KR101328350B1 - Taste masked pharmaceutical composition comprising sildenafil or pharmaceutically acceptable salts thereof as an active ingredient - Google Patents

Abstract

As a pharmaceutical composition containing a PDEv inhibitor and / or various drugs as an active ingredient, a pharmaceutical composition is provided in which hidden amounts of the active ingredient are concealed. Specifically, a pharmaceutical composition containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient and containing a specific alkalizing agent in combination is provided, furthermore, sildenafil or a pharmaceutically acceptable salt thereof. As a pharmaceutical composition in the form of an oral film containing a salt as an active ingredient, a pharmaceutical composition is concealed by containing a specific alkalizing agent in combination, and does not adversely affect film formation.

Description

Taste masking pharmaceutical composition containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient {TASTE MASKED PHARMACEUTICAL COMPOSITION COMPRISING SILDENAFIL OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AS AN ACTIVE INGREDIENT}

The present invention relates to a pharmaceutical composition containing a PDEv inhibitor and / or various drugs as an active ingredient, and relates to a pharmaceutical composition concealing the taste of the active ingredient. Specifically, the present invention relates to a pharmaceutical composition containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient, and relates to a pharmaceutical composition concealing the gluten of the active ingredient. More specifically, the present invention relates to a pharmaceutical composition concealed by bitter rice, characterized in that it contains sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient and an alkalizing agent. More specifically, the present invention relates to a pharmaceutical composition in which gluten is concealed by containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient and containing a combination of a specific alkalizing agent and / or a specific alkalizing agent. will be. Furthermore, the present invention is a pharmaceutical composition in the form of an oral film containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient, and the taste is concealed by containing a combination of a specific alkalizing agent and / or a specific alkalizing agent. It relates to a pharmaceutical composition that does not adversely affect film formation.

Erectile dysfunction refers to a condition in which normal sexual life is not possible, such as difficulty in inducing or maintaining an erection for sexual intercourse, or ejaculation disorders such as premature ejaculation or seborrhea, and extreme feeling. 3-5% of American men aged 18-75 have chronic erectile dysfunction, the majority of whom are reported to be 55 or older.

In order to treat such erectile dysfunction, a drug (PDEv inhibitor) that can inhibit subtype 5 of cGMP phosphodiesterase can be used. PDEv inhibitors inhibit the degradation of cGMP and increase the concentration of cGMP in the tissue. When the concentration of cGMP in the tissue is increased, the blood flow to the cavernous tissues of the penis is increased, resulting in relaxation of the penile smooth muscle, thereby treating erectile dysfunction. It becomes possible.

Examples of PDEv inhibitors known to date include Vardenafil, [3- (1,4-Dihydro-5-methyl-4-oxo-7-propylimidazo [5,1-f] [1,2 , 4] triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4-ethyl, C23H32N6O4S, CAS no.224785-90-4), sildenafil, 1-[[3- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methylpipe Razine, 22H30N6O4S, CAS no. 171599-83-0), tadalafil (Tadalafil, pyrazino [1 ', 2': 1,6] pyrido [3,4-b] indole-1,4-dione , 6- (1,3-benzodioxol-5-yl) -2,3,6,7,12,12a-hexahydro-2-methyl-, (6R, 12aR)-, C22H19N3O4, CAS no. 171596 -29-5), udenafil (Udenafil, C25H36N6O4S, CAS no. 268203-93-6) and the like. Vardenafil is disclosed in Korean Patent No. 0430355, Sildenafil in Korean Patent No. 00262626, Tadalafil in Korean Patent No. 0357411, and Udenafil in Korean Patent No. 0353014. Such PDEv inhibitors are commercially available as oral erectile dysfunction drugs in the form of tablets prepared using water soluble salts to ensure rapid absorption and good bioavailability in formulation.

On the other hand, sildenafil, one of the above PDEv inhibitors, is a compound represented by the following formula

This drug is used for the treatment of erectile dysfunction, angina and pulmonary hypertension. Sildenafil originally conducted clinical trials to treat angina, but it was found to have an excellent effect on stiffening male genitals during clinical trials. Developed as a drug for treating insufficiency, the citrate salt of sildenafil has been used as the most widely used drug in the treatment of erectile dysfunction since it was licensed by the US FDA in March 1998. In Korea, it is marketed since October 1999 under the trade name Viagra® tablet.

However, since sildenafil is a drug to be administered immediately before sexual activity, it is often administered at irregular intervals, and in some cases, it is urgently administered in a situation that is not scheduled in advance, and thus it is easy to carry it. In view of its desirability, attempts have been made to develop formulations which can be easily taken without water, rather than as conventional tablets or capsules.

For example, Korean Patent Laid-Open Publication No. 2006-31552 discloses an oral quick-release composition for PDE-5 inhibitors containing PDEv inhibitors such as sildenafil as an active ingredient, wherein sildenafil is enclosed with cyclodextrin. Disclosed is a tablet formulation (ODT) which disintegrates rapidly in the oral cavity using a solid dispersion.

In addition, Korean Patent No. 627199 discloses a soluble film type formulation (ODF) which uses sildenafil citrate as an active ingredient and rapidly dissolves in the oral cavity, wherein a hydrocolloid is used as a film forming polymer, and a film formulation The use of a starch graft copolymer as a mucoadhesive enhancer is disclosed.

However, sildenafil or a pharmaceutically acceptable salt thereof is a tasting drug, so when it is composed of a rapidly disintegrating formulation in the oral cavity, it can be taken without water. There was a fatal disadvantage that is greatly reduced. Therefore, when the sildenafil or a pharmaceutically acceptable salt thereof is composed of an intraorally disintegrating film formulation (ODF) or an intraorally disintegrating tablet (ODT), there is an urgent need for a means to conceal bitterness.

Accordingly, as a means of concealing the sildenafil or a pharmaceutically acceptable salt thereof as ODF or ODT, the above-mentioned Korean Patent Publication No. 2006-31552 discloses the formation of a clathrate compound between sildenafil citrate and cyclodextrin. Korean Patent No. 627199 discloses a technical idea of including a conventional sweetener. However, when the inclusion compound is used, an additional process occurs, and the inclusion of cyclodextrin and sildenafil increases the total amount of the active ingredient in the formulation, so that it can be loaded into the formulation, for example, film formulation. If the total amount of ingredients is limited, it is difficult to form a formulation, and when the sweetener is concealed using only a conventional sweetener, the sweetener is not completely removed, and a sweetener is used to remove the sweetener. In the case of excessive use, even after the drug is moved to the gastrointestinal tract, the sweetness caused by the sweetener and the sweetness due to the active ingredient coexist in the oral cavity, which leads to the desire to drink water, thereby not guaranteeing the safe hiding effect. As a result, the inherent properties of the formulations can be taken without water.

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 the ion exchange resin is included in the water-soluble polymer, there is a fear that scratches may occur during molding and the operation is complicated.

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 Korea Patent KR1074271, stevioside-based sweetener and high sweetener have been used to improve aftertaste, but this is an attempt to suppress the bitter taste of the active ingredient using a combination of conventional sweeteners, and has a high taste such as sildenafil citrate. In the case of the application was limited, and also, in this document, the content of the active ingredient is 0.1 to 30% by weight (w / w) relative to the film weight, the embodiment of more than 40% by weight (w / w) relative to the total weight of the formulation Invisible

US Patent Publication No. US2007 / 0292515A1 discloses loading ketoprofen with an increased pH using an alkalizing agent such as sodium hydroxide as a means of concealing the taste of ketoprofen into the film formulation. The content of 4mg is not suitable as a technique that can be applied when a high content of the active ingredient, such as sildenafil citrate, should be included in the formulation.

In addition, Korean Patent No. 354310 discloses a technical idea of including a basic buffer or a pH adjuster to minimize the bitter taste of azithromycin. It is judged to be different.

As seen above, until now, it is considered that there is no rapid disintegrating formulation in the oral cavity containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient, which completely hides the taste of the active ingredient.

Korean Patent Publication No. 2006-31552 Korean Patent No. 627199 International Publication WO2001 / 70194 WO2003 / 070227 Korea Patent Registration KR1074271 United States Patent Application Publication No. US2007 / 0292515A1 Korean Patent Registration No. 354310

Accordingly, the present invention, as a pharmaceutical composition containing a PDEv inhibitor, for example, sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient, to solve the problem to provide a pharmaceutical composition characterized in that the bleeding is concealed It is a task.

In addition, the present invention, in the pharmaceutical composition, by adjusting the pH range of the composition by using a combination of a specific alkalizing agent and / or specific alkalizing agent, pharmaceuticals, characterized in that the secret of the active ingredient is concealed It is an object to provide a composition.

Furthermore, the present invention relates to a pharmaceutical composition in the form of a film preparation for oral administration that disintegrates rapidly in the oral cavity containing a PDEv inhibitor, for example, sildenafil or a pharmaceutically acceptable salt thereof, as an active ingredient. By adjusting the pH range of the composition by using a combination of the above, to solve the problem of providing a pharmaceutical composition characterized in that it has a good film-forming ability while concealing the gourmet of the active ingredient.

In order to solve the above problems, in the present invention, a pharmaceutical composition containing a PDEv inhibitor as an active ingredient and concealed bitterness is provided.

More specifically, it contains sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient, and comprises sodium hydroxide, calcium phosphate, potassium hydroxide, calcium hydroxide, magnesium oxide, potassium dihydrogen phosphate, sodium dihydrogen phosphate, calcium chloride, potassium chloride. There is provided a pharmaceutical composition comprising an alkalizing agent selected from the group.

Furthermore, a pharmaceutical composition in the form of an oral film formulation containing sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient, comprising: sodium hydroxide and / or magnesium oxide as an alkalizing agent and having excellent film forming ability A pharmaceutical composition is provided.

The pharmaceutical composition of the present invention is not only excellent in high concealment effect, but also easily prepared by low cost and simplified preparation. In addition, when the pharmaceutical composition of the present invention in the form of an oral film formulation, it is completely concealed and at the same time excellent film forming ability. Therefore, it can be usefully used as an oral cleanser for cleanliness in the oral cavity, bad breath remover, nutritional supplement delivery agent and oral film formulation for absorption of the drug in the oral cavity and gastrointestinal tract.

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.

In particular, the pharmaceutical composition of the present invention can be, for example, oral film formulations, such oral film formulations eliminate the difficulty and fear of taking in patients suffering from swallowing, such as the elderly and the disabled It is possible to improve the safety and effectiveness by administering the correct dose when compared to the liquid solution, and depending on the drug, it is designed to directly deliver the drug without the first pass effect through the oral mucosa. It is possible to improve bioavailability, resulting in faster efficacy at relatively lower doses. 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, more than 50 mg of sildenafil citrate (70.23 mg as sildenafil citrate) should be loaded into the film formulation, and it is considered technically very difficult to mount 50 mg or more of the active ingredient in the film formulation. . If the amount of the active ingredient is increased, the amount of the film-forming agent should be increased. However, due to the nature of the film formulation that needs to disintegrate rapidly in the oral cavity, strict restrictions are imposed on the formulation size, thickness, and gross weight. If more than 50mg of the active ingredient, which means that the amount of the film-forming agent or other additives included in the formulation is reduced, it is difficult to mount a large amount of active ingredient while maintaining excellent film forming ability and physical properties .

Second, it is difficult to derive a means of concealing gourds without affecting the film forming ability. The present inventors have conducted extensive research on various gome concealment means that have been used in the past when incorporating a gome drug in an oral film. As a result, the gome concealment means can be concealed by using a conventional means. It has been found that, due to the adoption of the film, no film is formed, or even if the film is formed, its quality is extremely poor and therefore not suitable as a commercially available product.

Accordingly, the present inventors have repeatedly conducted research to derive a technical means that can solve the above two problems at the same time, that is, a new technical means that can effectively conceal the taste of the active ingredient while maintaining excellent film forming ability. It came to invention. That is, the present inventors have intensively studied, and in the pharmaceutical composition comprising sildenafil or a pharmaceutically acceptable salt thereof, for example sildenafil citrate, an alkalizing agent is used to increase the pH of the composition. The present invention has been accomplished by obtaining the knowledge that concealment of sildenafil or a pharmaceutically acceptable salt thereof can be concealed.

More specifically, the oral film formulation of the present invention may contain a therapeutically effective amount of an active ingredient, an alkalizing agent, a high sweetener, a film forming agent, and a pharmaceutically acceptable additive, and when taken without water Completely disintegrating and / or dissolving within the oral cavity within 100 seconds, preferably within 60 seconds, more preferably within 30 seconds, will migrate to the gastrointestinal tract for absorption.

More specifically, the preferred oral film formulation according to the present invention contains sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient, and may include an alkalizing agent, a sweetener, a film forming agent, and additional ingredients. It may be a pharmaceutically acceptable additive such as thickener, filler, plasticizer, additional sweetener, acidulant, flavoring agent, plasticizer, surfactant, water-soluble polymer, preservative, colorant, coolant and the like. The components will be described in detail as follows.

Alkalizing agent

The oral film of the present invention contains an alkalizing agent. The use of the alkalizing agent in the present invention is to conceal the bitterness of sildenafil citrate by adjusting the pH in the crude liquid for forming the oral film in the range of 4.38 to 5.25. That is, according to the researches of the present inventors, the bitterness of oral film preparations containing sildenafil citrate was found to be ineffective, but only by using general sweeteners. By using a combination of specific alkalizers and adjusting the pH range of the crude liquid to the above range, knowledge was obtained.

Suitable pH adjusting agents for raising the pH of the crude liquid include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, calcium carbonate, magnesium carbonate, sodium hydroxide, magnesium hydroxide, potassium hydroxide, and aluminum hydroxide. Can be mentioned.

The amount of the alkalizing agent can be adjusted as appropriate within the range that can be adjusted to the pH range, preferably it is preferably included in 1.0 to 10.0% by weight.

In particular, another great feature of the present invention is that the combination of a specific alkalizing agent and / or a specific alkalizing agent in the above alkalizing agent has led to the derivation of an optimum range which does not adversely affect film formation. According to the researches of the present inventors, when using a combination of the alkalizing agent to adjust the pH range and using a sweetener, etc., it was possible to achieve a high concealment effect, but found an unexpected problem that the film formation is not good. In other words, the use of an alkalizing agent affects the film forming ability of the film forming agent, which causes a problem that the film is not formed at all or the film is not formed with good quality. In order to solve this problem, the present inventors have confirmed that when the pH range is adjusted to the range of 4.38 to 5.25 using magnesium oxide and / or sodium hydroxide as the alkalizing agent, excellent film forming ability is achieved. In addition, it is preferable to use magnesium oxide and sodium hydroxide in the ratio of 1: 4-4: 1, and it is preferable that the combined amount of magnesium oxide and sodium hydroxide is 2-8% 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 drugs with a strong unpleasant taste, the taste and unpleasant taste are strongly felt even after taking, so when used together with 1.0 to 10.0% by weight (w / w) of aspartame and one kind of additional sweetener to the total weight, it is possible to mask the taste and unpleasant taste. In particular, when used in combination with aspartame and Tallinn MD90 was excellent in the high concealing effect and film-forming ability, and the taking feeling is extremely superior.

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. In particular, active ingredients having chemical properties such as pH-dependent solubility and taste change depending on the nitrogen atom in the structure, for example, mental neurological agents such as paroxetine; Erectile dysfunction agents such as sildenafil, vardenafil and the like; Alzheimer's therapies such as donepezil and the like: antihistamines such as diphenhydramine, loratadine and the like; And pharmaceutically acceptable salts thereof. The active ingredient may contain up to 75% by weight (w / w) relative to 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 at least one selected from the group consisting of microcrystalline cellulose, cellulose polymers, microcrystalline cellulose carboxymethylcellulose sodium, magnesium carbonate, calcium carbonate, limestone powder, silicate, clay, talc, titanium dioxide and calcium phosphate It may be a component.

Plasticizer

Oral film formulations of the present invention may include a plasticizer. The plasticizer can be used to adjust the flexibility of the film. Plasticizer may be added 0.5 to 10% by weight (w / w) relative to the total weight of the oral film formulation.

In one embodiment, the plasticizer is glycerin fatty acid ester, sucrose fatty acid ester, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, hydrogenated syrup, starch syrup It may be one or more components selected from the group consisting of, glycerin, triacetin, glycerol oleate, sucrose fatty acid esters and medium chain fatty acids.

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.

Coolant

Oral film formulations of the present invention may also further comprise a cooling agent. The refreshing agent may be, for example, but is not limited to, l-menthol, WS3, WS23 or quat-t-el. The refreshing agent can be appropriately adjusted in accordance with the content, if necessary, and generally can be added to 10% by weight (w / w) or less relative to the total weight of the oral film formulation.

Deodorant

Oral film formulations of the present invention may further include a bad breath remover to reduce oral odors.

The bad breath remover may be a metal salt. The metal salt may be, for example, one or more components selected from the group consisting of metal salts of chlorite, capper gluconate, zinc chloride, zinc citrate and zinc gluconate. In another embodiment, the bad breath remover is triclosan, alexidine, hextidine, benzalkonium chloride, salicylicanilide, domiphen bromide, tetradecylpyridinium chromide, N-tetradecyl-4-ethylpyridinium chloride , Octenidine, iodine, sulfonamide, bisbiguanide, phenols, delmopinol, octapinol, chlorhexitin, nisin preparation, nystatin, sangguinrin, cetylpyridinium chloride, red ginseng extract, green tea Extracts, seaweed extracts, herbal extracts, grapefruit extracts, apple extracts, thyme, thymol, antibiotics, geraniol, carbachol, citral, hinokithiol, eucalyptol, catechol, methylsalicylate and hydrogen peroxide It may be one or more components selected from the group consisting of. Such at least one bad breath remover component may be used with the at least one metal salt or independently.

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 0.5 cm to 10 cm, preferably 1 cm to 7 cm, most preferably 1 cm to 5 cm.

The present invention also provides a method for preparing the oral film formulation. In one embodiment, the method for preparing the oral film formulation of the present invention

(1) preparing an oral film formulation composition comprising the active ingredient, two kinds of sweetener, and a water-soluble polymer;

(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) Crude liquid process: uniformly stir the active ingredients, alkalizing agent, surfactant, plasticizer, etc.

Thereafter, a sweetening agent, a flavoring agent, a water-soluble polymer, and a coloring agent are added thereto, followed by homogeneous stirring to prepare a crude liquid for oral film preparation. At this time, the final pH of the crude liquid is 4.38 to 5.25, and preferably magnesium oxide and / or sodium hydroxide can be used as the alkalizing agent. Moreover, as a solvent (solvent), propylene glycol, polygil 35 castor oil, polyethylene glycol 400, polyethylene glycol 300, trichlormonofluoromethane, sodium hydrogencarbonate, ethyl acetate, water for injection, refined soybean oil, purified water, isopropanol, Liquid paraffin, sodium chloride, ethanol, acetone, physiological saline solution, benzyl alcohol, myristic acid isopropyl, anhydrous ethanol, sterile purified water, N-methylpyrrolidone, narcglycerin, glycerin, methylene chloride, toluene At least one solvent selected from the group consisting of sterile purified water, water for injection, purified water, isopropanol, ethanol, methylene chloride and toluene, more preferably selected from sterile purified water, purified water, ethanol, methylene chloride and toluene One or more solvents may be selected, but are not limited thereto. 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%. At this time, the water content is suitably 30% 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.

By this method, in the present invention, sildenafil or a pharmaceutically acceptable salt thereof is contained as an active ingredient, and an alkalizing agent, magnesium oxide (MgO) and / or sodium hydroxide (NaOH), is 1.0 to 4.0% by weight, respectively. w / w), the pH of the crude liquid is maintained at 4.38 to 5.25, and aspartame and Tallin MD90 are contained in the range of 1.0% to 4.0%, respectively, as a sweetener to effectively form the film and effectively mask the unpleasant taste of the drug. In the meantime, it was possible to prepare an oral film formulation which can be dissolved and eaten in the oral cavity without water, thereby increasing the patient's dose compliance. 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 21

A pharmaceutical composition for oral film preparation was prepared as shown in Table 1 below, and the pH, gloss score, and film forming ability of the crude liquid were evaluated according to the following criteria.

* Gummy score: We calculated the average value of 10 men and women aged 25 to 40 years. (Value is rounded to two decimal places)

0: no bitter taste

1: tasteless

2: perceives bitterness

3: bitter taste

4: can feel bitter

5: strong bitterness

* Film forming ability

O: film production

△: Film can be manufactured but product deterioration

X: No film production

In evaluating the film forming ability, the main considerations when deciding that film production is impossible or degrading the commerciality are as follows.

-Crude liquid phase: mixed homogeneity, precipitation, precipitation, phase separation, appearance (discoloration, etc.), internal curing and surface curing, etc.

-Drying stage: overdrying, poor drying, phase separation, edge warping (curling), foaming, spotting, etc.

-Slitting & Cutting Step: Sticky (Adhesive to Each Other), Film Peeling (Peeling from PET), Shatter & Crack, Roughness, etc.

-Final product: strong irritation, disintegration delay, dissolution delay, cold smell or taste

As can be seen in Table 1 above, it was confirmed that the delicacy of sildenafil citrate was not concealed by the sweetener alone.

Examples 1 to 27

A pharmaceutical composition for oral film preparation was prepared as described in Table 2 below, and the pH, gloss score, and film forming ability of the crude liquid were evaluated.

As can be seen from Table 2 above, when using a single alkalizing agent to set the pH range to 4.41 or more (maximum pH 5.81), it was found that the high concealment effect was achieved. It was judged that it was difficult to comprise in the film preparation for manufacture.

Examples 28-40

A pharmaceutical composition for oral film preparation was prepared as described in Table 3 below, and the pH, glutamate score and film forming ability of the crude solution were evaluated.

From Table 3 above, when using a combination of magnesium oxide and sodium hydroxide as the alkalizing agent it can be seen that the film forming ability as well as the high hiding effect.

Example  41 to 44

A pharmaceutical composition for oral film preparation was prepared as shown in Table 4 below, and the pH, glutamate score and film forming ability of the crude liquid were evaluated.

From Table 4 above, when using a combination of sodium hydroxide and magnesium oxide as an alkalizing agent, and mixed with Tallinn MD90 and aspartame in a certain ratio, it was confirmed that the high hiding effect, film-forming ability and the feeling of taking extremely good.

By using the pharmaceutical composition of the present invention, various effective ingredients having a high taste can be composed of oral film preparations.

Claims (15)

Sildenafil or a pharmaceutically acceptable salt thereof as an active ingredient;
Sodium hydroxide and magnesium oxide; And
Pullulan; Starches including pregelatinized starch, gelatinized starch and oxidized starch; Methyl cellulose; Hydroxy propyl methylcellulose; And a film forming agent selected from hydroxy propyl cellulose, wherein the bitumen is concealed. The oral film formulation according to claim 1, wherein the pH of the film-forming crude liquid of the film formulation is in the range of 4.38 to 5.25. delete delete The oral film formulation according to claim 1, wherein the sodium hydroxide is used at 1.0 to 5.0 wt% (w / w) of the total weight of the film. According to claim 1, wherein the sodium hydroxide and magnesium oxide is contained in a ratio of 1: 4 to 4: 1, the total amount is an oral film formulation, characterized in that 2 to 8% of the total weight of the film. According to claim 1, wherein the active ingredient oral film formulation, characterized in that the sildenafil citrate. delete Sildenafil or a pharmaceutically acceptable salt thereof; And
Pullulan; Starches including pregelatinized starch, gelatinized starch and oxidized starch; Methyl cellulose; Hydroxy propyl methylcellulose; And a film forming agent selected from hydroxy propyl cellulose, the method for concealing bitumen by adding sodium hydroxide and magnesium oxide to a film forming crude liquid. delete delete 10. The method of claim 9, wherein the sodium hydroxide is used at 1.0-5.0 wt% (w / w) of the total weight of the film. The method of claim 9, wherein the sodium hydroxide and magnesium oxide is used in a weight ratio of 1: 4 to 4: 1. (a) sildenafil citrate;
Film formers selected from pullulan, starch including pregelatinized starch, gelatinized starch and starch oxide, methylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose;
Alkalizing agent; And
Homogeneously stirring the pharmaceutically acceptable excipient to provide a crude solution for oral film preparation preparation;
(b) molding the film by injecting the crude solution into a molding machine;
(c) aging the molded film; And
(d) slitting and cutting the aged film, and then filling the container or an aluminum wrapper to produce an oral film formulation comprising sildenafil citrate, wherein in step (a) Alkalizing agents are magnesium oxide and sodium hydroxide, characterized in that the pH of the crude liquid is 4.38 to 5.25. delete