CN119280194B

CN119280194B - Sildenafil oral film-dissolving agent, and preparation method and application thereof

Info

Publication number: CN119280194B
Application number: CN202411244983.3A
Authority: CN
Inventors: 赵玉姣; 林美; 练华杰; 李宪楠
Original assignee: Regenex Corp
Current assignee: Regenex Corp
Priority date: 2024-09-06
Filing date: 2024-09-06
Publication date: 2025-10-28
Anticipated expiration: 2044-09-06
Also published as: CN119280194A

Abstract

本发明公开了一种西地那非口溶膜剂及其制备方法与应用，所述西地那非口溶膜剂包括如下物料：枸橼酸西地那非和/或其药学上可接受的盐、甲基丙烯酸甲胺基酯类共聚物、高分子成膜材料、抗粘剂、维生素C、增塑剂和保湿剂。本发明的口溶膜剂不仅可以有效掩盖西地那非本身苦异味，还具有良好口感和较短的崩解时间，解决了传统枸橼酸西地那非口溶膜在服用过程口感较苦的问题。另外，该口溶膜剂还具有良好的物理性能和药物稳定性，能够满足药物的保存、运输以及临床使用等需求。The present invention discloses a sildenafil orally disintegrating film, a preparation method, and an application thereof. The sildenafil orally disintegrating film comprises the following materials: sildenafil citrate and/or a pharmaceutically acceptable salt thereof, a methylamino methacrylate copolymer, a polymer film-forming material, an anti-adherent agent, vitamin C, a plasticizer, and a moisturizer. The orally disintegrating film of the present invention can not only effectively mask the bitter taste of sildenafil itself, but also has a good mouthfeel and a short disintegration time, thereby solving the problem of a bitter taste during the administration of traditional sildenafil citrate orally disintegrating films. In addition, the orally disintegrating film also has good physical properties and drug stability, and can meet the requirements of drug storage, transportation, and clinical use.

Description

Sildenafil oral film-dissolving agent, and preparation method and application thereof

Technical Field

The invention relates to the technical field of pharmaceutical preparation materials, in particular to a sildenafil oral film agent, a preparation method and application thereof.

Background

Erectile dysfunction (Erectiledysfunction, ED) is a common disease of sexual dysfunction and is clinically characterized by a failure of the penis to maintain adequate erection for more than 3 months in sexual activity. Drugs that have been marketed for the treatment of erectile dysfunction include PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil, and atorvastatin. Among them, sildenafil citrate is the drug of choice for the clinical treatment of various types of erectile dysfunction at present, and the dosage form on the market is a tablet. The traditional tablet has the problems of water requirement for oral administration, low compliance and the like, and the newly developed oral solid quick-release preparation can realize convenient administration and quick dissolution in the oral cavity.

The oral solid quick-release preparation comprises orally disintegrating tablet, sublingual tablet, dispersible tablet and oral instant film. The oral instant film is a preparation prepared by dispersing effective components of a certain dose of chemicals or traditional Chinese medicine extracts in film forming materials, can be rapidly dissolved in the oral cavity, and has the advantages of difficult spitting, rapid absorption, rapid onset of action, convenient swallowing and the like. The sildenafil citrate oral solution film is rapidly disintegrated in the oral cavity in the taking process, and related components of the sildenafil citrate oral solution film can be fully contacted with the oral cavity, so that the taste of the sildenafil citrate oral solution film is particularly bitter, and the existing process usually uses a sweetener or a taste masking agent to improve the taste, but the problem that the sildenafil oral solution film has bitter taste in the taking process is still difficult to solve.

Disclosure of Invention

In order to overcome the problems of the prior art, one of the purposes of the present invention is to provide a sildenafil oral film. The second purpose of the invention is to provide a preparation method of the sildenafil oral film.

In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:

The invention provides sildenafil oral solution, which comprises sildenafil citrate and/or pharmaceutically acceptable salts thereof, methacrylic acid methylamino ester copolymer, high polymer film forming material, anti-adhesive, vitamin C, plasticizer, humectant and cooling agent, wherein the mass ratio of the methacrylic acid methylamino ester copolymer to the anti-adhesive to the vitamin C is 1 (0.03-0.3) (0.15-0.7).

Preferably, the mass ratio of the methacrylic acid methylamino ester copolymer to the anti-adhesion agent to the vitamin C is 1 (0.05-0.15) (0.2-0.55).

More preferably, the mass ratio of the methyl methacrylate amino ester copolymer, sildenafil citrate and/or pharmaceutically acceptable salt thereof to the polymer film forming material is 1 (0.85-1.8) (3-7.5).

Preferably, the composition comprises 14-18 parts by mass of sildenafil citrate and/or pharmaceutically acceptable salt thereof, 10-16 parts by mass of methylamino methacrylate copolymer, 40-75 parts by mass of polymer film forming material, 0.5-3 parts by mass of anti-sticking agent, 3-7 parts by mass of vitamin C, 2-15 parts by mass of plasticizer and 2-5 parts by mass of humectant.

More preferably, the mass part of the polymer film forming material is 50-65 parts.

More preferably, the plasticizer is 3 to 10 parts by mass.

Preferably, the polymer film forming material is at least one selected from polyvinyl alcohol, hydroxypropyl cellulose, hypromellose and copovidone.

More preferably, the polymeric film-forming material is selected from polyvinyl alcohol and hypromellose.

Further preferably, the mass ratio of the polyvinyl alcohol to the hypromellose is 1 (1-2).

Preferably, the anti-sticking agent is at least one selected from talcum powder, magnesium stearate and stearic acid.

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

Preferably, the humectant is glycerin.

Preferably, the cooling agent is at least one selected from menthol, N,2, 3-trimethyl-2-isopropyl butyramide and menthol.

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

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.

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

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

The second aspect of the invention provides a preparation method of the sildenafil oral film agent in the first aspect, which comprises the following steps:

S1, carrying out fluidization coating on sildenafil citrate and/or pharmaceutically acceptable salts thereof by adopting an organic solution containing a methacrylic acid methylamino ester copolymer and an anti-sticking agent to prepare sildenafil taste masking particles;

s2, mixing sildenafil taste masking particles, a high polymer film forming material, vitamin C, a plasticizer, a humectant and a cooling agent in water to obtain slurry, coating and forming a film, and drying and cutting to obtain the sildenafil oral solution film agent.

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

More preferably, the organic solution is prepared by dissolving the methylamino methacrylate copolymer in ethanol water solution, adding the anti-adhesion agent, and mixing to obtain the organic solution containing the methylamino methacrylate copolymer and the anti-adhesion agent.

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

Preferably, in step S1, the material temperature is 22-25 ℃ during the fluidized coating process.

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

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

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

More preferably, the aromatic is at least one selected from strawberry flavor essence, juicy peach flavor essence, pomegranate flavor essence, and orange flavor essence.

Preferably, step S2 further comprises defoaming.

More preferably, the defoaming mode is standing defoaming.

Preferably, in the step S2, in the process of coating and film forming, the thickness of the paving film is 0.15-0.2mm, and the coating speed is 20-40cm/min.

Preferably, in step S2, the drying temperature is 50-70 ℃.

The beneficial effects of the invention are as follows:

the invention provides a sildenafil oral film, which adopts a coating formed by methacrylic acid methylamino ester copolymer and an anti-adhesive to reduce the bitter taste of sildenafil, the cooling agent further reduces the bitter taste, and the vitamin C has the effect of an acidulant, so that the specific proportion of the methacrylic acid methylamino ester copolymer, the anti-adhesive and the vitamin C is adopted, on one hand, the feeling of the oral cavity on the bitter taste is reduced, and on the other hand, the secretion of saliva is promoted, and the dissolution time of a film agent polymer film forming material in the oral cavity is shortened, so that taste masking particles are accelerated to enter the gastrointestinal tract, and the contact time of the taste masking particles and the oral cavity is reduced, thereby realizing that bitter feeling is not released in the oral cavity. The oral film can not only effectively mask the bitter peculiar smell of sildenafil, but also has good taste and shorter disintegration time, and solves the problem that the traditional sildenafil citrate oral film has bitter taste in the taking process. In addition, the oral film has good physical properties and drug stability, and can meet the requirements of storage, transportation, clinical use and the like of the drug.

The invention also provides a preparation method of the sildenafil oral solution, the addition of the anti-sticking agent in the coating process is favorable for the smooth operation of spray coating, and the prepared sildenafil oral solution has no gritty feel and no bitter taste in the taking process, has good taste, improves the clinical use compliance of the existing dosage forms on the market, and has clinical development and use values.

Detailed Description

The present invention will be described in further detail with reference to specific examples. The materials used in the examples below, unless otherwise specified, were either commercially available or isolated by simple synthetic preparation, and the procedures employed, unless otherwise specified, were all conventional in the art.

Example 1

The embodiment provides a sildenafil oral film, the specific formula of which is shown in table 1, and the sildenafil oral film is prepared from the following components:

TABLE 1

The preparation method of the sildenafil oral film agent comprises the following steps:

1. Adding Eudragit E100 into 95% ethanol, stirring for 40 min to dissolve, preparing solution with concentration of 20wt%, adding talcum powder, stirring and dispersing uniformly to obtain coating solution, and performing bottom spray coating on sildenafil citrate powder with particle diameter D90 not exceeding 10 μm by using fluidized bed bottom spray coating machine, wherein the material temperature is 22-25deg.C, and the coating weight is increased by 98% to obtain sildenafil taste masking granule;

2. 160 parts by mass of purified water (about 1565g of raw materials corresponds to 2500g of water) are weighed, heated to 50 ℃, polyvinyl alcohol, polyethylene glycol 400 and glycerin are added into the purified water, stirred and homogenized, cooled to room temperature, the prepared sildenafil taste-masking particles, vitamin C, hypromellose, steviosin, N,2, 3-trimethyl-2-isopropyl butyramide are added, mixed and stirred to prepare a solution, standing overnight to remove bubbles, a backing material is arranged, a coating dryer is arranged at a drying temperature of 60 ℃, coating and drying are started, the coating speed is 0.3 m/min, the film thickness is 0.17mm, the sildenafil oral solution film with the tablet weight of about 313mg is obtained after cutting according to proper size, and the sildenafil oral solution film is independently packaged by adopting a composite film bag.

Example 2

The embodiment provides a sildenafil oral film, the specific formula of which is shown in table 2, and the sildenafil oral film is prepared from the following components:

TABLE 2

1. Adding Eudragit E100 into 95% ethanol, stirring for 40 min to dissolve, preparing solution with concentration of 20wt%, adding talcum powder, stirring and dispersing uniformly to obtain coating solution, and performing bottom spray coating on sildenafil citrate powder with particle diameter D90 not exceeding 10 μm by using fluidized bed bottom spray coating machine, wherein the material temperature is 22-25deg.C, and the coating weight is increased by 100% to obtain sildenafil taste masking granule;

2. Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding the prepared sildenafil taste-masking particles, vitamin C, hypromellose, steviosin and N,2, 3-trimethyl-2-isopropyl butyramide, mixing and stirring to prepare a solution, standing overnight to remove bubbles, installing a backing material, setting the drying temperature of a coating dryer to be 70 ℃, starting coating and drying, the coating speed is 0.3 m/min and the film thickness is 0.17mm, cutting according to a proper size to obtain sildenafil oral solution films with the weight of about 313mg, and independently packaging the sildenafil oral solution films by adopting a composite film bag.

Example 3

The embodiment provides a sildenafil oral film, the specific formula of which is shown in table 3, and the sildenafil oral film is prepared from the following components:

TABLE 3 Table 3

1. Adding Eudragit E100 into 95% ethanol, stirring for 40 min to dissolve, preparing solution with concentration of 20wt%, adding talcum powder, stirring and dispersing uniformly to obtain coating solution, and performing bottom spray coating on sildenafil citrate powder with particle diameter D90 not exceeding 10 μm by using fluidized bed bottom spray coating machine, wherein the material temperature is 22-25deg.C, and the coating weight is increased by 80% to obtain sildenafil taste masking granule;

2. Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding the sildenafil taste-masking particles, vitamin C, hypromellose, steviosin and N,2, 3-trimethyl-2-isopropyl butyramide which are prepared by the steps of mixing and stirring, preparing a solution, standing overnight to remove bubbles, installing a backing material, setting the drying temperature of a coating dryer to 55 ℃, starting coating and drying, the coating speed is 0.3 m/min and the film thickness is 0.17mm, cutting according to a proper size to obtain sildenafil oral solution films with the weight of about 313mg, and independently packaging the sildenafil oral solution films by adopting a composite film bag.

Example 4

The embodiment provides a sildenafil oral film, the specific formula of which is shown in table 4, and the sildenafil oral film is prepared from the following components:

TABLE 4 Table 4

1. Adding Eudragit E100 into 95% ethanol, stirring for 40 min to dissolve, preparing solution with concentration of 20wt%, adding 20% polyethylene glycol 400 of talcum powder, stirring and dispersing uniformly to obtain coating solution, and performing bottom spray coating on sildenafil citrate powder with particle diameter D90 not more than 10 μm by using fluidized bed bottom spray coating machine, wherein the material temperature in the coating process is 22-25deg.C, and the coating weight is increased by 80% to obtain sildenafil taste-masking granule;

2. Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, residual polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding the prepared sildenafil taste-masking particles, vitamin C, hypromellose, steviosin and N,2, 3-trimethyl-2-isopropyl butyramide, mixing and stirring to prepare a solution, standing overnight to remove bubbles, installing a backing material, setting the drying temperature of a coating dryer to 55 ℃, starting coating and drying, the coating speed is 0.3 m/min and the film thickness is 0.17mm, cutting according to a proper size to obtain sildenafil oral solution films with the weight of about 313mg, and independently packaging the sildenafil oral solution films by adopting a composite film bag.

Comparative example 1

The comparative example provides a sildenafil oral film, the specific formula of which is shown in table 5, and the film is prepared from the following components:

TABLE 5

Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding sildenafil citrate raw material powder, vitamin C, hypromellose, steviosin, N,2, 3-trimethyl-2-isopropyl butyramide, mixing and stirring to prepare a solution, standing overnight to remove bubbles, installing a backing material, setting a coating dryer at a drying temperature of 55 ℃, starting coating and drying, coating at a coating speed of 0.3 m/min and a film thickness of 0.17mm, cutting according to a proper size to obtain sildenafil oral solution film with a piece weight of about 313mg, and independently packaging the sildenafil oral solution film by adopting a composite film bag.

Comparative example 2

The comparative example provides a sildenafil oral film, the specific formula of which is shown in table 6, and the film is prepared from the following components:

TABLE 6

2. Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding the sildenafil taste-masking particles, hypromellose, steviosin, N,2, 3-trimethyl-2-isopropyl butyramide, mixing and stirring to prepare a solution, standing overnight to remove bubbles, installing a backing material, setting a coating dryer at a drying temperature of 55 ℃, starting coating and drying, enabling the coating speed to be 0.3 m/min, enabling the film thickness to be 0.17mm, cutting according to a proper size to obtain sildenafil oral solution film with the weight of 313mg, and independently packaging the sildenafil oral solution film by adopting a composite film bag.

Comparative example 3

The comparative example provides a sildenafil oral film, the specific formula of which is shown in Table 7, and the film is prepared from the following components:

TABLE 7

1. Adding Eudragit E100 into 95% ethanol, stirring for 40min to dissolve, preparing solution with concentration of 20wt%, adding silicon dioxide, stirring and dispersing uniformly to obtain coating solution, and performing bottom spray coating on sildenafil citrate powder with particle diameter D90 not exceeding 10 μm by using fluidized bed bottom spray coater, wherein the material temperature is 22-25deg.C, and the coating weight is increased by 80% to obtain sildenafil taste masking granule;

Comparative example 4

The comparative example provides a sildenafil oral film, the specific formula of which is shown in table 8, and the film is prepared from the following components:

TABLE 8

1. Adding Eudragit L100 into 95% ethanol, stirring for 40 min to dissolve, preparing solution with concentration of 20wt%, adding talcum powder, stirring and dispersing uniformly to obtain coating solution, and performing bottom spray coating on sildenafil citrate powder with particle diameter D90 not exceeding 10 μm by using fluidized bed bottom spray coating machine, wherein the material temperature is 22-25deg.C, and the coating weight is increased by 80% to obtain sildenafil taste masking granule;

Comparative example 5

The comparative example provides a sildenafil oral film, the specific formula of which is shown in Table 9, and the film is prepared from the following components:

TABLE 9

1. Dissolving Eudragit E100 in 95% ethanol as binder, adding sildenafil citrate and talcum powder into wet granulator, mixing, adding binder, granulating for 10 min, and granulating at blade speed of 1500rpm and cutting knife rotation speed of 150rpm to obtain sildenafil taste-masking granule;

2. Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding the prepared sildenafil taste-masking particles, vitamin C, hypromellose, steviosin and essence, mixing and stirring to prepare a solution, standing overnight to remove bubbles, installing a backing material, setting a coating dryer at a drying temperature of 55 ℃, starting coating and drying, wherein the coating speed is 0.3 m/min, the film thickness is 0.17mm, cutting according to a proper size to obtain sildenafil oral solution film with the weight of 313mg, and independently packaging the sildenafil oral solution film by adopting a composite film bag.

Comparative example 6

The comparative example provides a sildenafil oral film, the specific formula of which is shown in table 10, and the film is prepared from the following components:

table 10

Material name	Action	Parts by mass
			Sildenafil citrate	Bulk drug	16
Eud E100	Taste masking material	13
			Talc powder	Anti-sticking agent	2.6
Polyvinyl alcohol	Film-forming material	38.4
			Hydroxypropyl methylcellulose	Film-forming material	17
Vitamin C	Sour agent	5
			Polyethylene glycol	Plasticizer(s)	6
Glycerol	Humectant type	4
			Steviosin (stevia rebaudiana)	Sweetener composition	0.2
Sweet orange flavor essence	Aromatic agent	0.5

1. Adding Eudragit E100 into 95% ethanol, stirring for 40 min to dissolve, preparing solution with concentration of 20wt%, adding talcum powder, stirring and dispersing uniformly to obtain coating solution, and performing bottom spray coating on sildenafil citrate powder with particle diameter D90 not exceeding 10 μm by using fluidized bed bottom spray coating machine, wherein the material temperature is 25-30deg.C, and the coating weight is increased by 98% to obtain sildenafil taste masking granule;

2. Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding the prepared sildenafil taste-masking particles, hypromellose, steviosin and sweet orange essence, mixing and stirring to prepare a solution, standing overnight to remove bubbles, setting a backing material, setting a coating dryer at 60 ℃, starting coating and drying, wherein the coating speed is 0.3 m/min, the film thickness is 0.17mm, cutting according to a proper size to obtain sildenafil oral solution films with the weight of about 313mg, and independently packaging the sildenafil oral solution films by adopting a composite film bag.

Comparative example 7

The comparative example provides a sildenafil oral film, the specific formula of which is shown in table 11, and the film is prepared from the following components:

TABLE 11

1. Adding Eudragit E100 into 95% ethanol, stirring for 40 min to dissolve, preparing solution with concentration of 20wt%, adding talcum powder, stirring and dispersing uniformly to obtain coating solution, and performing bottom spray coating on sildenafil citrate powder with particle diameter D90 of 25 μm by using fluidized bed bottom spray coater, wherein the material temperature is 22-25deg.C, and the coating weight is increased by 98% to obtain sildenafil taste masking granule;

2. Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding the sildenafil taste-masking particles, vitamin C, hypromellose, steviosin and orange flavor prepared by the method, mixing and stirring to prepare a solution, standing overnight to remove bubbles, installing a backing material, setting a coating dryer at 60 ℃, starting coating and drying, enabling the coating speed to be 0.3 m/min and the film thickness to be 0.17mm, cutting according to a proper size to obtain sildenafil oral solution film with the weight of about 313mg, and independently packaging the sildenafil oral solution film by adopting a composite film bag.

Comparative example 8

The comparative example provides a sildenafil oral film, the specific formula of which is shown in table 12, and the film is prepared from the following components:

table 12

1. Adding Eudragit E100 into 95% ethanol, stirring for 40 min to dissolve, preparing solution with concentration of 20wt%, adding talcum powder, stirring and dispersing uniformly to obtain coating solution, and performing bottom spray coating on sildenafil citrate powder with particle diameter D90 not exceeding 10 μm by using fluidized bed bottom spray coating machine, wherein the material temperature is 22-25deg.C, and the coating weight is increased by 50% to obtain sildenafil taste masking granule;

2. Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding the sildenafil taste-masking particles, hypromellose, steviosin, N,2, 3-trimethyl-2-isopropyl butyramide, mixing and stirring to prepare a solution, standing overnight to remove bubbles, installing a backing material, setting the drying temperature of a coating dryer to 60 ℃, starting coating and drying, enabling the coating speed to be 0.3 m/min, enabling the film thickness to be 0.17mm, cutting according to a proper size to obtain sildenafil oral solution film with the weight of 313mg, and independently packaging the sildenafil oral solution film by adopting a composite film bag.

Comparative example 9

The comparative example provides a sildenafil oral film, the specific formula of which is shown in table 13, and the film is prepared from the following components:

TABLE 13

2. Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding the prepared sildenafil taste-masking particles, hypromellose, steviosin and sweet orange essence, mixing and stirring to prepare a solution, standing overnight to remove bubbles, setting a backing material, setting a coating dryer at a drying temperature of 55 ℃, starting coating and drying, wherein the coating speed is 0.3 m/min, the film thickness is 0.17mm, cutting according to a proper size to obtain sildenafil oral solution films with the weight of about 313mg, and independently packaging the sildenafil oral solution films by adopting a composite film bag.

Comparative example 10

The comparative example provides a sildenafil oral film, the specific formula of which is shown in table 14, and the film is prepared from the following components:

TABLE 14

1. Adding Eudragit E100 into 95% ethanol, stirring for 40 min to dissolve, preparing solution with concentration of 20wt%, adding talcum powder, stirring and dispersing uniformly to obtain coating solution, and performing bottom spray coating on sildenafil citrate powder with particle diameter D90 not exceeding 10 μm by using fluidized bed bottom spray coating machine, wherein the material temperature is 32-36 ℃ during coating process, and the coating weight is increased by 80%, thus obtaining sildenafil taste masking granule;

2. Weighing 160 parts by mass of purified water, heating to 50 ℃, adding polyvinyl alcohol, polyethylene glycol 400 and glycerin into the purified water, stirring and homogenizing, cooling to room temperature, adding the prepared sildenafil taste-masking particles, hypromellose, steviosin and sweet orange essence, mixing and stirring to prepare a solution, standing overnight to remove bubbles, setting a backing material, setting a coating dryer at a drying temperature of 35 ℃, starting coating and drying, wherein the coating speed is 0.3 m/min, the film thickness is 0.17mm, cutting according to a proper size to obtain sildenafil oral solution films with the weight of about 313mg, and independently packaging the sildenafil oral solution films by adopting a composite film bag.

Performance test and results

1. The samples obtained in examples 1 to 4 and comparative examples 1 to 10 were subjected to a taste test.

10 Male and female volunteers 20-45 years old were selected, samples of examples 1-4 and comparative examples 1-10 were tried after 20min interval and drinking water rinse, respectively, and the scoring results were averaged, and the bitter scores were as shown in table 15 below. The scoring standard is that the whole course is almost free of bitter, the bitter is a little after 2-entrance for 5 seconds, the bitter is obvious in 3-entrance for 5 seconds, each group is the average value of scores of all volunteers, and the whole number is rounded off by adopting a rounding principle.

TABLE 15

2. The samples obtained in examples 1 to 4 and comparative examples 1 to 10 were subjected to oral film appearance, tensile strength, folding endurance and disintegration time test.

(1) Test method

Appearance detection, visual inspection under white light.

The tensile strength detection method comprises the steps of adopting a texture analyzer, setting the speed to be 100mm/min, clamping a sample on an instrument clamp after the measurement condition is set, and starting measurement after the initial value is reset to zero.

The method for measuring the folding endurance comprises the steps of taking 1 piece of the product, folding the piece of the product, placing the piece of the product on a PVC plate, adding about 500g of weight for 2s on the PVC plate, repeating the operation, and recording the folding times when the sample breaks.

Determination of disintegration time 25ml of purified water was added to a 250ml beaker and the water bath temperature was 37.+ -. 0.5 ℃. The paper clip is fixed at the middle position of the oral film, the paper clip is placed into a beaker to start timing until the oral film is completely dissolved, the time required by the complete dissolution of the oral film is recorded, and the measurement is repeated for 3 times.

(2) The test results are shown in table 16:

table 16

As can be seen from tables 15 and 16, examples 1 to 4 tested the feasibility of the product process, the appearance, the disintegration time and the taste of the product under different process parameters such as different weight gains of the taste masking coating, different coating drying temperatures, and the like, and did not greatly affect the quality of the product.

As can be seen from tables 15 and 16, the conventional taste masking method using sweetener and cooling agent adopted in comparative example 1 was free of addition of particular E100 coating, the bitter taste of the oral film after 5 seconds in the coating process was obvious, the E100 of comparative example 2 was free of addition of vitamin C and bitter taste after 5 seconds in the coating process, the anti-sticking agent type, the taste masking agent type and the granulating method were replaced in comparative examples 3,4 and 5 respectively, the oral film still had little bitter taste after 5 seconds in the coating process, the coating process was not smooth and the taste masking effect was reduced due to adhesion of the taste masking particles caused by softening of the coating material when the coating temperature was too high in comparative example 6, the effect of the particle size of the raw material was examined in comparative example 7, the appearance of the film was not qualified when the particle size of the raw material was 25 μm was used, the dosage ratio of different talcum powder in the coating was examined in comparative examples 8 and 9, a little bitter taste was still remained after 5 seconds in the inlet, and the surface of the film was not sufficiently smooth due to insufficient drying when the coating drying temperature was too low in comparative example 10.

In conclusion, the invention adopts the Eudragit E100 and talcum powder to carry out fluidized bed bottom spray coating on sildenafil, uses N,2, 3-trimethyl-2-isopropyl butyramide as a cooling agent and vitamin C to regulate bitter taste, and limits specific coating and coating conditions.

3. The samples of example 1, comparative example 4, comparative examples 8-10 were individually packaged using a composite film pouch and stability was investigated under accelerated (40 ℃ at 75% rh) conditions, the results of which are shown in table 17:

TABLE 17

As can be obtained from table 17, the sildenafil oral solution film prepared by the technology adopted by the invention has good quality stability and meets the requirements when the sample of the example 1 is placed for 6 months under the acceleration condition, and the folding endurance, the content and the disintegration time limit of the sildenafil oral solution film are not obviously changed. The comparative example 4 and comparative examples 8-10 show a decrease in sildenafil citrate content and a decrease in folding endurance of the film agent during stability than the examples.

The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims

1. A sildenafil orally disintegrating film-forming agent, characterized in that it comprises the following materials: sildenafil citrate and/or a pharmaceutically acceptable salt thereof, a methylamino methacrylate copolymer, a polymer film-forming material, an anti-adherent agent, vitamin C, a plasticizer, a humectant, and a cooling agent; the mass ratio of the methylamino methacrylate copolymer, the anti-adherent agent, and the vitamin C is 1:(0.03-0.3):(0.15-0.7); the mass ratio of the methylamino methacrylate copolymer, sildenafil citrate and/or a pharmaceutically acceptable salt thereof, and the polymer film-forming material is 1:(0.85-1.8):(3-7.5); the methylamino methacrylate copolymer is Eudragit E100;

The anti-sticking agent is talc; the cooling agent is N,2,3-trimethyl-2-isopropylbutanamide;

The sildenafil orally disintegrating film is prepared by a preparation method comprising the following steps:

S1. Fluidizing and coating sildenafil citrate and/or a pharmaceutically acceptable salt thereof with an organic solution containing a methylamino methacrylate copolymer and an anti-adherent agent to prepare sildenafil taste-masked particles; the material temperature during the fluidizing and coating process is 22-25° C.;

S2. Mix the sildenafil taste-masking particles, polymer film-forming material, vitamin C, plasticizer, moisturizer 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 orally disintegrating film.

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

3. The sildenafil orally disintegrating film according to claim 1, characterized in that it 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 copolymer, 40-75 parts of a polymer film-forming material, 0.5-3 parts of an anti-adherent agent, 3-7 parts of vitamin C, 2-15 parts of a plasticizer, 2-5 parts of a humectant, and 0.2-1 parts of a cooling agent.

4. The sildenafil orally disintegrating film-forming preparation according to claim 1, wherein the polymer film-forming material is selected from at least one of polyvinyl alcohol, hydroxypropyl cellulose, hypromellose, and copovidone.

5. The sildenafil orally disintegrating film according to claim 1, wherein the plasticizer is at least one selected from the group consisting of polyethylene glycol, propylene glycol, and triethyl citrate;

And/or, the humectant is glycerin.

6. The method for preparing the sildenafil orally disintegrating film according to any one of claims 1 to 5, comprising the steps of:

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

8. The method for preparing the orally disintegrating sildenafil film according to claim 6, wherein during the coating process, the film thickness is 0.15-0.2 mm and the coating speed is 20-40 cm/min.