KR20130123659A - Fast dissolving oral dosage form of sildenafil improved the property of matter and shielding a bitter taste - Google Patents

Abstract

The present invention relates to a sildenafil oral rapid-release film with improved physical properties and bitterness shielding effect, preferably in the oral flux film containing sildenafil for securing physical properties, 30 to 50wt% of hydroxypropylmethylcellulose relative to the total weight It provides a sildenafil oral rapid-release film comprising 1% to 5wt% of polyethylene oxide or polyvinyl alcohol. More preferably, the mixture of sucralose and acesulfame potassium in a ratio (w / w) of 1: 1 to 1: 2 for bitterness masking, further comprises 0.5 to 10 wt% of the total weight can do.
According to the present invention, (1) it is possible to obtain an advantageous effect that the cracking phenomenon of the oral dissolution film can also be prevented. (2) The disadvantages of citric acid sildenafil can be obtained by removing the bitter taste, improving the sensory properties, and further increasing the ease of taking. (3) Can improve dry mouth in elderly people.

Description

Fast dissolving oral dosage form of Sildenafil improved the property of matter and shielding a bitter taste}

1. The present invention is an improved invention of patent application No. 10-1074271 (file name of the invention: an oral quick-release film for concealing an unpleasant taste effectively) filed and filed by Chabio & Diotech Co., Ltd. of the present invention.

2. More specifically, in the sildenafil oral rapid-release film, various angles are determined to determine the optimum film composition to increase the organoleptic properties and ease of taking, improve the dryness of the elderly, and also prevent breakage of the film. The experiment was conducted several times in, and the technical content to be described below can be said to be a composition ratio in which the critical significance established in view of the above is recognized.

The medical definition of erectile dysfunction is 'repetitive and persistently lacking the ability to acquire or maintain a penile erection state that is essential for achieving satisfactory sexual activity'. In other words, erectile dysfunction is a type of male sexual dysfunction, a phenomenon in which male genitals are not erect or the erection is not continued, so sexual activity is not possible. Erectile dysfunction can be a cause of family discord by disturbing smooth sexual life and, in severe cases, can lead to lethargy in social life, requiring early and continuous treatment.

The causes of erectile dysfunction are largely divided into psychogenic causes and organic causes (reduction of blood flow in the cavernous body). In the case of the cause of disposition, there are commercially available methods of inserting a support into the penis and a drug injected into the urethra or self-injecting directly into the penis. However, the above-described drug injection method is disadvantageous because it requires an intubation or self-injection to the patient and is not widely used. Pfizer's commercially available sildenafil citrate tablet (trade name Viagra) is widely used as an oral erectile dysfunction treatment agent.

U.S. Patent 5,250,534 discloses a potent and selective inhibitor of cyclic guanosine 3 ', 5'-monophosphate phosphodiesterase (cGMP PDE), including sildenafil, and various cardiovascular such as angina, hypertension, heart failure and atherosclerosis. A series of pyrazolo [4,3-d] pyrimidin-7-ones having utility in various therapeutic fields, including the treatment of diseases.

In US Pat. No. 6,469,021, erectile dysfunction is reported by 2 to 7% of adult men under 50 years of age, and between 18 and 75% of men between 55 and 80 years of age. For example, in the United States alone, fewer than 10 million men are estimated to be erectile dysfunction patients, many of whom are believed to have organ problems rather than mental causes.

Sildenafil fast-acting film preparations suitable for oral administration can be easily disintegrated or dissolved in the oral cavity and can be taken without water. Therefore, patients suffering from erectile dysfunction have difficulty in taking tablets (Viagra), which are currently being developed. Can meet your special needs. Conventional tablets are not suitable for administration to all the elderly patients, and citric acid sildenafil, the main component of Viagra, has a very bitter taste. It includes adding acidifiers that promote saliva secretion in preparation for dry mouth. It also includes developing films containing high doses of the main component.

In the present invention, for the purpose of providing a sildenafil oral rapid-use film in sildenafil oral rapid-release film, which can increase the functionality and ease of taking, improve the dryness of the elderly, and also prevent the breakage of the film. do. In detail, an object of the present invention is to provide a sildenafil oral rapid-release film containing sucralose, acesulfame potassium or the like based on sildenafil.

The technical objects to be achieved by the present invention are not limited to the above-mentioned technical problems, and other technical subjects which are not mentioned can be clearly understood by those skilled in the art from the description of the present invention .

In the present invention, oral film for oral containing sildenafil to ensure physical properties, 30 to 50wt% of hydroxypropyl methylcellulose, polyethylene oxide or polyvinyl alcohol 1 to 5wt% relative to the total weight Provided is a sildenafil oral flux film.

Furthermore, sildenafil, characterized in that the mixture of sucralose and acesulfame potassium in a ratio (w / w) of 1: 1 to 1: 2 for the bitter taste masking, further comprises 0.5 to 10wt% of the total weight Provided is an oral rapid release film.

Preferably, the film is aspartame, saccharin salt, neotime, cyclate salt, taumate, Nahan fruit extract, sugar, glucose, maltose, oligosaccharide, dextrin, invert sugar, fructose, lactose, galactose, starch syrup, sorbitol, Maltitol, xylitol, erythritol, hydrogenated syrup, mannitol and trehalose may be characterized in that it further comprises 0.5 to 10 wt% of any one or more sweeteners selected from the group consisting of.

Preferably the film further comprises at least one acidulant selected from the group consisting of citric acid, malic acid, fumaric acid, tartaric acid, ascorbic acid, succinic acid, adipic acid and lactic acid, 0 to 5 wt% relative to the total weight You can do

Preferably the film is pullulan, gelatin, pectin, low viscosity pectin, hydroxypropyl methyl cellulose, low viscosity hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, polyvinyl alcohol, poly Acrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, whey protein isolate, soy protein isolate, zein, levan, elcinan, gluten , Acacia gum, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum and agar, any one or more water-soluble polymers selected from the group consisting of 20 to 70 wt% of the total weight can do.

Preferably the film is one or more plasticizers selected from the group consisting of glycerin, polyethylene glycol, propylene glycol, hydrogenated starch syrup, triacetin, glycerol oleate, sucrose fatty acid ester and medium chain fatty acid, 0.1 to 10 with respect to the total weight It may be characterized in that it further comprises wt%.

Preferably the film is one or more emulsifiers selected from the group consisting of glycerin fatty acid ester, sucrose fatty acid ester, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester and propylene glycol, 0.1 to 10 with respect to the total weight It may be characterized in that it further comprises wt%.

On the other hand, the critical significance of the numerical limitation of the present invention is further disclosed.

In this product, when the hydroxypropyl methyl cellulose is less than 30wt% of the total weight, the film is not formed, and when it is more than 50wt%, there is a problem that the thickness of the film becomes thick and the disintegration is slow, and 1wt% of polyethylene oxide or polyvinyl alcohol is used. When the percentage is less than the softness of the film falls, when it is more than 5wt% it appears that there is a problem to make a product too tough.

In addition, a mixture of sucralose and acesulfame potassium in a ratio of 1: 1 to 1: 2 (w / w) based on the total weight is less than 0.5wt%, and other physical properties such as excipients are felt as it is, and more than 10wt% In the case of too sweet, there was a problem that adversely affect the taste.

According to the sildenafil oral rapid-release film having improved physical properties and bitterness shielding effect of the present invention, the following advantageous effects are recognized.

First, it is possible to obtain an advantageous effect that can also prevent the cracking phenomenon of oral fast-dry film.

Secondly, the disadvantages of citric acid sildenafil can be obtained by removing the bitter taste, improving the sensory properties, and further increasing the ease of taking.

Third, the dry mouth of the elderly can be improved.

Figure 1 schematically shows a manufacturing process diagram of the present invention.
2 is a perspective view of a prototype of the present invention. The thickness is preferably 100 to 200 μm, and the width and length may be appropriately determined in consideration of dosage and ease of taking.
3 is a photograph of a prototype of the present invention.

The present invention relates to a fast-acting film formulation of sildenafil suitable for oral administration, which contains citric acid, promotes saliva secretion, induces rapid disintegration in the mouth, and effectively hides unpleasant tastes, thus reducing the ratio of sucralose to acesulfame potassium. Is contained in a ratio of 1: 1 to 1: 2 (w / w), effectively masking the unpleasant taste of the drug, and enhances the patient's dose compliance, that is, to quickly dissolve and eat in the mouth without water. It relates to a method of treating erectile dysfunction (impotence). The present inventors proceeded as follows to improve the disadvantages of citric acid sildenafil, such as bitterness and ease of taking, and to include a high dose of the main ingredient.

To develop into an oral fast-acting film formulation, it must be dissolved in the mouth. Sildenafil citrate has a very bitter taste. Therefore, even if high sweetener is administered 20% or more, the bitter taste does not disappear. To overcome this, the sildenafil base, which removes citric acid that represents bitter taste, slightly blocks bitter taste, and the ratio of sucralose to acesulfame potassium is 1: By adding 0.5 to 10% at a ratio of 1 to 1: 2 (1.16: 1.5), and using ziitol in combination with a refreshing and oral mint powder flavor and dental health, it was able to shield bitterness and unpleasant taste to the maximum. Acidic agents were administered to prepare for dry mouth in the elderly. In terms of physical properties, however, the sildenafil base has a low solubility, unlike sildenafil citrate, which makes it difficult to form a film and has difficulty in homogeneity.

Due to the high capacity and low solubility of sildenafil base, it is difficult to develop on fast-acting film formulations that mainly use water and ethanol. Due to the insoluble physical properties of the film breakage phenomenon occurs, if the moisture does not have more than 5% occurs when the water evaporates immediately occurs. In order to improve this property, 30-50% of hydroxypropylmethylcellulose was added based on the sildenafil base, and 1-5% of polyethylene oxide or polyvinyl alcohol was used to secure optimum properties as well as cracking at all. Develop a formulation free of symptoms.

The present invention relates to an oral cavity film composition having an active ingredient sildenafil base to improve the physical properties of the film, effectively masking unpleasant tastes and dissolving rapidly in the oral cavity.

Preferred fast-acting films according to the present invention comprise at least one agent selected from citric acid and the like in the acidifying agent which acts as a saliva stimulant, to improve the unpleasant taste, with pharmaceutical active agents, sucralose, acesulfame potassium, One or more sweeteners, film formers and one or more of the following additional ingredients.

In order to improve the physical properties of the film, the properties of the film are optimized using polyethylene methyl cellulose and a small amount of polyethylene oxide. The additional components include thickeners, fillers, plasticizers, acidulants, flavors, emulsifiers, and surfactants. And pharmaceutically acceptable additives such as binders, preservatives, colorants, coolants, and the like. The components are described in detail as follows.

The fast-drying film of this invention contains the 1st sweetener which is a high sweetness sweetener. In an embodiment, the high sweetening sweetener (first sweetener) is at least one selected from the group consisting of aspartame, acesulfame salt, sucralose, saccharin salt, neotime, cyclate salt, taumatin, nagwa extract, licorice extract It can be a high sweetness sweetener. More preferably, it may be one or more high sweetening sweeteners selected from sucralose, acesulfame salts.

The sweetener (second sweetener) is selected from the group consisting of sugar, glucose, maltose, oligosaccharide, dextrin, invert sugar, fructose, lactose, galactose, starch syrup, sorbitol, maltitol, xylitol, erythritol, hydrolyzed starch, mannitol, and trehalose It may be one or more components. More preferably, it may be at least one sweetener selected from xylitol, sorbitol, erythritol. The sweetener may be added to 0.5 to 10% by weight (w / w) relative to the total weight of the film composition for the flux.

The oral rapid release film of the present invention may also further comprise an acidulant. The acidulant, together with the sweetener, controls the taste and may play a role in stimulating the generation of saliva so that the edible film can be dissolved well. The acidulant may be added in an amount of 0 to 5 wt% (w / w) based on the total weight of the rapid film 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.

In the case of drugs with a strong unpleasant taste, especially sweet and unpleasant tastes are strongly felt in the aftertaste, using 0.5 to 10% by weight (w / w) of sucralose and acesulfame potassium relative to the total weight, and using the flavor of xylitol and mint powder The addition can mask the taste and unpleasant taste.

Oral rapid-release film of the present invention contains a water-soluble polymer.

The water-soluble polymer is pullulan, gelatin, pectin, low viscosity pectin, hydroxypropyl methyl cellulose, low viscosity hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, polyvinyl alcohol, polyacrylic acid, Methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, whey protein isolate, soy protein isolate, zein, levan, elcinane, gluten, acacia At least one water-soluble polymer selected from the group consisting of gums, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum and agar. Preferably, the water-soluble polymer may be at least one water-soluble polymer selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol and modified starch.

The water-soluble polymer is 20 to 70% by weight (w / w), preferably 30 to 60% by weight (w / w), more preferably 30 to 50% by weight (w / w), based on the total weight of the fastening film It may contain.

The plasticizer can be used to adjust the flexibility of the film. The plasticizer may be added in an amount of 0.1 to 10 wt% (w / w) based on the total weight of the flux film.

In one embodiment, the plasticizer may be at least one component selected from the group consisting of glycerin, polyethylene glycol, propylene glycol, hydrogenated syrup, syrup, triacetin, glycerol oleate, sucrose fatty acid ester, and medium chain fatty acid.

The oral rapid release film of the present invention may also contain a fragrance. Since the rapid-release film of the present invention is a product that is dissolved and absorbed in the oral cavity, it is necessary to add an appropriate scent. The flavor may be natural flavors, artificial flavors or mixtures thereof.

Natural flavors may be extracts from the leaves, flowers, fruits and the like of plants, oils of plants and the like. Plant oils include spearmint oil, cinnamon oil, peppermint oil, lemon oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil and sage ( sage) oil, almond oil, and the like. In addition, artificial flavors of fruits, such as lemon, orange, grape, lime, strawberry and artificial synthetic flavors such as vanilla, chocolate, coffee, cocoa, pine needles, ginseng, red ginseng, citrus may be used as artificial flavors.

The amount of fragrance used depends on a number of factors such as the type, type, and desired strength of the fragrance that is commonly used, and may generally comprise 0.1 to 5 wt% (w / w) based on the total weight of the flux film.

Perfume in oil form may be used together with an emulsifier to make it compatible with water-soluble substances. The amount of the emulsifier may be adjusted according to the type and amount of the fragrance, and in general, 0.1 to 5% by weight (w / w) based on the total weight of the film for the flux.

In one embodiment, the emulsifier may be at least one component selected from the group consisting of glycerin fatty acid ester, sucrose fatty acid ester, lecithin, enzyme treated lecithin, polysorbate, sorbitan fatty acid ester and propylene glycol.

In addition, the oral film for oral use of the present invention may contain a pigment suitable for the product. The pigment may be appropriately adjusted in its content as necessary, and in general, 0.0 to 2% by weight (w / w) relative to the total weight of the edible film may be added. The pigment may be a natural or synthetic pigment.

The present invention also provides a flux film comprising the oral flux film composition.

The oral rapid-release film of the present invention will preferably form a thin film that maintains an appropriate range of tensile strength and toughness in a very thin film state. As one embodiment, the thickness of the rapid-release film of this invention is 50 micrometers-300 micrometers, Preferably it is 100 micrometers-200 micrometers.

The present invention also provides a method for producing the oral flux film.

In one embodiment, the method for producing a rapid-release film of the present invention

(1) preparing a fast-acting film composition comprising an active ingredient, two kinds of high sweetener, an acidulant, and a water-soluble polymer; (2) putting the edible film composition into a molding machine to mold the film at 50 to 120 ° C; (3) may comprise aging the molded film for 1 to 7 days at room temperature.

The method for producing an edible film according to the present invention can be carried out through, for example, the following process.

(1) crude liquid process

a) 1st solution manufacturing process: Add additives, such as a pigment, a sweetener, an acidulant, a filler, and a refreshing agent.

b) Second solution preparation process: The active ingredient is mixed.

c) 3rd solution manufacturing process: It is prepared by mixing water-soluble polymer after administration of ethanol.

(2) forming process

The third solution is filtered and then introduced into a molding machine to form a film. At this time, the temperature of the molding machine is 50 to 120 ℃ and manufactured in roll form through a belt drum dryer.

(3) Aging process

The molded film contains moisture suitable for slitting or cutting through a aging process of about 1 to 7 days at room temperature (1 ~ 30 ℃). At this time, the moisture content is appropriate within 3%. The following process may be further performed as a subsequent process of the manufacturing method.

(4) cutting process

The aged rolls are slits into small rolls, cut into appropriate sizes and filled into small containers or aluminum wrappers.

(5) Packing process

Filled small containers or aluminum bags are repackaged in small boxes or blistered into products.

Sildenafil fast-acting film formulations prepared by the method of the present invention are rapidly disintegrated and dissolved by saliva in the mouth without additional water, so that tablets can be easily administered to the elderly or patients who have difficulty in swallowing, and patients with erectile dysfunction It can also be usefully administered.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

[Examples 1 to 6]

In the manufacturing process described above, the active ingredient sildenafil base is prepared as follows. Table 1 is summarized in Examples 1 to 6. On the other hand, the following experiment was performed to make a film characterized by the composition ratio below 22mm in length, 37mm in length, about 150㎛ thick.

ingredient Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 wt% wt% wt% wt% wt% wt% Polyethylene glycol 2.00 2.00 2.00 1.00 1.00 1.00 glycerin 1.00 1.00 1.50 2.00 2.00 1.00 Twin-80 1.00 2.50 1.00 1.00 1.00 1.00 Citric acid 0.25 - - 0.5 - - Tartaric acid - 0.25 - - 0.5 - Malic acid - - 0.25 - - 0.50 Polyvinyl alcohol 2.00 1.00 1.00 - - 2.00 Polyethylene oxide - - - 5.00 4.00 3.00 Sorbitol 0.75 1.00 1.00 - - 1.00 Sucralose 0.80 1.00 1.10 1.00 0.80 0.60 Acesulfame Potassium 1.00 1.10 1.50 1.10 1.00 0.75 Xylitol 1.00 0.60 0.70 1.00 1.00 1.00 Mint Powder Flavor 1.00 1.00 1.00 - - - Red ginseng - - - 0.50 0.50 1.00 Blue No. 2 0.01 0.02 0.02 0.01 0.01 0.01 Hydroxypropylmethylcellulose-L 38.59 37.53 38.33 35.89 35.19 32.14 Hydroxypropylmethylcellulose -H 0.60 1.00 0.60 1.00 3.0 5.0 Sildenafil base (sildenafil) 50.00 50.00 50.00 50.00 50.00 50.00 system 100.00 100.00 100.00 100.00 100.00 100.00 Thickness (㎛) 151 159 141 177 169 160

[Comparative Examples 1 to 4]

The active ingredient and the polymer are changed by the manufacturing process described above to prepare as follows. Table 2 below is summarized into Comparative Examples 1 to 4.

ingredient Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 wt% wt% wt% wt% Acesulfame Potassium 0.52 0.50 1.00 Sucralose 0.72 0.50 1.00 1.00 Sorbitol 1.03 1.00 1.00 1.00 Rebaudioside A 1.03 - - - Polyethylene Glycol 400 1.03 1.00 - - Tween 80 1.03 1.00 1.00 0.90 glycerin - 1.00 1.00 1.50 Polyvinyl alcohol - 5.00 5.00 4.50 Hydroxypropyl cellulose - 40.00 30.00 - Hydroxypropylmethylcellulose - - - 51.1 Pullulan 68.85 - 20.00 - Sildenafil Base 25.79 50.00 - - Citric Acid Sildenafil - - 40.00 40.00 system 100.00 100.00 100.00 100.00 Thickness (㎛) 223 135 185 192

[3] Experimental Example  1 (Sensory test)

Examples 1 to 6 and Comparative Examples 1 to 4 prepared as described above, well-trained sensory test personnel (12 males in their 30s to 50s), ease of taking, convenience of possession, unpleasant taste and overall sensory acceptability It evaluated and shown in the following [Table 3].

Furthermore, the experiment was performed by including Viagra tablet (Lot No. 111483371) in the sensory test as a comparative treaty.

As a result of the experiment, Example 1 using a sildenafil base and using an acidulant and a sweetener was confirmed to be excellent. In addition, Examples 1 to 6 showed a score of 1 point. Table 3 below shows the contents of Examples 1 to 6 and Comparative Examples 1 to 4 to summarize the convenience of taking.

Convenience to take * Convenience in possession ** Unpleasant taste *** Overall sensory preferences **** Example 1 67% 75% 0% 1.081 Example 2 0% 1.25 Example 3 0% 1.17 Example 4 0% 1.67 Example 5 0% 1.50 Example 6 0% 1.58 Comparative Example 1 0% 2.50 Comparative Example 2 0% 2.33 Comparative Example 3 35% 4.33 Comparative Example 4 57% 4.25 Treaty 33% 25% 8% 2.16 system 100% 100% 100% -

* Convenience: 67% of the respondents answered that the cases of Examples 1 to 6 and Comparative Examples 1 to 4 were excellent. It is thought that such a result came out because the formulation of an Example and a comparative example is the same.

** Convenient to carry: 75% of the respondents answered that the cases of Examples 1 to 6 and Comparative Examples 1 to 4 were excellent. It is thought that such a result came out because the formulation of an Example and a comparative example is the same.

*** Unpleasant taste: 35% of respondents answered that they had Comparative Example 3, 57% of respondents had Comparative Example 4, and 8% of respondents had the most unpleasant taste.

***** Overall sensory acceptability (the smaller the value on the 5-point scale method, the better the overall sensory acceptability): The result of calculating the average of respondents, Example 1 was the most sensory, and Example 3 was the next. Appeared. On the other hand, Comparative Example 3 showed the worst result, but rather worse than the reference drug.

[4] Experimental Example  2 (physical property verification experiment)

1 of 4 The tensile strength  Experiment

As described above, the samples of Examples 1 to 6 and Comparative Examples 1 to 4 were made to have the same width of 22 mm and length of 37 mm, and the experiment was performed using a tensile strength tester (TEST ONE, TO-101G). Table 4 below summarizes the tensile strength test results of Examples 1 to 6 and Comparative Examples 1 to 4.

standard Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 0.3 kgf / mm ²
More than 0.56 0.52 0.50 0.48 0.43 0.51 Not measurable Not measurable Not measurable 0.37

All of the examples prepared by adding hydroxypropylmethylcellulose and polyethylene oxide or polyvinyl alcohol were excellent results of 0.40 kgf / mm ² or more, but Comparative Examples 1 to 3 were broken as soon as the film was made to increase tensile strength. It could not be measured.

In particular, Example 1 was found to be the best. Considering that Example 1 was also excellent sensory as described above, it would be encouraging.

[4, 2] stability experiment

Samples 1 to 6 and Comparative Examples 1 to 4 were made to be the same as described above with 22mm in width, 37mm in length and about 150µm in thickness, and then packaged in the same aluminum pouch (Al-pouch), and then used for sildenafil. The stability of the film was tested (see FIG. 3). Specifically, dissolution, content, and moisture tests were conducted under harsh conditions (60 ° C. 75% RH) and accelerated conditions (40 ° C. 75% RH).

2 (a)] Dissolution Experiment

Among the general test methods of the Korean Pharmacopoeia, the eluting method was eluted with the following method (37 ± 5 ℃, 50rpm, 0.01M hydrochloric acid 900ml), and 5ml of the eluate filtrate was precisely taken. The absorbance of the sample solution and the standard solution was measured and the dissolution rate was calculated according to the absorbance method. Comparisons were made at 1, 2 and 4 weeks for harsh conditions and 1 month for accelerated conditions. For elution, Agilent's 708-DS and VK8000 were used, and the absorbance measurement device was used for Biobra's Libra S70. Thus, the dissolution rate change graph of Example 1 was obtained as follows. As a representative, when confirming the dissolution test results of Example 1, it can be confirmed that dissolution rate is hardly changed under severe 4 weeks and accelerated 1 month conditions.

[2 (b)] content experiment of [4

Examples 1 to 6 and Comparative Examples 1 to 4 were placed in a 250 mL volumetric flask, and acetonitrile and water (5: 5, v / v) were mixed. 5 ml of this solution was added to 0.05 M triethylamine phosphate (pH 3.0). ) Methanol Acetonitrile = 580: 250: 170 (v / v / v), exactly 50ml of the sample solution is used as the sample solution and the liquid chromatograph method (Agilent, 1200 series) as shown below. The analysis was carried out under the conditions.

Column: reversed-phase C18 column 15cm × 3.9mm, 5㎛, or equivalent

-Column temperature: 30 ℃

Mobile phase: 0.05M triethyl phosphate (pH 3.0), methanol, acetonitrile = 580: 250: 170 (v / v / v)

Detector: 290 nm

-Flow rate: 1.0ml / min

Table 5 below summarizes the results of the content stability test of 1 to 4 in comparison with Examples 1 to 6. As shown in Table 5 below, when the content test was compared with the initial and severe 4 weeks and 1 month acceleration data, it was confirmed that there was no difference at all.

Content standard Initial Harsh one week 2 weeks harsh Severe 4 weeks 1 month acceleration 95.0-105.0 * Example 1 99.7 99.7 100.3 100.1 101.0 Example 2 99.6 97.6 98.5 99.0 98.6 Example 3 99.2 101.6 98.3 102.0 102.0 Example 4 100.8 99.0 101.5 102.3 97.6 Example 5 101.9 98.7 98.5 99.4 99.1 Example 6 99.9 103.2 100.7 102.7 101.8 Comparative Example 1 101.4 99.5 100.6 99.0 98.4 Comparative Example 2 100.6 98.3 99.5 97.7 101.9 Comparative Example 3 103.1 99.5 99.1 100.9 99.3 Comparative Example 4 100.9 98.1 102.5 101.3 101.4

* When the measurement result belongs to 95.0-105.0, it means that there is no problem and there was no problem in content stability in Examples 1-6 and a comparison in 1-4.

[4 (2 (c)] Moisture Experiment and The tensile strength  Experiment

Take one film (about 100mg) and analyze it according to the KEPCO moisture test method (Kar Fischer method). Dissolve the film using methanol: formamide = 3: 1 (V / V) solution instead of methanol. Moisture tester was Metrohm, 870KF Titrino plus. In addition, the tensile strength test was carried out using a tensile strength tester (TEST ONE, TO-101G) after cutting the sample to 22mm width.

Table 6 summarizes the results of the moisture stability test of Examples 1 to 6 and Comparative Examples 1 to 4, and Table 7 summarizes the results of the tensile strength tests of Examples 1 to 6 and Comparative Examples 1 to 4. It is one content.

As shown in Table 6 below, the results of the moisture stability test showed that Examples 1 to 6 maintained a stable water content of 2% or less, and as shown in Table 7, the tensile strength was also relatively stable. It was confirmed.

standard Initial Harsh one week 2 weeks harsh Severe 4 weeks 1 month acceleration 5.0wt% or less Example 1 1.1 0.9 1.1 1.1 1.1 Example 2 1.5 1.6 1.8 1.8 1.6 Example 3 1.3 1.1 1.2 1.6 1.5 Example 4 1.2 1.3 1.3 1.6 1.5 Example 5 1.3 1.3 1.4 1.6 1.5 Example 6 1.4 1.3 1.5 1.8 1.4 Comparative Example 1 7.5 7.1 6.8 7.3 7.0 Comparative Example 2 4.2 4.5 4.3 5.0 4.7 Comparative Example 3 3.6 3.4 3.7 3.8 3.6 Comparative Example 4 2.8 3.5 3.1 3.0 3.0

standard Initial Harsh one week 2 weeks harsh Severe 4 weeks 1 month acceleration 0.3 kg / mm ² More than Example 1 0.56 0.55 0.53 0.52 0.54 Example 2 0.52 0.48 0.46 0.43 0.45 Example 3 0.50 0.47 0.46 0.43 0.47 Example 4 0.48 0.45 0.39 0.40 0.41 Example 5 0.43 0.41 0.37 0.38 0.43 Example 6 0.51 0.48 0.47 0.47 0.49 Comparative Example 4 0.37 0.36 0.34 0.29 0.33

Although the present invention has been described in connection with the specific embodiments of the present invention, it is to be understood that the present invention is not limited thereto. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. In addition, the materials of each component described herein can be readily selected and substituted for various materials known to those skilled in the art. Those skilled in the art will also appreciate that some of the components described herein can be omitted without degrading performance or adding components to improve performance. In addition, those skilled in the art may change the order of the method steps described herein depending on the process environment or equipment. Therefore, the scope of the present invention should be determined by the appended claims and equivalents thereof, not by the embodiments described.

Claims (7)

Oral rapid-release film containing sildenafil, Sildenafil oral flux for oral, characterized in that it comprises hydroxypropyl methylcellulose 30 ~ 50wt%, polyethylene oxide or polyvinyl alcohol 1 ~ 5wt% relative to the total weight.
The method according to claim 1, wherein the film is a mixture of sucralose and acesulfame potassium 1: 1 to 1: 2 (w / w), sildenafil characterized in that it further comprises 0.5 to 10wt% relative to the total weight Oral Rapid Film.
The method of claim 1, wherein the film is aspartame, saccharin salt, neotime, cyclate salt, taumate, Nahan fruit extract, sugar, glucose, maltose, oligosaccharide, dextrin, invert sugar, fructose, lactose, galactose, starch syrup Sildenafil oral rapid-use film, characterized in that it comprises at least one sweetener selected from the group consisting of sorbitol, maltitol, xylitol, erythritol, hydrogenated syrup, mannitol and trehalose, 0.5 to 10 wt% relative to the total weight.
According to claim 1, wherein the film is citric acid, malic acid, fumaric acid, tartaric acid, ascorbic acid, succinic acid, adipic acid and lactic acid any one or more selected from the group consisting of lactic acid, 0.1 to 10 wt% further comprises a total weight Sildenafil oral flux film for use.
The method of claim 1, wherein the film is pullulan, gelatin, pectin, low viscosity pectin, hydroxypropyl methyl cellulose, low viscosity hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, polyvinyl Alcohol, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, whey protein isolate, soy protein isolate, zein, levan, elci Egg, gluten, acacia gum, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum and agar, any one or more water-soluble polymer selected from the group comprising 20 to 70 wt% more Sildenafil oral flux film for use.
According to claim 1, wherein the film is glycerin, polyethylene glycol, propylene glycol, hydrogenated starch syrup, starch syrup, glycerin, triacetin, glycerol oleate, sucrose fatty acid ester and any one or more plasticizers selected from the group consisting of medium chain fatty acids, Sildenafil oral rapid-use film, characterized in that it further comprises 0.1 to 10 wt% by weight.
According to claim 1, wherein the film is selected from the group consisting of glycerin fatty acid ester, sucrose fatty acid ester, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester and propylene glycol, 0.1 to 10 wt. Sildenafil oral flux film for further comprising a%.

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