A tadalafil orodispersible film and preparation method thereof

Abstract

The invention provides a tadalafil oral dissolving film and a preparation method thereof, wherein the tadalafil oral dissolving film comprises the following components in percentage by weight: 5-20% of tadalafil, 10-80% of film-forming material, 0.1-20% of plasticizer, 0.5-10% of acid stabilizer, 0.1-10% of surfactant, 0.1-10% of sweetener, and 0.1-5% of flavor corrector. The tadalafil oral dissolving film of the invention can be smoothly prepared by hot melt extrusion film drawing process to obtain the tadalafil oral dissolving film, can effectively control the impurity content in the preparation process, and can make the prepared tadalafil oral dissolving film have good storage stability.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparation preparation, and relates to a tadalafil orosoluble film and a preparation method thereof. Background Art

[0002] Tadalafil is a poorly soluble drug, soluble only in a few solvents such as ethanol, methanol, and acetone. Oral tablets have low bioavailability and slow onset of action. In addition, tablets need to be taken with water, which is inconvenient to take, and will give patients a psychological hint that they are taking medicine, which can easily cause patients greater psychological pressure and lead to poor medication effects.

[0003] Orodispersible film is an oral preparation made by evenly dispersing the active ingredients of the drug in the film-forming material. This oral rapid-release dosage form is very important in the pharmaceutical industry. It can disintegrate in saliva in a short time to release the active ingredients of the drug, and then be absorbed by the oral mucosa or swallowed and then absorbed by the gastrointestinal tract. It has a fast onset of action and high bioavailability. It can be administered quickly and accurately at any time and any place without the need for water, and will not delay the time of taking the medicine. In addition, the orodispersible film dosage form also improves patient compliance.

[0004] CN106176685A discloses a tadalafil oral dissolving film and a preparation method thereof, wherein a drug-containing gelatin solution containing tadalafil is degassed, then coated, dried, and cut to obtain a tadalafil oral dissolving film. This solvent coating method requires the use of a solvent and requires degassing before coating. During the coating process, uneven heating or unreasonable parameter settings may cause problems such as wrinkles, unevenness, and air bubbles in the oral dissolving film product. In addition, the process has the disadvantages of multiple steps, solvent residue, energy consumption, and time consumption.

[0005] Therefore, it is desired in the art to develop a tadalafil orodispersible film that does not use a solvent, does not cause defects in the orodispersible film appearance, and can control the quality of the drug. Summary of the invention

[0006] In view of the deficiencies in the prior art, the object of the present invention is to provide a tadalafil orodispersible film and a preparation method thereof. The tadalafil orodispersible film of the present invention can effectively control the generation of impurities during the preparation process using a hot melt extrusion film drawing process and has good storage stability.

[0007] To achieve this object, the present invention adopts the following technical solutions:

[0008] In one aspect, the present invention provides a tadalafil orodispersible film, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0009]

[0010]

[0011] In the tadalafil orodispersible film of the present invention, citric acid is used so that the impurity content can be effectively controlled during the preparation of the tadalafil orodispersible film by hot melt extrusion film drawing technology, and the impurity content is lower than 0.05%, or even no impurities are detected.

[0012] In the tadalafil orosoluble film of the present invention, the weight percentage content of tadalafil is 5%, 8%, 10%, 12%, 15%, 18% or 20%.

[0013] In the tadalafil oral dissolving film of the present invention, the film-forming material is selected from any one or a combination of at least two of copolyvidone, polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer, povidone, hydroxypropyl methylcellulose, polyvinyl alcohol, polyoxyethylene, polyethylene glycol, hydroxypropyl cellulose or hydroxyethyl cellulose; preferably, copolyvidone, polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer or any one or a combination of at least two of polyoxyethylene, and most preferably copolyvidone and / or polyoxyethylene. The temperature of copolyvidone and polyoxyethylene is low when the oral dissolving film is prepared, because the tadalafil oral dissolving film will produce impurities when heated, and the film-forming material with a lower preparation temperature is selected. The time of disintegration and dissolution of the oral dissolving film prepared by using these two materials is short, which is more suitable for the characteristics of rapid dissolution of the oral dissolving film. In addition, the tadalafil oral dissolving film prepared by these two materials has good flexibility and moderate mechanical strength, so copolyvidone and / or polyoxyethylene are preferred in the present invention.

[0014] In the tadalafil orosoluble film of the present invention, the weight percentage content of the plasticizer can be 0.1%, 0.5%, 1%, 3%, 5%, 8%, 10%, 12%, 15%, 18% or 20%.

[0015] In the tadalafil orodispersible film of the present invention, the plasticizer is any one of polyethylene glycol, poloxamer or mannitol or a combination of at least two thereof, preferably polyethylene glycol. Polyethylene glycol has a good plasticizing effect, and the prepared film is not easy to be broken. Adding polyethylene glycol can also reduce the processing temperature during the preparation of the film, so polyethylene glycol is preferred in the present invention.

[0016] Preferably, the acid stabilizer is any one of citric acid, succinic acid, maleic acid or phthalic acid, or a combination of at least two thereof. Considering the cost, citric acid is preferred in the present invention.

[0017] In the tadalafil orodispersible film of the present invention, the weight percentage content of the acid stabilizer can be 0.5%, 1%, 3%, 5%, 8% or 10%. In the present invention, if the amount of the acid stabilizer is too little, the purpose of controlling the related substances of the tadalafil orodispersible film cannot be achieved. If the amount of the acid stabilizer is too much, there will be a strong acidity, which affects the taste of the orodispersible film. If it exceeds 10%, it will also affect the film-forming property.

[0018] In the tadalafil orosoluble film of the present invention, the weight percentage content of the surfactant may be 0.1%, 0.5%, 1%, 3%, 5%, 8% or 10%.

[0019] Preferably, the surfactant is selected from any one or a combination of at least two of sodium dodecyl sulfate, Tween, poloxamer, TPPS (tetrakis-(4-phenylsulfonic acid) porphyrin) or polyoxyethylene 40 hydrogenated castor oil, preferably sodium dodecyl sulfate.

[0020] In the present invention, in the tadalafil orosoluble film, the weight percentage of the sweetener may be 0.1%, 0.5%, 1%, 3%, 5%, 8% or 10%.

[0021] Preferably, the sweetener is selected from any one or a combination of at least two of sucralose, sorbitol, sucrose, aspartame, saccharin, and fructose; preferably any one or a combination of at least two of sucralose, aspartame, or sorbitol, and most preferably sucralose.

[0022] In the present invention, in the tadalafil orosoluble film, the weight percentage of the flavoring agent can be 0.1%, 0.5%, 0.8%, 1%, 2%, 3%, 4% or 5%.

[0023] Preferably, the flavoring agent is selected from any one of sweet orange flavor, strawberry flavor, vanilla flavor, banana flavor, peach flavor, milk flavor, cherry flavor, and mint flavor, or a combination of at least two of them; preferably, sweet orange flavor, strawberry flavor, vanilla flavor, and milk flavor, or a combination of at least two of them, and most preferably, sweet orange flavor and / or strawberry flavor.

[0024] On the other hand, the present invention provides a method for preparing a tadalafil orodispersible film, the preparation method comprising the following steps:

[0025] Tadalafil, film-forming material, plasticizer, acid stabilizer, surfactant, sweetener and flavoring agent are mixed, and the mixture is added into a hot melt extruder feeder, wherein the barrel temperature is 90-110°C, 110-130°C, 125-145°C, 140-160°C, 140-160°C, 140-160°C, 140-160°C, 140-160°C, 140-160°C, and the die temperature is 140-160°C, extruded, and film-drawn to obtain the tadalafil orosoluble film.

[0026] The setting of the barrel temperature as mentioned above is because the barrel temperature is divided into different temperature zones, and the temperature of each zone is set to 90-110℃, 110-130℃, 125-145℃, 140-160℃, 140-160℃, 140-160℃, 140-160℃, 140-160℃, 140-160℃.

[0027] In the present invention, a hot melt extrusion film drawing process is used to prepare a tadalafil orally dissolving film. The hot melt extrusion film drawing process does not require the use of solvents, has fewer processes, and can be produced continuously. However, the inventors found that when using this process, tadalafil and excipients need to be thermally stable, and there is currently no mature process route for preparing a tadalafil orally dissolving film using this process in the prior art. When using the hot melt extrusion film drawing process to prepare a tadalafil orally dissolving film, due to the heating and shearing in the process, the impurities related to the tadalafil orally dissolving film will increase significantly.

[0028] In order to solve the problem of increased impurity content in the process, the present invention improves the formula of the tadalafil orodissolving film and specifically controls the process parameters in the preparation process, so that not only the tadalafil orodissolving film can be smoothly prepared, but also the impurity content in the preparation process can be effectively controlled, and the prepared tadalafil orodissolving film can have good storage stability.

[0029] In the present invention, by controlling the temperatures of the eight temperature setting zones of the barrel and the die temperature, the impurity content in the preparation process can be effectively controlled.

[0030] In the present invention, the temperature of the first zone in the temperature setting zone of the barrel can be 90°C, 95°C, 98°C, 100°C, 105°C, 108°C or 110°C, the temperature of the second zone can be 110°C, 115°C, 118°C, 120°C, 125°C or 130°C, the temperature of the third zone can be 125°C, 130°C, 135°C, 140°C or 145°C, and the temperature of the fourth zone can be 140°C, 145°C, 150°C, 155°C or 156°C. The temperature of zone 5 is 140, 145, 150, 155 or 160°C, the temperature of zone 6 is 140, 145, 150, 155 or 160°C, the temperature of zone 7 is 140, 145, 150, 155 or 160°C, the temperature of zone 8 is 140, 145, 150, 155 or 160°C, and the die temperature is 140, 145, 150, 155 or 160°C.

[0031] Preferably, the rotation speed during mixing is 10-18 rpm, such as 10 rpm, 13 rpm, 15 rpm or 18 rpm, and the mixing time is 15-22 min, such as 15 min, 18 min, 20 min or 22 min.

[0032] Preferably, the extrusion speed during the extrusion is 300-350 rpm, for example, 300 rpm, 310 rpm, 320 rpm, 330 rpm, 340 rpm or 350 rpm.

[0033] Preferably, the feeding speed of adding the mixture into the hot melt extruder feeder is 10-40rpm, such as 10rpm, 15rpm, 20rpm, 25rpm, 30rpm, 35rpm or 40rpm.

[0034] Preferably, the film pulling speed is 1-3 rpm, for example, 1 rpm, 1.3 rpm, 1.5 rpm, 2 rpm, 2.5 rpm or 3 rpm.

[0035] After film drawing, the orodispersible film is cut into suitable sizes and shapes and packaged.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] The present invention can not only smoothly prepare the tadalafil orodissolving film by using the hot melt extrusion film drawing process, but also effectively control the impurity content in the preparation process (the total impurity content does not exceed 0.3%), and can make the prepared tadalafil orodissolving film have good storage stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1The HPLC chromatogram of the related substances of tadalafil API under undestructed conditions;

[0039] Figure 2 The HPLC chromatogram of the related substances of tadalafil API after destruction with 30% hydrogen peroxide for 6 hours;

[0040] Figure 3 This is the HPLC chromatogram of the related substances of the tadalafil API after being destroyed by 80°C high temperature solution for 24 hours;

[0041] Figure 4 This is the HPLC chromatogram of the related substances of the tadalafil API after solid destruction at 105°C for 24 hours;

[0042] Figure 5 This is the HPLC chromatogram of the related substances of the tadalafil API after being destroyed by 1 mol / L HCl for 24 hours;

[0043] Figure 6 This is the HPLC chromatogram of the related substances of tadalafil API after destruction by 1 mol / L NaOH for 4 hours;

[0044] Figure 7 This is the HPLC chromatogram of the related substances of the tadalafil API after solid destruction by light irradiation for 11 days;

[0045] Figure 8 The HPLC chromatogram of the related substances of the tadalafil API after being destroyed by light solution for 5 days;

[0046] Fig. 9 is a high performance liquid chromatogram of related substances of the tadalafil orodispersible film of Example 1;

[0047] Fig.10 is a high performance liquid chromatogram of related substances of the tadalafil orodispersible film of Example 2;

[0048] Fig.11 is a high performance liquid chromatogram of related substances of the tadalafil orodispersible film of Example 3;

[0049] Fig.12 is a high performance liquid chromatogram of related substances of the tadalafil orodispersible film of Example 4;

[0050] Fig.13 is a high performance liquid chromatogram of related substances of the tadalafil orodispersible film of Example 5;

[0051] Fig.14 is a high performance liquid chromatogram of related substances of the tadalafil orodispersible film of Example 6;

[0052] Fig.15is a high performance liquid chromatogram of related substances of the tadalafil orodispersible film of Comparative Example 2;

[0053] Fig.16 The HPLC chromatogram of the related substances on Day 0 of the accelerated stability test of the tadalafil orodispersible film of Example 1;

[0054] Fig.17 is a high performance liquid chromatogram of related substances of the tadalafil orodispersible film of Example 1 after one month of accelerated stability test;

[0055] Fig.18 The HPLC chromatogram of the related substances of the tadalafil orodispersible film of Example 1 after 3 months of accelerated stability test;

[0056] Fig.19 The HPLC chromatogram of related substances of the tadalafil orodispersible film of Example 1 after 6 months of accelerated stability test. DETAILED DESCRIPTION

[0057] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0058] Comparative Example 1

[0059] This comparative example provides a tadalafil orodispersible film and a preparation method thereof, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0060]

[0061] The preparation method of the tadalafil orosoluble film in this comparative example includes three preparation methods.

[0062] The first preparation method: add tadalafil, copovidone VA64, polyoxyethylene N80, polyethylene glycol, sodium lauryl sulfate, sucralose and sweet orange flavor to a mixer, mix at 15 rpm for 20 minutes, add the mixture to the feeder of a hot melt extruder, the feeding speed is 25 rpm, the barrel temperature is 100°C, 120°C, 135°C, 150°C, 150°C, 150°C, 150°C, 150°C, the die temperature is 150°C, extrude at an extrusion speed of 325 rpm, and draw a film at a film drawing speed of 2 rpm to obtain the tadalafil orosoluble film.

[0063] The second preparation method is different from the first preparation method in that the barrel temperatures are 100°C, 130°C, 160°C, 180°C, 180°C, 180°C, 180°C, and the die temperature is 180°C, and the rest are the same as the first preparation method.

[0064] The third preparation method is different from the first preparation method in that the barrel temperatures are 120°C, 150°C, 180°C, 220°C, 220°C, 220°C, 220°C, and the die temperature is 220°C. The rest are the same as the first preparation method.

[0065] The contents of the related substances in the preparation process of tadalafil orodispersible film under the three preparation methods in Comparative Example 1 were determined by high performance liquid chromatography (High Performance Liquid Chromatography in Chinese Pharmacopoeia 0512), and the specific method is as follows:

[0066] Diluent: acetonitrile-water (50:50).

[0067] Test solution: Take 5 tablets of this product, place them in a 200mL volumetric flask, add 100mL of acetonitrile and shake to dissolve, then dilute to the scale with water, shake well, filter and take the filtrate.

[0068] Reference solution: Take an appropriate amount of tadalafil reference substance, weigh accurately, dissolve and dilute with a diluent to make a solution containing approximately 0.25 mg of tadalafil per 1 mL.

[0069] Sensitivity solution: Pipette an appropriate amount of the reference solution, dissolve it in a diluent and dilute it to make a solution containing approximately 0.25 μg of tadalafil per 1 mL.

[0070] System suitability solution: Measure 25 mL of reference solution, add 0.25 mL of 5 mol / L sodium hydroxide solution, shake well, let stand for 30 minutes, and adjust the pH of the solution to 7 with trifluoroacetic acid.

[0071] Chromatographic conditions: Octylsilane bonded silica gel is used as filler (Agilent Zorbax SB-C8150mm×4.6mm, 3.5μm, or a chromatographic column with equivalent performance is recommended), acetonitrile-water-trifluoroacetic acid (35:65:0.1) is used as the mobile phase; the flow rate is 1.0mL per minute; the column temperature is 35℃; the detection wavelength is 285nm, and the injection volume is 10μl.

[0072] System suitability requirements: In the system suitability solution chromatogram, the separation degree of tadalafil and 6R, 12aS diastereoisomers should be no less than 3, and the tailing factor of tadalafil peak should be no more than 1.5. In the sensitivity solution chromatogram, the signal-to-noise ratio of tadalafil peak should be no less than 20.

[0073] Determination method: Accurately measure the test solution, inject it into the liquid chromatograph, and record the chromatogram.

[0074] Limits: If there are impurity peaks in the chromatogram of the test solution, calculated by the peak area normalization method, the single impurity shall not exceed 0.2%, the total amount of impurities shall not exceed 0.3%, and the chromatographic peaks less than 0.05% of the total peak area shall be ignored.

[0075] The test results are shown in Table 1.

[0076] Table 1

[0077]

[0078]

[0079] In Table 1, the early, middle and late stages are samples taken during continuous production. Samples are taken 10 minutes into the production as early stage samples, samples are taken 20 minutes into the production as middle stage samples, and samples are taken 30 minutes into the production as late stage samples.

[0080] It can be seen from the data in Table 1 that when the tadalafil orodispersible film was prepared by hot melt extrusion in Comparative Example 1, impurities were detected regardless of whether the final stable temperature was set at 150°C, 180°C or 220°C. When the stable processing temperature was 180°C and 220°C, the total impurity standard of 0.3% was exceeded. When the processing temperature was 150°C, although the quality standard of related substances of the product was met, more impurities could be detected.

[0081] A forced degradation test was further conducted on the tadalafil API, and the solution was prepared as follows:

[0082] Undamaged: Weigh about 25 mg of tadalafil API into a 100 mL volumetric flask, dissolve and dilute to scale with acetonitrile-water (50:50), and shake well.

[0083] Oxidative damage: Weigh about 25 mg of tadalafil raw material into a 100 mL volumetric flask, add 5 mL of 30% hydrogen peroxide, leave at room temperature for 6 hours, dissolve and dilute to the scale with acetonitrile-water (50:50), and shake well.

[0084] High temperature solution destruction: Weigh about 25 mg of tadalafil raw material into a 100 mL volumetric flask, dissolve and dilute to the scale with acetonitrile-water (50:50), shake well, and place in a 80°C water bath for 24 hours.

[0085] High-temperature solid destruction: Weigh about 25 mg of tadalafil raw material into an empty bottle, place it in a 105°C forced air drying oven for 24 hours, transfer it to a 100-mL volumetric flask with acetonitrile-water (50:50), and after it is completely dissolved, dilute it to the scale with acetonitrile-water (50:50) and shake well.

[0086] Acid destruction: Weigh about 25 mg of tadalafil raw material into a 100 mL volumetric flask, add 5 mL of 1 mol / L hydrochloric acid solution, leave at room temperature for 24 hours, add 5 mL of 1 mol / L sodium hydroxide solution, mix well, dissolve and dilute to the scale with acetonitrile-water (50:50), and shake well.

[0087] Alkali destruction: weigh about 25 mg of tadalafil raw material and place it in a 100 mL volumetric flask, add 5 mL of 1 mol / L sodium hydroxide solution, leave it at room temperature for 4 hours, add 5 mL of 1 mol / L hydrochloric acid solution, mix well, dissolve and dilute to the scale with acetonitrile-water (50:50), and shake well to obtain.

[0088] Illumination (solid): weigh about 25 mg of tadalafil API into a 100 mL transparent volumetric flask and place at 4500 Lux, 90 μW / cm 2 After being placed in the light box for 11 days, take it out, dissolve it with acetonitrile-water (50:50) and dilute it to the scale, and shake it well.

[0089] Irradiation (solution): weigh about 25 mg of tadalafil API into a 100 mL transparent volumetric flask, dissolve and dilute to scale with acetonitrile-water (50:50), shake well, and irradiate at 4500 Lux, 90 μW / cm 2 After placing in the light box for 5 days, take it out, dissolve it with acetonitrile-water (50:50) and dilute it to the scale, and shake it well.

[0090]

[0091] Among them, A 未破坏 It is the sum of all peak areas in the undestroyed test solution;

[0092] A 破坏 It is the sum of all peak areas in the test solution under each destruction condition;

[0093] C 破坏 is the concentration of the test solution under each destruction condition;

[0094] C 未破坏 It is the concentration of the test solution that is not destroyed.

[0095] The results of the forced degradation test are shown in Table 2 (RRT in the table represents retention time).

[0096] Table 2

[0097]

[0098]

[0099] Figure 1 This is the HPLC chromatogram of the related substances of tadalafil raw material under undestructed conditions. Figure 2-Figure 8 They are the HPLC chromatograms of the related substances of tadalafil raw material after 6 hours of destruction by 30% hydrogen peroxide, 24 hours of destruction by 80℃ high temperature solution, 24 hours of destruction by 105℃ high temperature solid, 24 hours of destruction by 1mol / L HCl, 4 hours of destruction by 1mol / L NaOH, 11 days of solid destruction by light irradiation and 5 days of destruction by light solution.

[0100] According to the data in Table 2 and Figure 1-Figure 8 It can be seen that the main degradation impurities of tadalafil solid under oxidation conditions are impurities with RRT0.27; no obvious degradation impurities are produced under high temperature and acid conditions, and it is stable; the sample is stable when placed in 1M hydrochloric acid solution for 24 hours; the sample is easily destroyed when placed in 1M sodium hydroxide for 4 hours; the solid is stable after 11 days of light exposure. After being prepared into a liquid, it is stable after 5 days of light exposure; a larger single impurity is destroyed at 80℃ for 24 hours.

[0101] Based on the above results, the present invention provides a solution for preparing a tadalafil orodissolving film by hot melt extrusion and controlling the total impurity content of the tadalafil orodissolving film to be below 0.2%, as described in the following examples.

[0102] Example 1

[0103] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0104]

[0105] The preparation method comprises the following steps:

[0106] Add tadalafil, copovidone VA64, polyoxyethylene N80, polyethylene glycol, citric acid, sodium lauryl sulfate, sucralose and sweet orange flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 25 rpm, the barrel temperature is 100°C, 120°C, 135°C, 150°C, 150°C, 150°C, 150°C, 150°C, the die temperature is 150°C, extrude at an extrusion speed of 325 rpm, and draw a film at a film drawing speed of 2 rpm to obtain the tadalafil orosoluble film.

[0107] Example 2

[0108] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0109]

[0110] The preparation method comprises the following steps:

[0111] Add tadalafil, copovidone VA64, polyoxyethylene N80, polyethylene glycol, citric acid, sodium lauryl sulfate, sucralose and sweet orange flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 10 rpm, the barrel temperature is 90°C, 110°C, 125°C, 140°C, 140°C, 140°C, 140°C, 140°C, the die temperature is 140°C, extrude at an extrusion speed of 300 rpm, and draw a film at a film drawing speed of 3 rpm to obtain the tadalafil orosoluble film.

[0112] Example 3

[0113] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0114]

[0115] The preparation method comprises the following steps:

[0116] Add tadalafil, copovidone VA64, polyoxyethylene N80, polyethylene glycol, citric acid, sodium lauryl sulfate, sucralose and sweet orange flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 40 rpm, the barrel temperature is 110°C, 130°C, 145°C, 160°C, 160°C, 160°C, 160°C, 160°C, the die temperature is 160°C, extrude at an extrusion speed of 350 rpm, and draw a film at a film drawing speed of 2 rpm to obtain the tadalafil orosoluble film.

[0117] Example 4

[0118] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0119]

[0120] The preparation method comprises the following steps:

[0121] Add tadalafil, copovidone VA64, polyoxyethylene N80, polyethylene glycol, citric acid, sodium lauryl sulfate, sucralose and sweet orange flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 30 rpm, the barrel temperature is 100°C, 110°C, 125°C, 140°C, 150°C, 150°C, 150°C, 150°C, the die temperature is 150°C, extrude at an extrusion speed of 300 rpm, and draw a film at a film drawing speed of 1 rpm to obtain the tadalafil orosoluble film.

[0122] Example 5

[0123] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0124]

[0125]

[0126] The preparation method comprises the following steps:

[0127] Add tadalafil, copovidone VA64, polyoxyethylene N80, polyethylene glycol, citric acid, sodium lauryl sulfate, sucralose and sweet orange flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 25 rpm, the barrel temperature is 110°C, 130°C, 145°C, 160°C, 160°C, 160°C, 160°C, 160°C, the die temperature is 160°C, extrude at an extrusion speed of 350 rpm, and draw a film at a speed of 2 rpm to obtain the tadalafil orosoluble film.

[0128] Example 6

[0129] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0130]

[0131] The preparation method comprises the following steps:

[0132] Add tadalafil, copovidone VA64, polyoxyethylene N80, polyethylene glycol, citric acid, sodium lauryl sulfate, sucralose and sweet orange flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 35 rpm, the barrel temperature is 100°C, 120°C, 135°C, 150°C, 160°C, 160°C, 160°C, 160°C, the die temperature is 160°C, extrude at an extrusion speed of 300 rpm, and draw a film at a film drawing speed of 2 rpm to obtain the tadalafil orosoluble film.

[0133] Example 7

[0134] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0135]

[0136]

[0137] The preparation method comprises the following steps:

[0138] Add tadalafil, hydroxypropyl methylcellulose, poloxamer, succinic acid, Tween, sorbitol and strawberry flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 25 rpm, the barrel temperature is 100°C, 120°C, 135°C, 150°C, 150°C, 150°C, 150°C, 150°C, the die temperature is 150°C, extrude at an extrusion speed of 325 rpm, and draw a film at a film drawing speed of 2 rpm to obtain the tadalafil orosoluble film.

[0139] Example 8

[0140] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0141]

[0142] The preparation method comprises the following steps:

[0143] Add tadalafil, polyethylene caprolactam polyvinyl acetate polyethylene glycol graft copolymer, mannitol, phthalic acid, poloxamer, aspartame and peach flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to a hot melt extruder feeder, the feeding speed is 35 rpm, the barrel temperature is 100°C, 120°C, 135°C, 150°C, 160°C, 160°C, 160°C, 160°C, the die temperature is 160°C, extrude at an extrusion speed of 300 rpm, and draw a film at a speed of 2 rpm to obtain the tadalafil orosoluble film.

[0144] Example 9

[0145] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0146]

[0147]

[0148] The preparation method comprises the following steps:

[0149] Add tadalafil, copovidone VA64, hydroxypropyl cellulose, polyethylene glycol, maleic acid, Tween 20, sucrose and cherry flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 25 rpm, the barrel temperature is 110°C, 130°C, 145°C, 160°C, 160°C, 160°C, 160°C, 160°C, the die temperature is 160°C, extrude at an extrusion speed of 350 rpm, and draw a film at a speed of 2 rpm to obtain the tadalafil orosoluble film.

[0150] Example 10

[0151] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0152]

[0153] The preparation method comprises the following steps:

[0154] Add tadalafil, copovidone VA64, polyoxyethylene N80, polyethylene glycol, succinic acid, Tween 20, sucralose and sweet orange flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 40 rpm, the barrel temperature is 110°C, 130°C, 145°C, 160°C, 160°C, 160°C, 160°C, 160°C, the die temperature is 160°C, extrude at an extrusion speed of 350 rpm, and draw a film at a speed of 2 rpm to obtain the tadalafil orosoluble film.

[0155] Embodiment 11

[0156] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0157]

[0158] The preparation method comprises the following steps:

[0159] Add tadalafil, povidone K30, polyoxyethylene N80, polyethylene glycol, succinic acid, sodium lauryl sulfate, sucralose and sweet orange flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 10 rpm, the barrel temperature is 90°C, 110°C, 125°C, 140°C, 140°C, 140°C, 140°C, 140°C, the die temperature is 140°C, extrude at an extrusion speed of 300 rpm, and draw a film at a film drawing speed of 3 rpm to obtain the tadalafil orosoluble film.

[0160] Example 12

[0161] In this embodiment, a tadalafil orodispersible film and a preparation method thereof are provided, wherein the tadalafil orodispersible film comprises the following components in percentage by weight:

[0162]

[0163] The preparation method comprises the following steps:

[0164] Add tadalafil, povidone K30, polyoxyethylene N80, polyethylene glycol, citric acid, Tween 20, fructose and sweet orange flavor to a mixer, mix at 15 rpm for 20 min, add the mixture to the feeder of a hot melt extruder, the feeding speed is 25 rpm, the barrel temperature is 110°C, 130°C, 145°C, 160°C, 160°C, 160°C, 160°C, 160°C, the die temperature is 160°C, extrude at an extrusion speed of 350 rpm, and draw a film at a speed of 2 rpm to obtain the tadalafil orosoluble film.

[0165] Comparative Example 2

[0166] The only difference between this comparative example and Example 1 is that in the preparation method, the barrel temperatures are 100°C, 130°C, 160°C, 180°C, 180°C, 180°C, 180°C, and the die temperature is 180°C.

[0167] The content of related substances in Examples 1-6 and Comparative Example 2 was determined in the same manner as in Comparative Example 1 during the preparation process. The sampling time was after the preparation was completed to perform the related substance test. The HPLC chromatograms of the related substances in Examples 1-6 and Comparative Example 2 were as shown in FIG. Figure 9-Figure 15 The measurement results are shown in the following Table 3.

[0168] Table 3

[0169]

[0170] Depend on Figure 9-Figure 15 As can be seen from the data in Table 3, the tadalafil orodispersible film of the present invention can be prepared by hot melt extrusion film drawing process, and the impurity content in the preparation process can be effectively controlled to a level lower than 0.05%, thereby achieving undetectable impurities.

[0171] In addition, an accelerated stability test was conducted on the tadalafil orodispersible film prepared in Example 1. The test process was to place the tadalafil orodispersible film in a stability test chamber at a temperature of 40°C ± 2°C and a humidity of 75% ± 5% RH after packaging, and take out appropriate amounts of the film at day 0, 1 month, 3 months, and 6 months for high performance liquid chromatography detection of related substances, water content, and isomers. Figure 16-Figure 19 The HPLC chromatograms of the related substances at day 0, 1 month, 3 months and 6 months are shown in Table 4. The results of the accelerated stability test are shown in Table 4.

[0172] Table 4

[0173]

[0174] The tadalafil orodispersible films in Examples 2-12 were subjected to the same accelerated stability test as above, wherein the total impurities of the tadalafil orodispersible films of Examples 2-6 after accelerated 6 months were <0.1% (calculated as <0.05% excluding total impurities), and the total impurities of the tadalafil orodispersible films of Examples 7-12 after accelerated 6 months were <0.24% (calculated as <0.05% excluding total impurities), which met the limit requirements.

[0175] The results show that the tadalafil orodispersible film of the present invention can not only reduce product-related substances during preparation, but also does not produce excessive impurities during storage.

[0176] The applicant declares that the present invention illustrates the tadalafil orodispersible film and the preparation method thereof through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials selected by the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A tadalafil orodispersible film, characterized in that: The tadalafil orosoluble film comprises the following components in percentage by weight: Tadalafil 5-20% Film-forming material 60-80% Plasticizer 0.1-20% Acid stabilizer 0.5-10% Surfactant 0.1-10% Sweetener 0.1-10% Flavoring agent 0.1-5%, Wherein, the film-forming material is copolyvidone and polyoxyethylene; The plasticizer is polyethylene glycol; The acid stabilizer is citric acid; The surfactant is sodium lauryl sulfate; The preparation method of the tadalafil orosoluble film comprises the following steps: Tadalafil, film-forming material, plasticizer, acid stabilizer, surfactant, sweetener and flavoring agent are mixed, and the mixture is added into a hot melt extruder feeder, wherein the barrel temperature is 90-110°C, 110-130°C, 125-145°C, 140-160°C, 140-160°C, 140-160°C, 140-160°C, 140-160°C, 140-160°C, and the die temperature is 140-160°C, extruded, and film-drawn to obtain the tadalafil orosoluble film.

2. The tadalafil orosoluble film according to claim 1, characterized in that: The sweetener is selected from any one of sucralose, sorbitol, sucrose, aspartame, saccharin, and fructose, or a combination of at least two thereof.

3. The tadalafil orosoluble film according to claim 2, characterized in that: The sweetener is any one of sucralose, aspartame or sorbitol, or a combination of at least two of them.

4. The tadalafil orosoluble film according to claim 3, characterized in that: The sweetener is sucralose.

5. The tadalafil orosoluble film according to claim 1, characterized in that: The flavoring agent is selected from any one of sweet orange flavor, strawberry flavor, vanilla flavor, banana flavor, peach flavor, milk flavor, cherry flavor, and mint flavor, or a combination of at least two of them.

6. The tadalafil orosoluble film according to claim 5, characterized in that: The flavoring agent is any one of sweet orange flavor, strawberry flavor, vanilla flavor, and milk flavor, or a combination of at least two of them.

7. The tadalafil orosoluble film according to claim 6, characterized in that: The flavoring agent is sweet orange flavor and / or strawberry flavor.

8. A method for preparing a tadalafil orosoluble film according to any one of claims 1 to 7, characterized in that: The rotation speed during mixing is 10-18 rpm, and the mixing time is 15-22 min.

9. The preparation method according to claim 8, characterized in that: The extrusion speed during the extrusion is 300-350 rpm.

10. The preparation method according to claim 8, characterized in that: Add the mixture to the hot melt extruder feeder and set the feeder speed to 10-40 rpm.

11. The preparation method according to claim 8, characterized in that: The film pulling speed is 1-3 rpm.

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