Sildenafil oral soluble film and preparation method thereof

Abstract

The invention discloses a sildenafil oral soluble film and a preparation method thereof.The sildenafil oral soluble film comprises a sildenafil active ingredient and a film forming material, the film forming material is a mixture of polyvinyl alcohol and a polyvinyl alcohol polyethylene glycol grafted copolymer, and the sildenafil active ingredient accounts for more than or equal to 50% by mass of the oral soluble film. And the mass percent of the film forming material in the oral soluble film is 20.2%-36.2%. The oral soluble film has good mechanical performance and low hygroscopicity under the conditions of high drug loading capacity and low moisture, and has the advantages of being small, light and convenient to carry.

Description

Technical Field

[0001] The invention relates to a sildenafil orodispersible film and a preparation method thereof. Background Art

[0002] Erectile dysfunction (ED) refers to the inability of the penis to achieve or maintain sufficient erection hardness to complete a satisfactory sexual life. It is one of the most common sexual dysfunction diseases in men. It not only seriously affects the patient's physical and mental health and quality of life, causes family disharmony, but may also be an early symptom and danger signal of cardiovascular disease. The results of the National Health Commission survey show that the prevalence of ED in adult men in China is as high as 40.5%. However, the rate of medical treatment is low and patients attach great importance to privacy. According to the survey results of the "Sexual Happiness in China Blue Book" released by the Chinese Society of Sexology in 2014, 40% of ED patients will choose to seek help from doctors, and 24% choose to seek help online or bear it alone.

[0003] At present, the treatment of ED mainly relies on drugs. The "Guidelines for Erectile Dysfunction" published by the American Urological Association (AUA) in 2018, the "Guidelines for Erectile Dysfunction, Premature Ejaculation, Penile Curvature and Abnormal Erectile Function" published by the European Association of Urology (EAU) in 2019, and the "Guidelines for the Diagnosis and Treatment of Erectile Dysfunction in China in 2016" and other domestic and foreign guidelines unanimously recommend selective phosphodiesterase type 5 inhibitors (PDE5i) as the first choice for the treatment of ED. At present, there are 4 PDE5i (sildenafil, vardenafil, tadalafil and avanafil) on the market in the mainstream countries of the world, and there is no difference in the recommended ranking of the guidelines. Evidence-based evidence shows that the overall efficacy and safety of each PDE5i are comparable, but real clinical practice believes that sildenafil maintains hardness best and can be used on demand. It is a product with high market recognition and distinct highlights.

[0004] As the world's first PDE5 inhibitor, sildenafil citrate has a wide range of clinical applications, good safety and tolerance, rapid onset, stable drug absorption and peak concentration, and can significantly improve endothelial cell function and significantly improve the sexual life satisfaction of both partners. In clinical practice, whether it is used on demand, long-term or regularly, its efficacy is very definite. Sildenafil citrate tablets were first developed by Pfizer Pharmaceuticals Co., Ltd. in the United States. They were launched in the United States and Europe in 1998 and in China in 2000. They have been on the market overseas for more than 20 years and have 20 years of clinical use experience in China. They have the characteristics of definite efficacy and good safety. Various ED guidelines use it as a first-line treatment for ED. A large amount of evidence-based medical data shows that sildenafil is safe and effective in treating ED with different co-morbidities.

[0005] Among the sildenafil citrate preparations currently on the market, ordinary tablets are the main ones. Considering that in many cases, sildenafil needs to be taken irregularly and in a hidden and waterless environment, and users mostly expect it to take effect quickly, orodispersible films are considered to be the most ideal preparation form to meet the above requirements. Orodispersible films are film-like preparations made by processing drugs and suitable film-forming materials. They are a new dosage form developed mainly to solve dysphagia, improve the convenience of taking medicine without water, and improve patient compliance. The US FDA evaluated this dosage form as "an irreplaceable new dosage form in traditional oral dosage forms." Compared with ordinary tablets, orodispersible films are small and light, not easy to break, and easy to transport during the production process. At the same time, the single-piece independent packaging and anti-folding properties make it easier for patients to carry with them, providing great convenience for patients in use. In clinical use, the orodispersible film does not need to be taken with water, and is convenient to use. It is especially suitable for patients with dysphagia, which improves the clinical compliance of patients. At the same time, the orodispersible film is concealed and easy to carry, which has an excellent protective effect on the privacy of patients in the special disease field of ED. In many cases, sildenafil needs to be used irregularly before sexual activity, and most people cannot use these drugs publicly due to "shame". At the same time, the part of the drug dissolved in the mouth can be absorbed through the oral mucosa and can quickly reach the effective concentration, which has the characteristics of fast onset time. At the same time, the drug absorption of the mucosa can avoid the first-pass effect of the liver. Therefore, the orodispersible film can also be applied to drugs absorbed from the digestive tract. It is a new and useful preparation for drugs that are highly sensitive to liver metabolism. Therefore, the preparation of an orodispersible film preparation containing sildenafil is of great significance in meeting clinical medication compliance and convenience.

[0006] Although the preparation of orodispersible films containing sildenafil is of great significance in meeting the requirements of clinical medication compliance and convenience, since sildenafil has specifications of 25mg, 50mg, 100mg, etc., which far exceed the specifications of general orodispersible film preparations, it is generally believed that specifications that are too large are not suitable for the preparation of orodispersible films. Therefore, this poses a great challenge to the drug prescription design.

[0007] The preparation process of orodispersible film has been reported in various forms, such as solvent coating, hot melt extrusion, and semi-solid casting. However, due to its simple operation and stable process, the solvent coating method is the most mature method currently used, and the orodispersible film products that have been marketed are basically prepared by this method. Orodispersible film is usually made into a stamp size with a thickness of 50 to 200 um, because a film that is too large or too thick does not meet the characteristics of the orodispersible film dosage form, which is small and light, quickly disintegrates, and is easy to carry. Due to the limitations of size and thickness, the weight of the orodispersible film that has been marketed is basically below 200 mg. As mentioned above, due to the limitations of orodispersible film preparations in terms of weight, size, thickness, etc., for larger drugs such as sildenafil, the amount of other materials used in the prescription has actually been limited to a very small range, that is, the film is required to have an extremely high drug loading. The higher the drug loading, the more difficult it is to prepare. How to ensure that the film can form a film with an extremely high drug loading and have good mechanical properties is a big challenge. Poor mechanical properties may cause the film to be damaged due to falling, impact, wrinkling, etc. during packaging, transportation, and carrying.

[0008] The film-forming material in orally dissolving film is a key excipient, which has a direct relationship with the mechanical properties of the film. Commonly used film-forming materials are basically hydrophilic polymers. They have a common feature that the film often has acceptable mechanical properties at higher moisture levels, but the mechanical properties drop rapidly with the decrease of moisture. It becomes brittle and easy to break at low moisture levels, which is not conducive to product packaging, transportation and carrying. However, too high moisture is usually not conducive to the storage of drugs, which will accelerate the production of degradation impurities and microorganisms in the drug and shorten the storage time of the drug. Another important issue is that most film-forming materials have strong hygroscopicity, which means that even if the film has low moisture during preparation, it will quickly absorb moisture during storage, resulting in high moisture.

[0009] For the large-scale drugs of sildenafil, it is required to have a high drug loading when prepared into an oral dissolving film, that is, a small amount of excipients are added to ensure that the weight, thickness and size of the film as a whole are within a suitable range of a dosage form, which is determined by the characteristics of the oral dissolving film dosage form. Secondly, under the premise of limited excipient addition, a sildenafil oral dissolving film with good mechanical properties under low moisture is prepared, and the film has low hygroscopicity, and can keep a slight increase or substantially no increase of moisture during continuous storage, which is not only conducive to the film in packaging, transportation and carrying to ensure the integrity of the film, but also prolong the drug storage time, so that the drug can maintain a good product quality in long-term storage, which is of great significance in the clinical use and quality control of the drug. In the existing disclosed technical solutions, pullulan, gelatin, hydroxypropyl cellulose, etc. are used as film-forming materials, which have strong hygroscopicity, fast moisture growth, poor mechanical properties under low moisture, etc., which are also problems to be solved in the existing technical solutions.

[0010] The present invention has been found in the research that during the coating and drying process of the sildenafil citrate orodispersible film, part of the raw materials dissolved in the solvent precipitate crystals during drying, resulting in deterioration of the appearance and physical properties of the film. No relevant reports have been found in the prior art solutions.

[0011] The present invention also found during the research that the sildenafil citrate orodispersible film is prone to mechanical property degradation during storage, and no related reports have been found in the prior art solutions.

[0012] In addition, the oral dissolving film of sildenafil citrate provided in the prior art scheme has undergone a substantial change in its in vivo pharmacokinetic parameters or this part of the data is not provided in the technical scheme. The maximum blood concentration (Cmax) and absorption extent (AUC) of the drug are two important evaluation indicators that affect the safety and effectiveness of the drug. The prior art scheme has made substantial changes in the pharmacokinetic parameters of the marketed sildenafil citrate preparations without sufficient clinical trials to confirm their safety and effectiveness, which brings safety and effectiveness risks to patients and has no practical value. The present invention attempts to provide an oral dissolving film of sildenafil citrate that fully reflects the advantages of the oral dissolving film dosage form and does not affect the safety and effectiveness of the drug. Summary of the invention

[0013] The first object of the present invention is to provide a sildenafil orodispersible film having high drug loading (active ingredient loading ≥ 50%), which is compact, light, easy to carry, and has good mechanical properties and low hygroscopicity.

[0014] The second object of the present invention is to provide a sildenafil orodispersible film which can improve the appearance and physical properties of the film.

[0015] The third object of the present invention is to provide a sildenafil orodispersible film having good demoulding performance.

[0016] The fourth object of the present invention is to provide a sildenafil orodispersible film having a good mouthfeel.

[0017] The first aspect of the present invention provides a sildenafil orodispersible film, comprising a sildenafil active ingredient and a film-forming material, wherein the film-forming material is a mixture of polyvinyl alcohol and a polyvinyl alcohol-polyethylene glycol graft copolymer, the mass percentage of the sildenafil active ingredient in the orodispersible film is ≥50%, and the mass percentage of the film-forming material in the orodispersible film is 20.2% to 36.2%.

[0018] In some embodiments of the present invention, the mass percentage of the sildenafil active ingredient in the orodispersible film is 50-75%.

[0019] In some embodiments of the present invention, the mass ratio of polyvinyl alcohol to polyvinyl alcohol-polyethylene glycol graft copolymer in the film-forming material is 2.5:1 to 1:1.5, preferably 2:1 to 1:1.

[0020] In some embodiments of the present invention, the polyvinyl alcohol-polyethylene glycol graft copolymer is a graft copolymer of polyvinyl alcohol and polyethylene glycol in a mass ratio of 75:25.

[0021] During the research process, the applicant found that the active ingredient of sildenafil (such as sildenafil citrate) is dissolved in the solvent during the slurry preparation. The active ingredient of sildenafil dissolved in the solvent is prone to crystallization during the coating and drying process. The precipitated crystals are in the shape of snowflakes or needles, resulting in a deterioration in the appearance of the drug. The applicant found that adding a certain amount of stabilizer can inhibit the occurrence of crystallization and improve the appearance of the product.

[0022] In some embodiments of the present invention, the sildenafil orodispersible film further comprises a stabilizer, and the stabilizer is selected from one or more of povidone, copovidone, and hydroxypropyl cellulose.

[0023] In some embodiments of the present invention, the weight percentage of the stabilizer in the orodispersible film is 2-10%, preferably 3-6%.

[0024] In some embodiments of the present invention, the sildenafil orodispersible film further comprises a plasticizer, and the plasticizer is selected from polyethylene glycol 400, glycerol or a mixture thereof.

[0025] In some embodiments of the present invention, the mass percentage of the plasticizer in the orally dissolving film is 2-10%, preferably 4-7%.

[0026] In some embodiments of the present invention, the sildenafil orodispersible film further includes a flavoring agent, wherein the flavoring agent is selected from a sweetener or a flavoring agent, wherein the sweetener is selected from one or more of aspartame, sucralose, acesulfame potassium, and stevioside, and the flavoring agent is selected from one or more of menthol, mint flavor, strawberry flavor, orange flavor, and vanilla flavor.

[0027] In some embodiments of the present invention, the mass percentage of the sweetener in the orodispersible film is 0.1% to 5%, preferably 0.5% to 2%.

[0028] In some embodiments of the present invention, the mass percentage of the flavoring agent in the orodispersible film is 0.1% to 2%, preferably 0.5% to 1%.

[0029] In some embodiments of the present invention, the sildenafil orodispersible film further comprises a colorant, and the colorant is selected from one or more of titanium dioxide, red iron oxide, yellow iron oxide, and pharmaceutical lakes.

[0030] In some embodiments of the present invention, the particle size D90 of the sildenafil active ingredient is ≤60 μm, preferably, the particle size D90 of the sildenafil active ingredient is ≤20 μm.

[0031] In some embodiments of the present invention, the sildenafil active ingredient is selected from sildenafil citrate, sildenafil hydrochloride, sildenafil phosphate, sildenafil hydrobromide, sildenafil mesylate or sildenafil free base.

[0032] In some embodiments of the present invention, the sildenafil orodispersible film comprises the following components by mass percentage: 50-75% of sildenafil active ingredient, 20.2% to 36.2% of film-forming material, 2-10% of stabilizer and 2-10% of plasticizer.

[0033] In some embodiments of the present invention, the sildenafil orodispersible film comprises the following components in mass percentage: 50-75% of sildenafil active ingredient, 20.2% to 36.2% of film-forming material, 2-10% of stabilizer, 2-10% of plasticizer, 0.1% to 5% of sweetener and 0.1% to 2% of flavoring agent.

[0034] In some embodiments of the present invention, the moisture content of the sildenafil orodispersible film is less than 5%.

[0035] In some embodiments of the present invention, after the sildenafil orodispersible film contacts the oral cavity, the disintegration time of the orodispersible film is less than 60 seconds.

[0036] In some embodiments of the present invention, the tensile strength of the sildenafil orodispersible film is ≥20 N / mm 2 .

[0037] The second aspect of the present invention provides a method for preparing an orodispersible sildenafil film, which comprises the following steps: adding a prescribed amount of raw materials and a solvent into a homogenizer, and homogenizing and stirring at a high speed to obtain a uniform drug-containing slurry; uniformly coating the drug-containing slurry on a flat backing material to prepare a drug film with a specified unit area weight and moisture content; and cutting the dried drug film into a suitable size and demolding.

[0038] In some embodiments of the present invention, a method for preparing an orodispersible sildenafil film comprises the following steps: adding a prescribed amount of excipients and a solvent into a homogenizer, and homogenizing and stirring at high speed to obtain a uniform slurry; adding a sildenafil active ingredient with a particle size of D90≤60 μm into the slurry, and homogenizing and stirring at high speed to obtain a uniform drug-containing slurry; uniformly coating the drug-containing slurry on a flat backing material to prepare a drug film with a specified unit area weight and moisture content; and cutting the dried drug film into a suitable size and demolding.

[0039] In some embodiments of the present invention, the solvent is selected from water, ethanol or a mixture thereof, such as water, ethanol aqueous solution, wherein the volume percentage of ethanol in the ethanol aqueous solution is ≤50% (such as ethanol aqueous solution with a volume percentage of 25% or 50%).

[0040] In some embodiments of the present invention, the mass of the solvent is 1-2.5 times the mass of the raw materials, preferably 1.2-1.8 times, for example 1.2 times, 1.3 times, 1.4 times, 1.5 times.

[0041] The present invention has the following beneficial effects:

[0042] 1) By using the film-forming material of the present invention, the prepared orally dissolving film can have good mechanical properties and low hygroscopicity at high drug loading and low moisture content, and at the same time has the advantages of being small, light and easy to carry.

[0043] 2) The orally dissolving film of the present invention contains a certain amount of stabilizer, so that crystals do not precipitate when the film is dried, thereby further improving the appearance and physical properties of the product.

[0044] 3) The orally dissolving film of the present invention contains a certain amount of plasticizer and has suitable demoulding properties, which greatly facilitates the industrial production of drugs.

[0045] 4) The orodispersible film of the present invention can be taken with or without water, is convenient to use, and takes effect quickly, and is particularly suitable for patients with dysphagia, thereby improving the clinical compliance of patients; at the same time, the medication is concealed and easy to carry, and has an excellent protection effect on the privacy of patients in the special disease field of ED. While fully reflecting the advantages of the orodispersible film dosage form, it is particularly important that it does not change the key pharmacokinetic parameters of the sildenafil citrate preparation that has been marketed, and does not affect the safety and effectiveness of the drug. DETAILED DESCRIPTION

[0046] The present invention is further described below through examples. The examples of the present invention are only used to illustrate the technical solution of the present invention and are not used to limit the scope of the present invention. Those skilled in the art may make some non-essential improvements and adjustments, which still fall within the protection scope of the present invention.

[0047] The terms in this invention are explained as follows:

[0048] The "high drug loading" sildenafil orodispersible film described herein means that the mass percentage of the sildenafil active ingredient in the orodispersible film is ≥50%.

[0049] The "low moisture" sildenafil orodispersible film described herein refers to the sildenafil orodispersible film having a moisture content of less than 5% after drying.

[0050] The "good mechanical properties" of the sildenafil orodispersible film mentioned in this article refers to the sildenafil orodispersible film measured by a universal material testing machine with a tensile strength of ≥20N / mm 2 .

[0051] The "low hygroscopic" sildenafil orodissolving film described herein refers to a sildenafil orodissolving film having an equilibrium moisture absorption weight gain of ≤5% at 50% relative humidity as measured by dynamic vapor sorption (DVS) as disclosed in Bergren, MS Int. J. Pharm 103: 103-114 (1994).

[0052] The "no change in the key pharmacokinetic parameters of the marketed sildenafil citrate preparations" mentioned in this article means that through the bioequivalence test, the 90% confidence interval (CI) value of the ratio of the Cmax and AUC geometric means of the sildenafil citrate orodispersible film and the marketed sildenafil citrate preparations is not less than 80.00% and not more than 125.00%.

[0053] The performance testing method of the sildenafil orodispersible film of the present invention is as follows:

[0054] Moisture content determination method: Determine according to the moisture content determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0832, Method 1).

[0055] Disintegration time determination method: Take 6 tablets of this product, fix them with paper clips respectively, use water as the medium, temperature is 37℃, take 10mL of purified water in a 10mL beaker, put this product into the medium, start timing when it touches the liquid surface, and record the time when the drug film is completely disintegrated.

[0056] Mechanical strength measurement method: Use a universal material testing machine to measure. Hold the film with two clamps and keep it in a vertical state. Stretch it at a speed of 300 mm / min and record the external stress (load) that the film bears when it breaks. Mechanical strength = external stress (load) / cross-sectional area of ​​the film.

[0057] Hygroscopicity determination method: The hygroscopicity is tested according to the dynamic vapor absorption (DVS) method disclosed in Bergren, MS Int. J. Pharm 103: 103-114 (1994). Specifically, the film is accurately weighed and placed under a dynamic humidity of 50%. The film is accurately weighed every 2 hours until equilibrium is reached, and the weight gain after moisture absorption is calculated.

[0058] The related substances were detected by HPLC method established and systematically verified with reference to the detection methods for related substances of sildenafil citrate in domestic and foreign pharmacopoeias.

[0059] Microbiological determination was carried out in accordance with General Rules 1105 (Microbiological Limit Test for Non-sterile Products: Microbial Count Method) and 1106 (Microbiological Limit Test for Non-sterile Products: Control Bacteria Test Method) in the 2020 edition of the Chinese Pharmacopoeia.

[0060] The peeling performance evaluation method uses the ease of peeling the drug film from the carrier film as the peeling performance evaluation standard, which is divided into peeling (*): the drug film automatically falls off the backing film;

[0061] Easy to peel (+): The drug film is easy to peel off from the carrier film;

[0062] Moderate peelability (++): It can be peeled off by applying a certain external force, and the drug film is intact without residue;

[0063] Difficult to peel off (-): The film can be peeled off by applying external force, the film is intact, but there is residue;

[0064] Difficult to peel off (--): The film cannot be completely peeled off by applying external force.

[0065] Demolding property refers to the ease with which the drug film can be peeled off from the carrier film. Appropriate demolding property can ensure that the drug film can be peeled off from the carrier film smoothly. The easier the drug film is to peel off, the better it is. Too good demolding property will cause the drug film to fall off the backing film before it is packaged into the inner packaging bag, making it impossible to carry out industrial packaging. Too poor demolding property will make it impossible to completely peel the drug film from the backing film, resulting in a rough, damaged or wrinkled appearance of the drug film. The easy peeling (+) and moderate demolding property (++) in the above evaluation criteria can both meet the demolding performance required by the process, and moderate demolding property (++) is a demolding performance that can well meet the process requirements.

[0066] Embodiment 1:

[0067] The sildenafil citrate orodispersible film comprises the following components in percentage by weight:

[0068]

[0069] The sildenafil citrate orodispersible film was prepared according to the following preparation method:

[0070] Step 1: Grind the sildenafil citrate by air flow grinding to obtain the ground sildenafil citrate with D90≤60μm.

[0071] Step 2: Take 1.2-1.4 times the amount of the prescription ethanol-water solution and add it into a homogenizer, and add plasticizer (if any), flavoring agent (if any), colorant (if any), stabilizer (if any) and film-forming material (if any) in sequence, and add the crushed sildenafil citrate after homogenizing and stirring, and homogenize and stir under vacuum to obtain a uniform drug-containing slurry.

[0072] Step 3: Evenly spread the drug-containing slurry on a flat polyester film and dry it to prepare a drug film with a specified unit area weight and moisture content, cut it to a suitable size, and demold it.

[0073] Embodiment 2:

[0074] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0075]

[0076] Embodiment 3:

[0077] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0078]

[0079] Embodiment 4:

[0080] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0081]

[0082]

[0083] Embodiment 5:

[0084] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0085]

[0086] Embodiment 6:

[0087] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0088]

[0089] Embodiment 7:

[0090] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0091]

[0092] Embodiment 8:

[0093] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0094]

[0095] Embodiment 9:

[0096] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0097]

[0098]

[0099] Embodiment 10:

[0100] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0101]

[0102] Embodiment 11:

[0103] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0104]

[0105] Embodiment 12:

[0106] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0107]

[0108]

[0109] Embodiment 13:

[0110] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0111]

[0112] Embodiment 14:

[0113] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0114]

[0115] Embodiment 15:

[0116] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0117]

[0118] Embodiment 16:

[0119] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0120]

[0121] Embodiment 17:

[0122] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0123]

[0124]

[0125] Embodiment 18:

[0126] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0127]

[0128] Comparative Example 1:

[0129] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0130]

[0131] Comparative Example 2:

[0132] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0133]

[0134]

[0135] Comparative Example 3:

[0136] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0137]

[0138] Comparative Example 4:

[0139] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0140]

[0141] Comparative Example 5:

[0142] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0143]

[0144]

[0145] Comparative Example 6:

[0146] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0147]

[0148] In Comparative Example 6, no stabilizer was added. During the coating and drying process, the raw materials dissolved in the solvent precipitated crystals during drying, affecting the appearance of the film.

[0149] Comparative Example 7:

[0150] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0151]

[0152] Comparative Example 8:

[0153] The sildenafil citrate orodispersible film comprises the following components in percentage by weight, and the orodispersible film is prepared according to the preparation method of Example 1.

[0154]

[0155] Performance of sildenafil citrate orodispersible film:

[0156] The properties of the sildenafil citrate orodispersible films prepared in the examples and comparative examples, such as moisture, hygroscopicity, mechanical strength, disintegration time, and peelability, are shown in the following table.

[0157] Evaluating performance Moisture Machine strength Moisture absorption and weight gain Disintegration time Peelability Example 1 3.2％ 29.5 2.1％ 33 seconds ++ Example 2 2.7％ 25.4 1.7％ 28 seconds ++ Example 3 3.3％ 34.7 2.5％ 38 seconds ++ Example 4 3.8％ 32.0 1.8％ 37 seconds ++ Example 5 3.6％ 26.6 2.0％ 29 seconds ++ Example 6 3.6％ 30.8 1.8％ 30 seconds ++ Embodiment 13 3.4％ 30.0 2.3％ 37 seconds ++ Embodiment 14 3.1％ 27.6 2.4％ 42 seconds ++ Embodiment 15 3.8％ 29.1 2.7％ 41 seconds ++ Example 16 4.2％ 26.1 2.8％ 44 seconds + Embodiment 17 4.1％ 33.2 2.0％ 31 seconds + Embodiment 18 3.9％ 31.6 1.9％ 30 seconds ++ Comparative Example 1 2.8％ 12.3 16.2％ 37 seconds ++ Comparative Example 2 3.5％ 7.5 9.9％ 58 seconds + Comparative Example 3 3.6％ 25.2 6.3％ 104 seconds - Comparative Example 4 3.7％ 14.2 11.9％ 77 seconds ++ Comparative Example 5 2.9％ 21.0 8.8％ 92 seconds ++ Comparative Example 7 3.5％ 28.3 1.2％ 42 seconds - Comparative Example 8 3.7％ 16.2 6.7％ 29 seconds ++

[0158] From the table above we can see that:

[0159] 1) When pullulan, hydroxypropyl cellulose, gelatin or any combination thereof is used as a film-forming material to prepare the sildenafil citrate orodispersible film, the film cannot have the characteristics of high mechanical strength under low moisture conditions, low hygroscopicity and good demolding performance, and some orodispersible films have a phenomenon of excessively long disintegration time.

[0160] 2) Using polyvinyl alcohol or polyvinyl alcohol-polyethylene glycol copolymer alone as the film-forming material cannot make the film have the characteristics of high mechanical strength under low moisture content, low hygroscopicity and good demolding performance.

[0161] 3) When one or both of glycerol or polyethylene glycol 400 are used as plasticizers, it can be ensured that the film has excellent mechanical properties. As the proportion of plasticizer added increases, the mechanical strength increases, but too much or too little plasticizer will show weakened peeling properties. When the plasticizer dosage is between 2% and 10%, it shows peeling properties that can meet the process requirements (easy peeling and moderate peeling properties). When the plasticizer dosage ranges from 4 to 7%, it shows excellent peeling properties (moderate peeling properties).

[0162] Stability of sildenafil citrate orodispersible film:

[0163] The stability data of the sildenafil citrate orodispersible films prepared in Examples 1, 5, 6, 12 and 18 placed under accelerated conditions (temperature 40°C / 75%RH) for 6 months are shown in the following table:

[0164]

[0165] As can be seen from the above table, the sildenafil orodispersible film provided in the present invention not only has good product quality indicators on day 0, but also still has good mechanical strength and good chemical stability after being placed under accelerated conditions for 6 months, and the moisture content and disintegration time have not changed significantly.

[0166] Pharmacokinetic study of sildenafil citrate orodispersible film:

[0167] 44 healthy male subjects were used to conduct a comparative study on the in vivo pharmacokinetic of the 50 mg sildenafil citrate orodispersible film in Example 13 and the 50 mg sildenafil citrate tablets produced by Pfizer Pharmaceuticals Co., Ltd.

[0168] Test preparations <![CDATA[C max (ng / mL)]]> <![CDATA[AUC 0-t (mg / mL)]]> <![CDATA[T max (h)]]> <![CDATA[T 1 / 2 (h)]]> Sildenafil citrate orodispersible film 131±59 449±202 0.651 3.80±1.50 Sildenafil Citrate Tablets 137±54 448±189 0.996 3.76±1.58

[0169] The sildenafil citrate orodispersible film provided by the present invention can be taken with or without water, is convenient to use, and takes effect quickly. It is particularly suitable for patients with dysphagia, and improves the clinical compliance of patients; at the same time, the medication is concealed and easy to carry, and has an excellent protective effect on the privacy of patients in the special disease field of ED. While fully reflecting the advantages of the orodispersible film dosage form, it is particularly important that the applicant found that the sildenafil citrate orodispersible film of the present invention has a significantly shortened peak time of the drug in the blood compared to the sildenafil citrate preparation that has been marketed, which means that the drug can take effect more quickly for ED patients. At the same time, the maximum blood drug concentration (Cmax) and absorption degree (AUC) of the sildenafil citrate preparation that has been marketed have not changed significantly, that is, it does not change the key pharmacokinetic parameters of the sildenafil citrate preparation that has been marketed, and does not affect the safety and effectiveness of the drug.

[0170] The methods and products of the present application have been described through preferred embodiments, and relevant technical personnel can obviously modify or appropriately change and combine the methods and products described herein without departing from the content, spirit and scope of the present application to implement the technology of the present application. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the spirit, scope and content of the present application.

Claims

1. A sildenafil orodispersible film, characterized in that: The invention comprises a sildenafil active ingredient and a film-forming material, wherein the film-forming material is a mixture of polyvinyl alcohol and a polyvinyl alcohol-polyethylene glycol graft copolymer, the mass percentage of the sildenafil active ingredient in the orodispersible film is ≥50%, and the mass percentage of the film-forming material in the orodispersible film is 20.2% to 36.2%; Preferably, the mass percentage of the sildenafil active ingredient in the orodispersible film is 50-75%.

2. The sildenafil orally dissolving film according to claim 1, characterized in that: The mass ratio of polyvinyl alcohol to polyvinyl alcohol-polyethylene glycol graft copolymer in the film-forming material is 2.5:1 to 1:1.5, preferably 2:1 to 1:

1.

3. The sildenafil orodispersible film according to any one of claims 1 to 2, characterized in that: The sildenafil orodispersible film further comprises a stabilizer, wherein the stabilizer is selected from one or more of povidone, copovidone, and hydroxypropylcellulose; Preferably, the mass percentage of the stabilizer in the orally dissolving film is 2-10%, preferably 3-6%.

4. The sildenafil orodispersible film according to any one of claims 1 to 3, characterized in that: The sildenafil orodispersible film also includes a plasticizer, and the plasticizer is selected from polyethylene glycol 400, glycerol or a mixture thereof; Preferably, the mass percentage of the plasticizer in the orally dissolving film is 2-10%, preferably 4-7%.

5. The sildenafil orodispersible film according to any one of claims 1 to 4, characterized in that: The sildenafil orodispersible film also includes a flavoring agent, wherein the flavoring agent is selected from a sweetener or a flavoring agent, wherein the sweetener is selected from one or more of aspartame, sucralose, acesulfame potassium, and stevioside, and the flavoring agent is selected from one or more of menthol, mint flavor, strawberry flavor, orange flavor, and vanilla flavor; Preferably, the mass percentage of the sweetener in the orodispersible film is 0.1% to 5%, preferably 0.5% to 2%; Preferably, the mass percentage of the flavoring agent in the orally dissolving film is 0.1% to 2%, preferably 0.5% to 1%.

6. The sildenafil orodispersible film according to any one of claims 1 to 5, characterized in that: The sildenafil orodispersible film also includes a colorant, which is selected from one or more of titanium dioxide, red iron oxide, yellow iron oxide, and medicinal lakes.

7. The sildenafil orodispersible film according to any one of claims 1 to 6, characterized in that: The particle size D90 of the sildenafil active ingredient is ≤60 μm, preferably, the particle size D90 of the sildenafil active ingredient is ≤20 μm; Preferably, the sildenafil active ingredient is selected from sildenafil citrate, sildenafil hydrochloride, sildenafil phosphate, sildenafil hydrobromide, sildenafil mesylate or sildenafil free base.

8. The sildenafil orodispersible film according to any one of claims 1 to 7, characterized in that: The sildenafil orodispersible film comprises the following components in percentage by mass: 50-75% of sildenafil active ingredient, 20.2% to 36.2% of film-forming material, 2-10% of stabilizer and 2-10% of plasticizer; Preferably, the sildenafil orodispersible film comprises the following components by mass percentage: 50-75% of sildenafil active ingredient, 20.2% to 36.2% of film-forming material, 2-10% of stabilizer, 2-10% of plasticizer, 0.1% to 5% of sweetener and 0.1% to 2% of flavoring agent.

9. The sildenafil orodispersible film according to any one of claims 1 to 8, characterized in that: The moisture content of the sildenafil orodispersible film is less than 5%; Preferably, after the sildenafil orodispersible film contacts the oral cavity, the disintegration time of the orodispersible film is less than 60 seconds; Preferably, the tensile strength of the sildenafil orosoluble film is ≥20N / mm 2 .

10. The method for preparing the sildenafil orodispersible film according to any one of claims 1 to 9, comprising the following steps: The raw materials and solvents in the prescribed amount are added to a homogenizer, and the mixture is homogenized and stirred at high speed to obtain a uniform drug-containing slurry; the drug-containing slurry is evenly coated on a flat backing material to prepare a drug film with a specified unit area weight and water content; the dried drug film is cut into a suitable size and demolded; Preferably, the preparation method of sildenafil orodispersible film comprises the following steps: adding the prescribed amount of excipients and solvent into a homogenizer, and homogenizing and stirring at high speed to obtain a uniform slurry; adding the sildenafil active ingredient with a particle size of D90≤60 μm into the slurry, and homogenizing and stirring at high speed to obtain a uniform drug-containing slurry; uniformly coating the drug-containing slurry on a flat backing material to prepare a drug film with a specified unit area weight and moisture content; cutting the dried drug film into a suitable size and demolding; Preferably, the solvent is selected from water, ethanol or a mixture thereof, such as water, ethanol aqueous solution, wherein the volume percentage of ethanol in the ethanol aqueous solution is ≤50% (such as ethanol aqueous solution with a volume percentage of 25% or 50%); Preferably, the mass of the solvent is 1-2.5 times the mass of the raw materials, preferably 1.2-1.8 times, for example 1.2 times, 1.3 times, 1.4 times, 1.5 times.

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