparative Example 4

[0092] This comparative example provides a sildenafil orodispersible film preparation, the specific formula of which is shown in Table 8, and is prepared from the following components:

[0093] Table 8

[0094]

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

[0096] 1. Add Eudragit L100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 22-25°C, the coating weight gain is 80%, and the sildenafil taste-masked particles are obtained;

[0097] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, vitamin C, hydroxypropyl methylcellulose, stevioside, N,2,3.trimethyl-2-isopropylbutyramide, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer to a drying temperature of 55°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0098] Comparative Example 5

[0099] This comparative example provides a sildenafil orodispersible film preparation, the specific formula of which is shown in Table 9, and is prepared from the following components:

[0100] Table 9

[0101]

[0102]

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

[0104] 1. Dissolve Eudragit E100 in 95% ethanol as a binder, add sildenafil citrate and talc into a wet granulator, mix, add the binder, and granulate for 10 minutes. During the granulation process, the paddle speed is 1500 rpm and the cutting knife speed is 150 rpm to obtain sildenafil taste-masked granules;

[0105] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, vitamin C, hydroxypropyl methylcellulose, stevioside, and flavors, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer to a drying temperature of 55°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0106] Comparative Example 6

[0107] This comparative example provides a sildenafil orodispersible film preparation, the specific formula of which is shown in Table 10, and is prepared from the following components:

[0108] Table 10

[0109] Material Name effect Mass Sildenafil Citrate API 16 Eudragit E100 Taste masking materials 13 talcum powder Anti-sticking agent 2.6 Polyvinyl alcohol Film-forming materials 38.4 Hydroxypropyl methylcellulose Film-forming materials 17 Vitamin C Acidulants 5 Polyethylene glycol Plasticizers 6 glycerin Moisturizer 4 Stevia Sweeteners 0.2 Sweet orange flavor Fragrance 0.5

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

[0111] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 25-30°C, the coating weight gain is 98%, and the sildenafil taste-masked particles are obtained;

[0112] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil masking particles, hydroxypropyl methylcellulose, stevioside, and sweet orange flavor, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer to a drying temperature of 60°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0113] Comparative Example 7

[0114] This comparative example provides a sildenafil orodispersible film preparation, the specific formula of which is shown in Table 11, and is prepared from the following components:

[0115] Table 11

[0116]

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

[0118] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 of 25μm, the material temperature during the coating process is 22-25°C, the coating weight gain is 98%, and the sildenafil taste-masked particles are obtained;

[0119] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, vitamin C, hydroxypropyl methylcellulose, stevioside, and sweet orange flavor, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer to a drying temperature of 60°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0120] Comparative Example 8

[0121] This comparative example provides a sildenafil orodispersible film preparation, the specific formula of which is shown in Table 12, and is prepared from the following components:

[0122] Table 12

[0123]

[0124]

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

[0126] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 22-25°C, the coating weight gain is 50%, and the sildenafil taste-masked particles are obtained;

[0127] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, hydroxypropyl methylcellulose, stevioside, N,2,3.trimethyl-2-isopropylbutyramide, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer drying temperature to 60°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0128] Comparative Example 9

[0129] This comparative example provides a sildenafil orodispersible film preparation, the specific formula of which is shown in Table 13, and is prepared from the following components:

[0130] Table 13

[0131]

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

[0133] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 22-25°C, the coating weight gain is 80%, and the sildenafil taste-masked particles are obtained;

[0134] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil masking particles, hydroxypropyl methylcellulose, stevioside, and sweet orange flavor, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer to a drying temperature of 55°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0135] Comparative Example 10

[0136] This comparative example provides a sildenafil orodispersible film preparation, the specific formula of which is shown in Table 14, and is prepared from the following components:

[0137] Table 14

[0138]

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

[0140] 1. Add Eudragit E100 to 95% ethanol and stir for 40 minutes until dissolved to prepare a solution with a concentration of 20wt%, add talcum powder, stir and disperse evenly to prepare a coating solution; use a fluidized bed bottom spray coating machine to bottom spray coat the sildenafil citrate raw material powder with a particle size D90 not exceeding 10μm, the material temperature during the coating process is 32-36°C, the coating weight gain is 80%, and the sildenafil taste-masked particles are obtained;

[0141] 2. Weigh 160 parts by mass of purified water, heat it to 50°C, add polyvinyl alcohol, polyethylene glycol 400, and glycerol to the purified water, stir and homogenize, cool to room temperature, add the above-prepared sildenafil taste-masking particles, hydroxypropyl methylcellulose, stevioside, and sweet orange flavor, mix and stir to form a solution, and let it stand overnight to remove bubbles; install the backing material, set the coating dryer to a drying temperature of 35°C, start coating and drying, the coating speed is 0.3 m / min, and the film thickness is 0.17 mm; cut according to the appropriate size to obtain a sildenafil orodispersible film with a tablet weight of about 313 mg; use a composite film bag to independently package the sildenafil orodispersible film.

[0142] Performance Testing and Results

[0143] 1. The samples obtained from Example 1 to Example 4 and Comparative Example 1 to Comparative Example 10 were subjected to a taste test.

[0144] A total of 10 male and female volunteers aged 20 to 45 were selected to try the samples of Examples 1 to 4 and Comparative Examples 1 to 10 respectively after rinsing their mouths with drinking water at an interval of 20 minutes. The scoring results were averaged, and the bitterness score is shown in Table 15. Scoring criteria: 1-almost no bitterness throughout the process, 2-slight bitterness after 5 seconds after entering the mouth, 3-obvious bitterness within 5 seconds after entering the mouth, and the score of each group is the average score of all volunteers, and the integer is rounded off.

[0145] Table 15

[0146]

[0147] 2. The samples obtained from Examples 1 to 4 and Comparative Examples 1 to 10 were tested for appearance, tensile strength, folding endurance and disintegration time of the orally disintegrating film.

[0148] (1) Test method

[0149] Appearance inspection: visual inspection under white light.

[0150] Tensile strength test 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 returning the initial value to zero.

[0151] Folding endurance determination method: Take 1 piece of this product, fold it and place it on a PVC board, add a weight of about 500g on it for 2s, repeat the above operation, and record the number of folds until the sample breaks.

[0152] Disintegration time determination: Take a 250ml beaker and add 25ml purified water, the water bath temperature is 37±0.5℃. Fix a paper clip to the middle of the orodispersible film, put it into the beaker and start timing until it is completely dissolved, record the time required for the orodispersible film to completely dissolve, and repeat the measurement 3 times.

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

[0154] Table 16

[0155]

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

[0157] From Table 15 and Table 16, it can be seen that Comparative Example 1 adopts the traditional taste masking method of sweeteners and cooling agents, and does not add Eudragit E100 coating. The orodispersible film has obvious bitterness after 5 seconds of ingestion; although E100 in Comparative Example 2 adopts coating technology, vitamin C is not added, and there is still bitterness after 5 seconds of ingestion; Comparative Examples 3, 4, and 5 respectively change the type of anti-adhesive agent, the type of taste masking agent, and adopt granulation instead of coating technology, and the orodispersible film still has a little bitterness after 5 seconds of ingestion; When the coating temperature of Comparative Example 6 is too high, the taste masking particles adhere due to the softening of the coating material, resulting in an unsmooth coating process and a decrease in the taste masking effect; Comparative Example 7 investigates the influence of the particle size of the raw material drug. When the particle size of the raw material drug is 25 μm, the appearance of the film is unqualified; Comparative Examples 8 and 9 investigate the dosage ratio of different talcum powders in the coating. Compared with the embodiment, there is still a little bitterness after 5 seconds of ingestion; When the coating drying temperature of Comparative Example 10 is too low, the surface of the film is uneven due to insufficient drying.

[0158] In summary, the present invention uses Eudragit 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 adjust the bitterness, and defines specific coating and coating conditions. The above improvement method has a very significant effect on solving the bitterness of sildenafil orodispersible film.

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

[0160] Table 17

[0161]

[0162] As shown in Table 17, the sildenafil oral dissolving film folding resistance, content, and disintegration time of the sample in Example 1 were placed under accelerated conditions for 6 months, and there was no significant change, indicating that the sildenafil oral dissolving film product prepared by the technology adopted by the present invention had good quality stability and met the requirements. The sildenafil citrate content and folding resistance of the films of Comparative Examples 4 and Comparative Examples 8-10 decreased significantly during the stability process than those of the examples.

[0163] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A sildenafil orodispersible film preparation, characterized in that: The invention comprises the following materials: sildenafil citrate and / or its pharmaceutically acceptable salt, methyl methacrylate amino copolymer, polymer film-forming material, anti-adhesive agent, vitamin C, plasticizer, moisturizer and cooling agent; the mass ratio of the methyl methacrylate amino copolymer, anti-adhesive agent and vitamin C is 1:(0.03-0.3):(0.15-0.7).

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

3. The sildenafil orodispersible film preparation according to claim 1, characterized in that: The mass ratio of the methylamino methacrylate copolymer, sildenafil citrate and / or its pharmaceutically acceptable salt to the polymer film-forming material is 1:(0.85-1.8):(3-7.5).

4. The sildenafil orodispersible film preparation according to claim 1, characterized in that: The invention comprises the following materials in parts by weight: 14-18 parts of sildenafil citrate and / or a pharmaceutically acceptable salt thereof, 10-16 parts of methylamino methacrylate copolymers, 40-75 parts of polymer film-forming materials, 0.5-3 parts of anti-adhesive agents, 3-7 parts of vitamin C, 2-15 parts of plasticizers, 2-5 parts of moisturizers and 0.2-1 parts of cooling agents.

5. The sildenafil orodispersible film preparation according to claim 1, characterized in that: The polymer film-forming material is selected from at least one of polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose and copovidone.

6. The sildenafil orodispersible film preparation according to claim 1, characterized in that: The anti-adhesive agent is selected from at least one of talc, magnesium stearate and stearic acid; And / or, the cooling agent is selected from at least one of menthyl amide, N,2,3-trimethyl-2-isopropylbutyramide and menthol.

7. The sildenafil orodispersible film preparation 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 humectant is glycerin.

8. The sildenafil orodispersible film preparation according to claim 1, characterized in that: The methylamino methacrylate copolymer is a butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate copolymer.

9. The sildenafil orodispersible film preparation according to claim 8, characterized in that: The methylamino methacrylate copolymer is Eudragit E100 or Eudragit EPO.

10. The method for preparing the sildenafil orodispersible film according to any one of claims 1 to 9, characterized in that: The steps include: S1. Fluidizing and coating sildenafil citrate and / or a pharmaceutically acceptable salt thereof with an organic solution containing methylamino methacrylate copolymer and an anti-adhesive agent to prepare sildenafil taste-masked particles; S2. Mix the sildenafil taste-masking particles, polymer film-forming material, vitamin C, plasticizer, humectant and cooling agent in water to obtain a slurry, apply the slurry to form a film, and then dry and cut the slurry to obtain the sildenafil orodispersible film.

11. The method for preparing the sildenafil orodispersible film according to claim 10, characterized in that: At least one of a sweetener and a flavoring agent is further added to the slurry in step S2.

12. The method for preparing the sildenafil orodispersible film according to claim 10, characterized in that: The material temperature during the fluidized coating process is 22-25°C.

13. The method for preparing the sildenafil orodispersible film according to claim 10, characterized in that: 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.

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