KR101440808B1 - Fast dissolving film comprising high dose of sildenafil or pharmaceutically acceptable salts thereof - Google Patents

Abstract

A fast film composition containing a medically active ingredient as an active ingredient, wherein a sweetness of the active ingredient is concealed and a fast film composition having a high content of 50% or more is provided. More specifically, the present invention provides a pharmaceutical composition containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient and containing a specific antiseptic in combination with the antiseptic, further comprising a combination of a specific plasticizer Thereby providing a fast film composition in which the abrasion is concealed and a high content of film properties is good.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a film containing sildenafil or a pharmaceutically acceptable salt thereof in a high content. BACKGROUND OF THE INVENTION < RTI ID = 0.0 >

The present invention relates to a fast film comprising a high content of sildenafil or a pharmaceutically acceptable salt thereof. More specifically, it is characterized in that it contains at least 100 mg of sildenafil or a pharmaceutically acceptable salt thereof, which has not been considered to be heretofore possible by using a specific plasticizer in a certain amount, or at least 50% of the total film weight Speed film. In addition, the present invention further relates to a film containing a sildenafil or a pharmaceutically acceptable salt thereof in an amount of 100 mg or more per film or 50% or more of the total weight of the film, Wherein the film is a high-content concealed film. More specifically, the present invention relates to a sildenafil or a pharmaceutically acceptable salt thereof, which is contained in at least 100 mg of the film or at least 50% of the total weight of the film, And a rapid film having a significantly improved brilliance even though the content is high.

Rapidly disintegrating or dissolving fast-dissolving films in the mouth can be taken without water, making it very useful for elderly people who have difficulty taking tablets or capsules, as well as for children with disabilities, patients lying in bed, to be. It is possible to prescribe liquid preparations in place of tablets or capsules for the elderly and children, but the liquid formulation has a disadvantage in that the stability is poor and the dosage is not accurate.

 Particularly, when the drug is absorbed into the buccal mucosa, liver transfusion can be avoided, so that the fast-acting film is a useful new formulation that can be applied to drugs that are highly metabolized among the drugs absorbed from the digestive tract

Since the application of loratadine in 1996 and the commercialization of fast-breaking liquor, it has become convenient to drink water, and dozens of products are continuously being commercialized. Despite the high production cost, the film formulation seems to be preferred due to convenience and covertness of the film. Since the film was applied to Novartis's triaminic thin strip® and commercialized, various applications have been attempted.

However, since the film preparation is a film-forming agent having a property of being disintegrated within one minute, it is generally 50-150 mu m in thickness and 22 mm in length and 32 mm in length and 7 cm in width. There are some formulations with a slightly larger size, but no cases of more than 10 cm2 have been reported, taking into account consumer convenience. Limitations on thickness and size? Weighing from 50mg to 150mg per film is commercialized on the door.

Despite the convenience of such a film preparation, it can not be applied to a high-dose preparation due to the limitation of the weight per film. So far, Novartis's Gas-X Thin Strips® has a weight of 110mg per film and 62.5mg of active ingredient (Simethicone), which contains 57% of the active ingredient per film and more than 50% of the active ingredient Is known to be the only fast-acting film formulation commercialized. In general, the content of the active ingredient per 1 film is known to be about 30% or less. When the active ingredient is contained in an amount of 30% or more, the physical properties of the film are weakened to increase the degree of brilliance and breakage during the manufacturing process and circulation. it's difficult. The Gas-X thin strip is the fastest film formulation that has a relatively good Brittleness ratio of more than 50% of the active ingredient in the commercialized film.

Sildenafil citrate-containing preparations are currently marketed under the Viagra® brand by Pfizer, and three doses of 25 mg, 50 mg and 100 mg are on the market. 100 mg of sildenafil is 100 mg, so it is 140.45 mg in terms of sildenafil citrate, which is larger than the weight of the high-content preparation Gas-X currently on the market. Therefore, to make 100 mg of sildenafil as a film preparation, a formulation containing more than 50% active ingredient should be designed. When the active ingredient sildenafil citrate is contained in an amount of 50%, the weight of the film is about 281 mg, the thickness of the film is too thick to 280 탆, and the physical properties and the breadthiness of the film are remarkably weakened.

In addition, sildenafil citrate has a bitter taste and should be supplemented with additional coding, ion exchange resin adsorption or masking adjuvants, which in turn will make the thickness thicker and the film properties and brilliance become worse.

In an attempt to overcome these disadvantages, US Patent Publication No. US2008 / 0220029 discloses a fast film containing more than 40% of the active ingredient by weight of the film. This patent discloses, as an embodiment, a fast film such as ibuprofen masked through a precoating process.

US 2008/0233174 discloses a fast film containing at least 30% of the active ingredient by weight of the film. An embodiment of this patent discloses the use of encapsulated acetaminophen. A patent to manufacture high-content fast film after pre-masking through coating or encapsulation describes high-throughput films through the use of two polymers with different glass transition temperatures. United States patent US652024 describes a fast film containing sildenafil citrate. However, there is no description about masking even though sildenafil citrate is used as an active ingredient. Because of the nature of the formulation, immediate-release film formulations must be masked for the bitter or unpleasant taste of the active ingredient when the active ingredient disintegrates or dissolves in the mouth and is of industrial applicability. US Patent Publication No. 2009/0047330, which describes the masking of sildenafil preparations, discloses a film composition for oral use of PDE-5 inhibitors containing PDEv inhibitors such as sildenafil as an active ingredient, wherein sildenafil is masked with cyclodextrin And discloses an embodiment.

In addition, as a document disclosing a means for concealing the bitterness of a drug having a bitter taste, WO 2001/70194 discloses a method for adsorbing an active ingredient to an ion exchange resin as a taste-masking agent, Film. However, in this case, since 1-3 times the amount of the resin is used for the masking, it is difficult to produce a film having a high content of 50% or more. Also, WO 2003/070227 discloses that a carbon dioxide-forming substance such as sodium bicarbonate is contained to mask the taste. In the case of sodium bicarbonate, however, there is a disadvantage that there is a limit to concealing a drug having a bitter taste.

In Korean Patent No. 1074271, a stevioside-based sweetener and a high-sweetening sweetener were used for improving the taste, but this is an attempt to suppress the bitter taste of an active ingredient by using a combination of conventional sweeteners. As a result, (W / w) based on the total weight of the formulation, with the content of active ingredient being 0.1 to 30% by weight (w / w) relative to the weight of the film, I can not see. US Patent Application Publication No. 2007/0292515 discloses a method of loading keto-propene, which has been increased in pH by using an alkalizing agent such as sodium hydroxide, as a means of concealing the bittern of ketoprofen, into a film formulation. Korean Patent No. 354310 Discloses a technique to include a basic buffer or a pH adjuster in order to minimize the bitter taste of azithromycin. Korean Patent No. 10-1188594 discloses bittering masking with sodium hydroxide, sodium bicarbonate or a mixture thereof. Korean Patent Laid-Open No. 10-2012-0101301 discloses a technique using sildenafil free base. This also describes an embodiment wherein the content of the active ingredient is 50% or less.

As can be seen from the above, up to now, there has been proposed an oral disintegrating film formulation containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the active ingredient is contained in an amount of not less than 50% Is not considered to be present. In case of concealing the gummy hair, the film properties and the brilliness are remarkably lowered. If the film has good physical properties, it is difficult to prepare a rapid film formulation containing Viagra 100 mg which contains a low amount of active ingredient and is distributed in the market.

US Published Patent Application No. US2008 / 0220029 US Published Patent US 2008/0233174 US registered patent US652024 US Published Patent 2009/0047330 WO2001 / 70194 WO2003 / 070227 Korea Patent No. 1074271 US Published Patent Application No. US2007 / 0292515 Korea Patent No. 354310 Korean Patent No. 1188594 Korean Patent Laid-Open No. 10-2012-0101301

Accordingly, it is an object of the present invention to provide a quick release film containing sildenafil or a pharmaceutically acceptable salt thereof in a high content.

Particularly, in the prior art, it is noted that when the active ingredient is contained in an amount of 50% or more of the total weight of the film, the problem of bleaching of the film is seriously raised, In the present invention, it is an object of the present invention to provide a fast film that does not cause a problem of brilliance even when the active ingredient is loaded with a high content. Further, the present invention is based on the finding that, even if the problem of brilliance is solved, the adherence of the patient to the medication is significantly lowered when the effective ingredient of sildenafil citrate is not concealed effectively It is a further object to provide an artificial concealing means specialized for the present formulation.

In order to solve the above problems, the present invention provides a fast film comprising sildenafil or a pharmaceutically acceptable salt thereof, a water-soluble hydrocolloid and a plasticizer, wherein the sildenafil or a pharmaceutically acceptable salt thereof contains 100 mg or more, By weight or more and 50% or more per 100% by weight of the film.

The plasticizer may be selected from glycerin fatty acid esters, sucrose fatty acid esters, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, Triacetin, glycerol oleate, sucrose fatty acid esters and medium chain fatty acids.

Also, there is provided a fast film characterized in that the plasticizer comprises glycerin or sorbitol.

Also, the fast release film is characterized by comprising at least one antiseptic selected from the group consisting of sodium hydroxide and magnesium oxide.

Also, as a method for producing the above-mentioned film for rapid application,

(a) uniformly stirring sildenafil citrate, a film former, a plasticizer, an antiseptic, and a pharmaceutically acceptable additive to provide a bath liquid for preparation of an oral film formulation;

(b) molding the film by injecting the crude solution into a molding machine; And

(c) slitting and cutting the molded film to fill the container or the aluminum wrapping paper, the method comprising the steps of: (a) preparing an oral film formulation comprising sildenafil citrate, Wherein the agent is selected from the group consisting of magnesium oxide and sodium hydroxide.

The rapid film of the present invention can contain sildenafil or its pharmaceutically acceptable salt as an active ingredient in an amount of 50% or more of the total weight of the film, or 100 mg or more per film, and at the same time, The problem of brilliantness that occurs when the active ingredient is added is solved, and further, the bitter taste of the active ingredient is solved.

The present invention relates to an oral film for oral use. Such an oral film preparation can alleviate the difficulty and fear of taking it for a patient suffering swallowing difficulties such as an elderly person or a handicapped person, And the drug can be designed so that direct drug delivery can be achieved without first pass effect through the oral mucosa or the like depending on the drug, so that the bioavailability can be improved and the relatively low dose The faster the effect can be obtained. In addition, oral film formulations are unit packaged in very thin packaging materials different from conventional formulations, and are easy to carry and store. Further, it is possible to substitute oral pharmaceutical formulations for medicines such as pediatric, geriatric, neurological diseases and erectile dysfunction drugs which are sold in the form of conventional tablets, capsules or liquid syrup, Drug Delivery System (DDS) has the advantage of being able to provide opportunities for pharmaceutical companies to increase their Going Concern Value and profits.

Despite these advantages, however, there are a number of technical difficulties in making PDEv inhibitors, such as sildenafil or its pharmaceutically acceptable salts, as oral film preparations.

First, it concerns the film forming ability and the loading amount of the effective component. For example, when sildenafil citrate is used as an active ingredient, since 50 mg and 100 mg of the presently marketed Viagra are present, when 100 mg of sildenafil (140.45 mg as sildenafil citrate) It is considered technically very difficult to mount more than 100 mg of the active ingredient in the film formulation. However, since the size, thickness, and gross weight of the formulation are strictly limited due to the nature of the film formulation that must be rapidly disintegrated in the oral cavity, the total weight of the limited film formulation , It means that the amount of the film forming agent or other additives contained in the formulation should be reduced. Therefore, it is difficult to mount a large amount of the active ingredient while maintaining excellent film forming ability and physical properties . Particularly, according to the study of the present inventors, it has been found that when 100 mg or more of sildenafil citrate is loaded on a film in accordance with a conventional film formulation, the problem of brilliantness is serious and a commercially available fast film can not be formed . That is, when the amount of sildenafil citrate is excessively increased to 100 mg or more in the case of ordinary prescription, the film itself is not formed or is easily broken even if it is formed. Therefore, when the sildenafil citrate is stored and distributed, It was found that the product could not maintain its original shape. For this reason, there has been no successful commercialization of an oral film containing sildenafil citrate at present with a load of 100 mg or more.

Second, in the case of a fast film containing a high content of sildenafil citrate in such a manner, it is difficult to derive a means for concealing the stain without affecting the film forming ability. The inventors of the present invention have repeatedly carried out intensive studies on a variety of conventional gummy hiding means for incorporating a gummy drug into an oral film. As a result, the conventional means is applied to a fast film to be loaded with a high content of effective ingredient , It has been found that the film is not formed or the film is formed due to the adoption of the conventional grit hiding means at the time of extreme deterioration and is not suitable as a commercially available product. That is, when the present invention is applied to conventional prescription, when the sildenafil citrate is contained in an amount of 100 mg or more as in the present invention, it has been found that adverse effect on the film formability is adversely affected if conventional known antiseptic means are applied thereto. This is because, in the case of the present formulation, at least 50% of the total weight of the film is composed of the active component, so that the amount of the component other than the active component, for example, film forming agent, Under such an environment, it means that the conventional hiding means can not be applied as it is. Therefore, in the case of the present invention, which contains a high content of sildenafil citrate, it is necessary to incorporate a special hiding function.

Third, it is a problem of brilliance in a high-content fast film. In the case where the active ingredient is contained in a high content as in the present invention, in the case of following the usual prescription, the film is not well formed, and even when the film is successfully formed, A problem arises. That is, since the high-content rate film contains a large amount of the active ingredient, the amount of the film-forming agent is inevitably reduced. When a small amount of the film-forming agent is used, even if the film is formed, Even if a small impact is applied thereto, a phenomenon of breakage is likely to occur. For this very reason, it has been considered in the art that it is not possible to make a film formulation containing sildenafil citrate in an amount of 100 mg or more as a practical industrially applicable product.

In particular, the above three problems are not caused independently of each other, but are related to each other organically, so it is very difficult to solve them. That is, when a large amount of sweetener is used or cyclodextrin is used in order to strengthen the oily hiding means, the active ingredient can not be loaded in a high content in the fast film, and the problem of brutality can not be improved. In addition, when the amount of the film forming agent is increased in order to solve the problem of Brittris, there is a limit in increasing the amount of the active ingredient. In other words, in order to maximize the amount of active ingredients and conceal bitterness and solve the problem of brutality, a new and advanced prescription that does not exist in the past is required.

Accordingly, the present inventors have repeatedly conducted researches and found that a technical means capable of solving the above three problems at the same time, that is, an effective ingredient is contained in a high content, while maintaining excellent film forming ability and effectively hiding the active ingredient And also to a new technical means for solving the problem of brutality, leading to the present invention. That is, as a result of intensive studies, the inventors of the present invention have found that, in a fast film containing a high content of sildenafil or a pharmaceutically acceptable salt thereof, a specific plasticizer is used in a specific amount, and sodium hydroxide And magnesium oxide are used, it is possible to solve the problem of brilliance and to effectively conceal dirt, leading to the present invention.

More specifically, the oral film formulations of the present invention may contain a therapeutically effective amount of an active ingredient, an antiseptic, a plasticizer, a high sweetening sweetener, a film former, and a pharmaceutically acceptable additive, Upon ingestion, it completely disintegrates and / or dissolves within 1 minute in the oral cavity and moves to the gastrointestinal tract and is absorbed.

More specifically, a preferred oral film formulation according to the present invention comprises a high content of sildenafil or a pharmaceutically acceptable salt thereof, i.e. at least 50% of the total weight of the film or at least 100 mg per film, , Sweeteners, film formers and additional ingredients, and the additional ingredients may be pharmaceutically acceptable such as thickeners, fillers, further sweeteners, acidifiers, flavors, surfactants, water-soluble polymers, preservatives, Lt; / RTI > The components will be described in detail as follows.

Antiseptic

In the case of a drug having a bitterness, when the tablets are made into ordinary tablets or capsules, the time for the tablets to stay in the oral cavity is extremely short, and since they are hardly dissolved in the oral cavity, the patient rarely feels discomfort due to bitter taste . If, however, the drug with a bitterness is included in a formulation disintegrating in the mouth, for example, in an oral inhalation disintegration (ODT) or an oral disintegration film formulation (ODF), these formulations may contain less than a few seconds to a few minutes Disintegrating and / or dissolving while staying in the oral cavity. Therefore, a patient taking the medicine must feel a bitter taste, and accordingly, there is a high necessity to derive appropriate means for concealing the bitterness. As a means for concealing gummy hair, various types of sweeteners are most commonly used. In many cases, it is not possible to conceal the gummy hair to such an extent that the patient can not feel the bitter taste by simply incorporating the sweetener into the formulation. Many means have been proposed for controlling the particle size of the active ingredient, using an inclusion compound, coating the drug with an insoluble polymer, or using a solid dispersion. However, this means that there is a large variation in the effect of the hiding concealment depending on the physical properties of each drug and the form of the final formulation, and therefore, it is assumed that any specific drug and the specific formulation have been effective, It is understood that it is not of nature to be able to do.

On the other hand, PDEv inhibitors, such as sildenafil citrate, have been extensively used in medicine for a long time to develop ODT or ODF, which is a rapidly disintegrating drug in the oral cavity, It has been adopted, however, that it is difficult to effectively attain the antiseptic effect without undermining the original characteristics of ODT or ODF formulations. As described above, in the case of the present invention, since the present invention contains a high content of the active ingredient, when conventional antiseptic hiding means is applied, the hiding hiding effect is not excellent, or the problem of Brittley occurs, There is a problem in that the film is not formed.

Accordingly, the present invention discloses a new germicidal hiding means as follows. In the present invention, the use of an anti-hiding agent is intended to conceal the syrup of sildenafil citrate by controlling the pH in the crude solution for forming an oral film to a range of 4.8 to 7. [ That is, according to the study of the present inventors, it has been found from studies that an effective oily concealment can not be achieved only by using a general sweetening agent for the oily taste of an oral film preparation containing sildenafil citrate. As a result, And / or by using a combination of specific antiseptic agents to adjust the pH range of the crude solution to the above range. According to a further study by the inventor of the present invention, however, when the pH is limited to the above-mentioned range, the effect of concealment may not be sufficient depending on the substance to be used, I got additional knowledge that Nice is having problems.

That is, in the present invention, suitable pH adjusting agents for raising the pH of the crude liquid are sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, calcium carbonate, magnesium carbonate, Potassium hydroxide, and aluminum hydroxide can be used. The amount of the horseradish scouring agent used can be adjusted within the range capable of adjusting the pH range, but it is preferably 1.0 to 10.0 wt% Knowledge.

However, another important feature of the present invention is that the combination of a specific antiseptic agent and / or a specific antiseptic agent among the antiseptic agents does not adversely affect the film formation, and in particular, And the optimal range that does not occur is deduced. That is, according to the studies of the present inventors, it has been found that when the pH range is adjusted by using the antiseptic agent and the sweetener is used in combination, it is possible to attain an antiseptic effect, but the film is not easily formed, I found an unexpected problem that a problem occurred. In other words, when the content of sildenafil citrate is set to a high content, the pH is simply adjusted to the above-mentioned range, and it is difficult to form a rapid film formulation capable of actual production.

In order to solve such problems, the present inventors have found that when a pH range is adjusted to a range of 4.8 to 7 by using a combination of magnesium oxide and sodium hydroxide as an antiseptic hiding agent, an excellent film forming ability is attained, And confirmed that the problem was eliminated. The magnesium oxide and sodium hydroxide are preferably used in a ratio of 1: 4 to 4: 1, and the sum of magnesium oxide and sodium hydroxide is preferably 1 to 10% of the total formulation weight.

Sweetener

The pharmaceutical composition of the present invention may contain a sweetening agent. Examples of the sweetening agent include sugar, glucose, maltose, oligosaccharide, galactose, starch, sorbitol, maltitol, phytonutrients, xylitol, erythritol, hydrogenated starch syrup, mannitol, trehalose, aspartame, acesulfam salt, sucralose, saccharin salt, And may be one or more high sweetening sweeteners selected from the group consisting of tartaric acid, tartaric acid, tartaric acid, neomycin, martin, tomutin mixture, cyclamate salt, tau martin, nahan and extract, licorice extract, stevioside, enzyme treated stevioside, neohesperidin and monelin. More preferably at least one high sweetening sweetener selected from aspartame, tomaton mixture, sucralose, neotime, and acesulfame.

In the case of a drug having an unpleasant taste, it is felt strong and unpleasant taste even after taking it. Therefore, when 1.0 to 10.0% by weight (w / w) aspartame and one or more additional sweeteners based on the total weight are used in combination, In particular, when aspartame and Tallin MD90 are used in combination, they have excellent antiseptic effect and film-forming ability, and also have a superior feeling of taking.

Film forming agent

The oral film formulation of the present invention comprises a water-soluble polymer as a film-forming agent. The water-soluble polymer is selected from the group consisting of pullulan, gelatin, pectin, low viscosity pectin, hydroxypropylmethylcellulose, low viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinylalcohol, polyacrylic acid, methyl But are not limited to, polyvinylpyrrolidone, methacrylate copolymers, carboxyvinyl polymers, polyethylene glycol, alginic acid, low viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, whey protein isolate, soy protein isolate, , Carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum and agar. Preferably, it may be at least one water-soluble polymer selected from the group consisting of pullulan, gelatin, pectin, low viscosity pectin, low viscosity alginic acid, hydroxypropyl methylcellulose and modified starch.

The water-soluble polymer may contain 5 to 70% by weight (w / w) based on the total weight of the oral film formulation.

Active ingredient

The pharmaceutically active ingredient used in the oral film formulation of the present invention can be a pharmacologically active ingredient orally administered.

Diabetes therapeutic agents such as, for example, glimepiride, pioglitazone and the like; Agents for treating insomnia such as zolpidem, eszopikclone and the like; Genitourinary therapeutic agents such as tolterodine, trospium and the like; An obesity treating agent such as sibutramine; Enzymes such as streptokinase and the like; Peptic ulcer solvents such as omeprazole and the like; Enzymatic expectorants such as theophylline, glenbuterol and the like; A skin disease treatment agent such as pinastelide; Antimicrobial agents such as ondansetron; Antidepressants such as fluoxetine and the like; Antihistamines such as fexofenadine hydrochloride and the like; Antipyretic analgesic anti-inflammatory agents such as aspirin, ibuprofen, ketoprofen, meloxicam and the like; Hormone preparations such as testosterone and the like; Therapeutic agents for circulating agents such as felodipine, atorvastatin, amlodipine camsylate, doxazosin, simvastatin, lercanidipine and the like; Therapeutic agents for gastrointestinal tract such as famotidine, ranitidine, lansoprazole and the like; Cardiovascular agents such as amlodipine, nitroglycerin and the like; psychotropic solvents such as paroxetine; Erectile dysfunction drugs such as sildenafil, tadalafil, and vardenafil; Alzheimer's treatment agent such as donepezil: osteoporosis treatment agent; Arthritis remedy; Antiepileptics; Muscle relaxants; Brain function improvers; A therapeutic agent for schizophrenia; Immunosuppressants; Antibiotics such as ampicillin and amoxicillin; Anticancer agents; Anticancer adjuvants; Vaccines; Mouthwash; Anemia treatment agent; Constipation remedy; Allergy Remedy: Anti-coagulant: Oral Vaccine: Melatonin: Vitamin; Nutrients; Lactic acid bacteria preparation; Comprehensive cold medicine; Or health functional foods, and the like.

In addition, it is also possible to use at least one compound selected from the group consisting of triclosan, cetylpyridinium chloride, domiphen bromide, quaternary ammonium salts, zinc compounds, angarin, fluoride, alexidine, octonidine, EDTA, aspirin, acetaminophen, ibuprofen, ketoprofen, But are not limited to, fenoprofen calcium, naproxen, tolmetin sodium, indomethacin, benzonatate, caramiphen, edicylate, menthol, dextromethorphan hydrobromide, ciphedianol hydrochloride, diphenhydramine, pseudoephedrine, phenyl But are not limited to, perylene, phenylpropanolamine, pseudoephedrine sulfate, bromphenylamine maleate, chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate, dexchlorpheniramine maleate, diphenhydramine hydrochloride, Diphenhydramine citrate, diphenyl pyraline hydrochloride, toxic amine succinate, promethazine hydrochloride, Thiophenol amine citrate, triprolidine hydrochloride, acryvastine, lauratadine, brompheniramine, dexbrompheniramine, guineafenesin, epikac, calcium iodide, ter But are not limited to, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, But are not limited to, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, fumaric acid, , Methopone, oxymorphone, levorphanol, codeine, hydrocodone, zyocodon, nalpine, naloxone, naltrexone, salicylate. But are not limited to, phenylbutazone, indomethacin, phenacetin, chlorpromazine, methotrimeprazine, haloperidol, clozapine, reserpine, imipramine, tranylcypromine, phenelzine, lithium, apomorphine, sildenafil, But are not limited to, vardenafil, ondansetron, donepezil, zolpidem tartrate, granicetrone, montelukast, polacodine, butylscopolamine, fentanyl citrate, oxicycloine hydrochloride, buprenorphine hydrochloride, escitalopram oxalate, But are not limited to, taurate, esomeprazole magnesium, aripiprazole, zolmitriptan, lizatriptan benzoate, telmisartan, risperidone, benzocaine, cetirizine hydrochloride, bambuterol hydrochloride, galantamine hydrobromide, Chloride, paroxetine hydrochloride, meloxicam, tolteridine tartrate and doxazosin mesylate, and pharmaceutically acceptable < RTI ID = 0.0 > A salt thereof, and a salt thereof. The active ingredient may contain up to 75% by weight (w / w) based on the total weight of the oral film formulation.

Filler

Oral film formulations of the present invention may comprise a filler. The filler serves to maintain the density and shape of the film. It also reduces the stickiness between the films and can control the rate of dissolution of the film and the dissolution rate of the film in the oral cavity. The filler may be added in an amount of 0.5 to 10% by weight (w / w) based on the total weight of the oral film formulation.

In one embodiment, the filler is selected from the group consisting of microcrystalline cellulose, cellulose polymer, microcrystalline cellulose, carboxymethylcellulose sodium, magnesium carbonate, calcium carbonate, limestone powder, silicate, clay, talc, titanium dioxide, Or more.

Plasticizer

Oral film formulations of the present invention may include a plasticizer. The plasticizer can be used to control the flexibility and brilliance of the film. A feature of the present invention is that the amount of sildenafil citrate contained in the film is 50% or more or 100 mg or more of the total weight of the film. On the other hand, when a high content of sildenafil citrate is used as described above, a problem of brutality occurs according to ordinary prescriptions, and the product does not become commercially available products.

On the other hand, currently available sildenafil citrate preparation is a formulation containing three doses of 25 mg, 50 mg and 100 mg under the trade name of Viagra and a dose of about 140.45 mg as sildenafil citrate in a dose of 100 mg. When 50% of the total weight of the film is used as the active ingredient, 280 mg of the film preparation should be prepared. Usually, the formulation of 250 mg or more is too large to be applied to the oral cavity at once, Which is suitable for one administration at a time, is 27 mm in length and 32 mm in length. Accordingly, in the present invention, it was tried to prepare a fast film capable of containing 100 mg of sildenafil, while defining the film formulation as about 220 mg in weight by 27 mm by 32 mm by 32 mm.

In this case, the content of sildenafil citrate is 60 to 70% per one rapid film at this time. When such a film is prepared by applying the ordinary prescription, the flexibility and strength of the film are remarkably reduced. In particular, when the brittleness is remarkably reduced and the bending test is performed after opening at a temperature of 22 ° C and a relative humidity of 55% RH after opening from the aluminum silver foil wrapping paper, most of the brittleness is immediately broken.

The inventors of the present invention have conducted intensive studies to improve the bleachability of such high-content preparations. As a result, the inventors of the present invention found that the administration of 1% to 10% of glycerin, 0.1 to 10% of sorbitol, New films can be produced. That is, when the above plasticizer is used, the amount of the film-forming agent does not cause at least the problem of brilliance, and furthermore, the combination of the sodium hydroxide and the magnesium oxide, And it was found that the gummy was completely removed.

On the other hand, the plasticizer may be selected from glycerin fatty acid esters, sucrose fatty acid esters, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, Triacetin, glycerol oleate, sucrose fatty acid esters and heavy chain fatty acids, with glycerin or sorbitol being most preferred as described above.

Moisturizer

Oral film formulations of the present invention may further comprise a moisturizing agent. Moisturizers are not mainly used in film formulations, but in high-content solvents, adequate moisture retention of 1% to 7% is required. Increasing the amount of brininess is often caused by a drastic decrease in water content, so it is necessary to use a moisturizer to maintain an adequate amount of moisture. The moisturizing agent may be added in an amount of 0.5 to 10% by weight (w / w) based on the total weight of the oral film-forming composition. Sugars such as sorbitol, xylitol, fructose and the like, salts such as sodium chloride having hygroscopicity, and polymers.

Acidic

Oral film formulations of the present invention may further comprise an acidifier. Sanmije can control taste with sweeteners and stimulate the occurrence of acupuncture so that the edible film can dissolve well. The acidic agent may be added in an amount of 0.5 to 10% by weight (w / w) based on the total weight of the oral film-forming composition.

In one embodiment, the acid agent may be at least one component selected from the group consisting of citric acid, malic acid, fumaric acid, tartaric acid, ascorbic acid, succinic acid, adipic acid and lactic acid.

Spices

Oral film formulations of the present invention may also include a flavoring. Since the oral film formulation of the present invention is a product that is dissolved and absorbed in the oral cavity, it is necessary to apply an appropriate flavor. The fragrance may be a natural fragrance, an artificial fragrance or a mixture thereof.

Natural spices can be plant leaves, flowers, extracts from fruits and the like, vegetable oils and the like. The vegetable oils may be selected from the group consisting of spearmint oil, cinnamon oil, peppermint oil, lemon oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil and almond oil. Artificial flavors include artificial synthetic fruit flavors such as lemon, orange, grape, lime and strawberry, and artificial synthetic flavors such as vanilla, chocolate, coffee, cocoa, pine leaf, ginseng, red ginseng and citrus.

The amount of the perfume to be used depends on a number of factors such as the type, kind and desired strength of the perfume to be used, and may generally be 0.1 to 10.0% (w / w) based on the total weight of the oral film formulation. The oil type flavor can be used together with an emulsifier to make it compatible with water-soluble materials. The content of the emulsifying agent may be adjusted according to the kind and amount of the perfume, and may be generally 0.5 to 10% by weight (w / w) based on the total weight of the oral film preparation.

Pigment

In addition, the oral film formulation of the present invention may contain a pigment suitable for the product. The pigment can be appropriately adjusted in its content as required and may be added in an amount of 0.1 to 1.0% by weight (w / w) based on the total weight of the oral film formulation. The pigment may be a natural or synthetic pigment.

It would be desirable for the oral film formulations of the present invention to form a thin film film that maintains an appropriate range of tensile strength and toughness in a very thin film state.

In one embodiment, the thickness of the oral film formulation of the present invention is from 50 탆 to 300 탆, preferably from 60 탆 to 280 탆, and most preferably from 70 탆 to 260 탆. The size of the oral film formulation of the present invention is 1 cm 2 to 12 cm 2, preferably 2 cm 2 to 10 cm 2, and more preferably 4 cm 2 to 8 cm 2.

The invention also provides a method of making an oral film dosage form. In one embodiment, the process for preparing an oral film formulation of the invention comprises

(1) preparing an oral film-forming composition comprising an active ingredient, a plasticizer, an antiseptic, a water-soluble polymer, a sweetener and other pharmaceutically acceptable additives;

(2) introducing the oral film-forming composition into a molding machine to form a film at 15 to 150 캜, preferably 25 to 120 캜, more preferably 40 to 100 캜;

(3) aging the molded film at a relative humidity of 30 to 90% for 1 to 30 days.

More specifically, the process for producing an oral film formulation according to the present invention can be carried out, for example, through the following process.

(1) Liquid preparation process: The active ingredient is mixed with an antiseptic, a surfactant, a plasticizer and the like and uniformly stirred. Then, a sweetener, a flavoring agent, a water-soluble polymer and a coloring agent are added and stirred homogeneously to prepare an oral film formulation preparation liquid. At this time, the final pH of the crude liquid is set to a range of 4.8 to 7. The magnesium oxide and / or sodium hydroxide can be used as the antistatic agent, and griserin and / or sorbitol can be used as the plasticizer. Examples of the solvent (solvent) include propylene glycol, polyglycol 35 castor oil, polyethylene glycol 400, polyethylene glycol 300, trichloromonofluoromethane, sodium hydrogencarbonate, acetic acid, water for injection, purified soybean oil, purified water, isopropanol, At least one solvent selected from the group consisting of liquid paraffin, sodium chloride, ethanol, acetone, physiological saline, benzyl alcohol, isopropyl myristate, anhydrous ethanol, sterile purified water, N methyl pyrrolidone, glycerin, methylene chloride and toluene Is selected from the group consisting of sterilized purified water, injectable water, purified water, isopropanol, ethanol, methylene chloride, toluene, more preferably sterile purified water, purified water, ethanol, methylene chloride, toluene One or more solvents may be selected, but limited to is. The pH of the crude solution is obtained by dissolving the pharmaceutical composition of the present invention in a solvent and measuring the pH of the crude solution.

(2) Forming step: The coating solution is put into a molding machine to form a film. At this time, the temperature of the molding machine is formed into a roll shape by molding the film at a temperature of 15 to 150 ° C, preferably 25 to 120 ° C, more preferably 40 to 100 ° C.

(3) Aging process: The formed film contains moisture suitable for slitting or cutting through a maturing process of about 1 to 30 days at a relative humidity of 30 to 90%. The moisture content at this time is preferably 15% or less.

(4) Cutting process: The aged rolls are slit into small rolls, cut to the appropriate size and filled into small containers or aluminum wrappers.

(5) Packing process: Small packed containers or products of aluminum wrapper are re-packaged in small boxes or made into blisters.

According to this method, magnesium oxide (MgO) and / or sodium hydroxide (NaOH), which are sphygmomanometry or pharmaceutically acceptable salts thereof, as active ingredients, w / w), the pH of the crude solution was maintained at 4.8 to 7, and the content of aspartame and tallin MD90 as sweetening agents in the range of 1.0% to 4.0%, respectively, effectively formed the film, effectively suppressing the unpleasant taste of the drug It was possible to prepare an oral film formulation which can be melted and eaten in the mouth without water and which has improved patient compliance and film properties. In addition, the oral film formulations produced by the method of the present invention can be easily administered to patients who are difficult to swallow tablets because they rapidly disintegrate and dissolve in oral saliva without consuming additional water.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example

Comparative Examples 1 to 15

The oral film compositions for oral use were prepared as described in the following table, and the pH, gumminess score, peel test and film properties, i.e., bending test, of the crude solution were evaluated according to the following criteria. In the following table, each component contained in one film is expressed as% by weight.

* Gummy score: We calculated the average value of 10 men and women aged 25 to 40 years. (Figures are rounded to the first decimal place)

1: Almost no bitter taste

2: Little bitter taste

3: bitter taste is common

4: Bitter bitter

5: Extremely bitter

* Peel test

The peel test measures the degree of peeling from the PET film as the support film

1: very little peeling

2: Peeling is not good

3: Peeling is normal

4: Good peeling

5: Very good peeling

* Bending test

The bending test was performed by using two fingers. When the film was folded in half, the folded film was folded until it was folded in half. The bending test in Tables 1 to 3 was conducted after 30 minutes after opening the film wrapped in aluminum film. The temperature and humidity were 22 ℃ and 55% RH. The higher the number, the better the brilliance.

Furtherance Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Sildenafil citrate 46.7%

(70 mg) 46.7%

(70 mg) 70%

(140 mg) 70%

(140 mg) 70%

(140 mg) 70%

(140 mg) Pullulan 38.3% 34.3% 17% 17% 17.6% 17.1% glycerin 1.4% 1.4% Propylene glycol 1.4 Polyethylene glycol
600 4.5% 3% 3% One% 2% 0.5% Xylitol 3.5% 2% 2% One% One% 0.5% Sodium hydroxide 4% 4% 4% Aspartame 1.5% 2% 2% 1.5% 2% 1.5% Sucralose 1.5% 3% 3% 2.5% 3% 2.5% Spices 2% 2% 0.5% 0.5% 0.5% 0.5% menthol 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% Polysorbate 20 1.5% 1.5% One% One% One% One% Pigment a very small amount a very small amount a very small amount a very small amount a very small amount a very small amount sub Total 100% 100% 100% 100% 100% 100% Gross weight (mg / h) 150 150 200 200 200 200 Whether the film is formed ○ ○ △ △ ○ ○ pH 3.95 5.5 3.9 5.6 3.85 5.7 Sensory test result 5 2 5 4 5 4 Bending Test Results 4 3 One One 2 2 Peeling test result 3 3 2 One 2 One

Examples were prepared as described in Tables 2 to 5 below. Example 8 - Example 15 further examined casting, slitting and cutting suitability as a result of a pilot test of 20,000 sheets per one badge as a peel test, a slitting test and a cutting test result

Furtherance Comparative Example 7 Comparative Example 8 Example 1 Example 2 Example 3 Sildenafil citrate 64.9%
(100 mg as sildenafil) 63.8%
(100 mg as sildenafil) 63.8%
(100 mg as sildenafil) 63.8%
(100 mg as sildenafil) Simethicone 55.8% Metocell E15 10.3% Polyoxamer L-44 5.2% Pullulan 17.0% 17.0% 17.0% Polypro 2.1% Propylene glycol 8.2% 8.2% glycerin Polyethylene glycol 600 8.2% Xylitol 7.2% 8.2% Sorbitol Sodium hydroxide 2.0% 2.0% 2.0% Magnesium oxide 0.7% 0.7% 0.7% Aspartame 1.0% 1.4% 1.4% 1.4% Sucralose 1.0% 1.0% 1.0% Tallinn MD90 1.9% 1.9% 1.9% Citric acid 1.0% 1.0% 1.0% Peppermint oil 1.0% Strawberry flavor 1.0% 1.0% 1.0% menthol 0.5% 0.5% 0.5% Polysorbate 20 1.5% 1.5% 1.5% FD & C Red No. 40 0.01% 0.01% 0.01% Benzoic acid 0.01% Sodium EDTA 0.01% sub Total 100.0% 100.0% 100.0% 100.0% pH 3.9 4.38 4.4 4.37 Sensory test result 5 5 5 5 bending test result 2 3 One One One Peel test result 3 3 3 3

(In the above table,

1) Comparative Example 7 is an embodiment of US 652024

2) In Comparative Example 8, the prescription of Gas-X is not known, but it is known that the API is the highest among commercially available products with more than 50%

3) Sensory test: 1: Almost no bitter taste, 2: Little bitter taste, 3: Bitter bitter taste, 4: Bitter taste, 5: Very bitter taste

4) bending test: When using two fingers folded in half, the number of times to break, the higher the number, the smaller the degree of breakage

5) The peel test measures the degree to which the film is peeled off from the PET film as a support film after drying. The higher the number, the better the peeling.)

Furtherance Example 4 Example 5 Example 6 Example 7 Sildenafil citrate 63.8% 69.8% 67.2% 63.2% Simethicone Metocell E15 Polyoxamer L-44 Pullulan 17.0% 17.0% 17.0% 17.0% Polyvinyl alcohol Polypro Propylene glycol glycerin Polyethylene glycol 600 0.5% 0.5% 0.5% Xylitol Sorbitol 8.2% Sodium hydroxide 2.0% 4.0% 8.0% 12.0% Magnesium oxide 0.7% 1.4% 0.0% 0.0% Aspartame 1.4% 1.4% 1.4% 1.4% Sucralose 1.0% 1.0% 1.0% 1.0% Tallinn MD90 1.9% 1.9% 1.9% 1.9% Citric acid 1.0% Peppermint oil Strawberry flavor 1.0% 1.0% 1.0% 1.0% menthol 0.5% 0.5% 0.5% 0.5% Polysorbate 20 1.5% 1.5% 1.5% 1.5% FD & C Red No. 40 0.01% 0.01% 0.01% 0.01% Benzoic acid Sodium EDTA sub Total 100.0% 100.0% 100.0% 100.0% pH 4.38 4.8 5.8 6.9 Sensory test result 4 2 2 One bending test result 2 2 One One Peel test result 3 3 One One

(In the above table,

1) sensory test: 1: almost no bitter taste, 2: little bitter taste, 3: bitter bitter taste, 4: bitter taste, 5: very bitter taste

2) bending test: When using two fingers folded in half, the number of times to break, the higher the number, the smaller the degree of breakage

3) The peel test measures the degree to which the film is peeled off from the PET film as a support film after drying. The higher the number, the better the peeling.)

Furtherance Example 8 Example 9 Example 10 Example 11 Example 12 Sildenafil citrate 68.3% 67.9 67.3% 65.3% 63.3% Simethicone Metocell E15 Polyoxamer L-44 Pullulan 17.0% 17.0% 17.0% 17.0% 17.0% Polyvinyl alcohol Polypro Propylene glycol glycerin 1.0% 1.4% 2.0% 4.0% 6.0% Polyethylene glycol 600 0.5% 0.5% 0.5% 0.5% 0.5% Xylitol Sorbitol 0.5% 0.5% 0.5% 0.5% 0.5% Sodium hydroxide 4.0% 4.0% 4.0% 4.0% 4.0% Magnesium oxide 1.4% 1.4% 1.4% 1.4% 1.4% Aspartame 1.4% 1.4% 1.4% 1.4% 1.4% Sucralose 1.0% 1.0% 1.0% 1.0% 1.0% Tallinn MD90 1.9% 1.9% 1.9% 1.9% 1.9% Peppermint oil Strawberry flavor 1.0% 1.0% 1.0% 1.0% 1.0% menthol 0.5% 0.5% 0.5% 0.5% 0.5% Polysorbate 20 1.5% 1.5% 1.5% 1.5% 1.5% FD & C Red No. 40 0.01% 0.01% 0.01% 0.01% 0.01% sub Total 100.0% 100.0% 100.0% 100.0% 100.0% Sensory test result One One One One One bending test result One 2 3 4 5 Disintegration test result 20 seconds 21 seconds 23 seconds 25 seconds 28 seconds Peel test result 5 5 5 4 3 Results of slitting test ○ ○ ○ ○ ○ Cutting test result ○ ○ ○ ○ ○

(In the above table,

1) sensory test: 1: almost no bitter taste, 2: little bitter taste, 3: bitter bitter taste, 4: bitter taste, 5: very bitter taste

2) bending test: When using two fingers folded in half, the number of times to break, the higher the number, the smaller the degree of breakage

3) The peel test measures the degree to which the film is peeled off from the PET film as a support film after drying. The higher the number, the better the peeling.)

Furtherance Example 13 Example 14 Example 15 Example 16 Sildenafil citrate 61.3% 59.3% 54.3% 50%
(Using sildenafil base) Simethicone Metocell E15 Polyoxamer L-44 Pullulan 17.0% 17.0% 17.0% 34% Polyvinyl alcohol Polypro Propylene glycol glycerin 8.0% 10.0% 15.0% 4% Polyethylene glycol 600 0.5% 0.5% 0.5% 3% Xylitol Sorbitol 0.5% 0.5% 0.5% 3.59% Sodium hydroxide 4.0% 4.0% 4.0% 0% Magnesium oxide 1.4% 1.4% 1.4% 0% Aspartame 1.4% 1.4% 1.4% 1.4% Sucralose 1.0% 1.0% 1.0% One% Tallinn MD90 1.9% 1.9% 1.9% 0% Peppermint oil Strawberry flavor 1.0% 1.0% 1.0% One% menthol 0.5% 0.5% 0.5% 0.5% Polysorbate 20 1.5% 1.5% 1.5% 1.5% FD & C Red No. 40 0.01% 0.01% 0.01% 0.01% sub Total 100.0% 100.0% 100.0% 100.0% Sensory test result One One One One bending test result 6 7 10 3 Disintegration test result 31 seconds 34 seconds 41 seconds 50 seconds Peel test result One One × 5 Results of slitting test ○ ○ ○ ○ Cutting test result △ △ × ○

(In the above table,

1) sensory test: 1: almost no bitter taste, 2: little bitter taste, 3: bitter bitter taste, 4: bitter taste, 5: very bitter taste

2) bending test: When using two fingers folded in half, the number of times to break, the higher the number, the smaller the degree of breakage

3) The peel test measures the degree to which the film is peeled off from the PET film as a support film after drying. The higher the number, the better the peeling.)

Example 16

The syrinafil base was used instead of sildenafil citrate, and the sensory test, the bending test, and the peel test were performed after the prescription described in Table 5, liquid preparation, molding, slitting, cutting and packaging were performed by the above-described manufacturing method. The test results were as good as those of Example 10.

 The bending test was performed by using two fingers. When the folding film was folded in half, it was folded until it was folded in half. The bending test in Tables 1 to 5 was conducted after 30 minutes after opening the fast film wrapped with aluminum film. The temperature and humidity were 22 ℃ and 55% RH. The higher the number, the better the brilliance.

As can be seen from Table 1, Comparative Example 2 is a fast film containing sildenafil citrate of 72 mg (50 mg of sildenafil citrate) as an example of Korean Patent No. 10-1188594, When it was manufactured with 22mm length and 32mm length, the bitterness was well masked, the physical properties were good, and the brilliantness was not bad. In Comparative Example 4, as a result of the prescription and experimentation of a rapid film to which 144 mg (100 mg of sildenafil citrate) of sildenafil citrate was added in almost the same formulation except for some excipients, the weight was 200 mg in width and 25 mm in width and 32 mm in width, And the film had poor physical properties and film formation was not smooth. As the amount of the active ingredient increased from 70.23 mg to 140.45 mg, it was found that sodium hydroxide alone did not provide enough antiseptic effect, and film formability and brilliance were poor and new means were required. In Comparative Example 6, the effect of adding 1.4% of glycerin to the prescription of Comparative Example 4 was measured. The film was formed, but the bitter taste was significantly expressed and the physical properties of the film were not good. As a result of the test in Comparative Example 1, Comparative Example 3, and Comparative Example 5, when the sodium hydroxide was excluded from the prescriptions of Comparative Example 2, Comparative Example 4 and Comparative Example 6, the bitterness was remarkably expressed as a result of the sensory test, The physical properties of the film were very poor due to the increase of the amount of the additive.

Comparative Example 7 in [Table 2] does not mask the bitter taste unique to sildenafil citrate as an experimental example of US652024. In the case of Comparative Example 8, a bending test was performed after 30 minutes from opening at 55 RH and 22 < 0 > C relative humidity using Gas-X Thin Strips of Novartis, which is a commercially available high-content fast film product. .

In the case of Examples 1 to 4, sodium hydroxide was added in an amount of 2% based on the weight of the film without adding glycerin, and bending test and sensory test were conducted using various plasticizers such as propylene glycol, polyethylene glycol 600, xylitol and sorbitol But the bitter taste was overexposed and the results of the bending test were not improved.

As can be seen in Examples 5 to 7, the bitterness was well masked by using 4 wt% (w / w) or more of sodium hydroxide, 1.4 wt% (w / w) or more of magnesium oxide and using a suitable high- Excessive increase in sodium hydroxide resulted in poor peel test results. Also, brilliant results were not good.

In Examples 8 to 14, the bitterness was well masked by using 4 wt% (w / w) or more of sodium hydroxide and 1.4 wt% (w / w) or more of magnesium oxide and a suitable high- (w / w) - 10 wt.% (w / w), polyethylene glycol 600, sorbitol, the physical strength, especially the brilliance, of the film was significantly improved from the test results. However, when glycerin was excessively used as in Example 15, the results in the peel test and the cutting test were not good, and thus it was judged that the product was not suitable for actual use.

When a bending test was performed after 30 minutes of opening at a relative humidity of 55% RH and 22 ° C using a gas-X thin strip, it was found that the bending test was carried out three times and divided into two. As a result of performing the bending test under the same conditions, it was found that the test results of Example 10 and Test Example 14 were able to withstand three times and seven times in Examples 11 to 14, respectively. The results of the bending test in Example 15 were better, but it was found that it was difficult to apply the bending test because the peeling with the supporting PET film was not smooth in the cutting process for packaging.

Novartis's Gas-X Thin Strips are 110mg of film and 62.5mg of active ingredient (Simethicone). The content of active ingredient per one film is 57%, which is more than 50% of active ingredient. Is known to be the only fast-acting film formulation commercialized.

In general, the content of the active ingredient per 1 film is known to be within about 30%. When the active ingredient is contained in an amount of 30% or more, the physical properties of the film are weakened and the brilliance is increased. The Gas-X thin strip is the fastest film formulation that has a relatively good Brittleness ratio of more than 50% of the active ingredient in the commercialized film. It can be confirmed that the fast film in which the active ingredient is sildenafilate and the content thereof is 50% or more per one quick film and the bitterness is well masked and the brilliance is significantly improved as compared with Gss-X can be obtained in Examples 10 to 14.

When the pharmaceutical composition of the present invention is used, sildenafil or a pharmaceutically acceptable salt thereof having an affinity as well as an oral film preparation containing various active ingredients can be constituted.

Claims (16)

Sildenafil or a pharmaceutically acceptable salt thereof;
Gelatin, pectin, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinylalcohol, polyacrylic acid, polyethylene glycol, alginic acid, sodium alginate, modified starch, casein, levan, gluten , Water-soluble hydrocolloids selected from the group consisting of acacia gum, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum and agar; And
Glycerol fatty acid esters, sucrose fatty acid esters, lecithin, enzyme treated lecithin, polysorbate, sorbitan fatty acid ester, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, hydrogenated starch syrup, starch syrup, glycerin, triacetin, Wherein the plasticizer comprises a plasticizer selected from the group consisting of lactose, sucrose fatty acid ester and medium chain fatty acid,
Wherein said film comprises at least 100 mg of sildenafil or a pharmaceutically acceptable salt thereof, and comprises sodium hydroxide and magnesium oxide. The film of claim 1, wherein the plasticizer is glycerin or sorbitol. 2. The film of claim 1, wherein the plasticizer is glycerin and sorbitol, each comprising from 1 to 10% and from 0.1 to 10% of the total weight of the film. The film of claim 1, wherein the water-soluble hydrocolloid is pullulan. The film of claim 1, wherein the total amount of magnesium oxide and sodium hydroxide is 1 to 12% of the total weight of the film. 6. The film according to any one of claims 1 to 5, further comprising a sweetener, a surfactant, a flavoring agent, a coloring matter, or a preservative agent The sweetener according to claim 6, wherein the sweetener is selected from the group consisting of sugar, glucose, maltose, oligosaccharide, galactose, starch, sorbitol, maltitol, phytonutrient, xylitol, erythritol, mannitol, trehalose, aspartame, acesulfame, sucralose, , Stevioside, neohesperidine, tau martin, and monelin. ≪ / RTI > 8. The film of claim 7, wherein the sweetener is at least one high sweetening sweetener selected from aspartame, sucralose, tau martin and acesulfame. 9. The film of claim 8, wherein the sweetener is at least one high-sweetening sweetener selected from aspartame, tau Martin and sucralose.
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