KR20160039050A - Oral disintegrating film composition containing entecavir - Google Patents

Abstract

The present invention relates to a mono-layered or multi-layered oral disintegrating film formation containing entecavir which is a component of a hepatitis B medicine. Disclosed is the mono-layered or multi-layered oral disintegrating film formation containing entecavir, which is taken without water.

Description

≪ Desc / Clms Page number 2 > Oral disintegrating film composition containing entecavir &

The present invention relates to an enteric-coated, oral disintegrating film formulation.

Entecavir is an antiviral agent used as a hepatitis B treatment. Entecavir is administered in a dose of 0.5 mg to 1.0 mg per day, and is commercially available in the form of tablets and syrups for these unit doses. However, there is an inconvenience that it is necessary to take the tablet together with an appropriate amount of water in order to take the drug while taking it every day, and in case of syrup, it is inconvenient to take a constant dose (10 ml once) while taking it daily. In addition, these formulations can feel discomfort in the throat or esophagus when swallowing the drug, and it is very difficult for the elderly patient or pediatric patient to take the drug when the dose is high. Particularly, since the hepatitis B therapeutic agent should be taken every day, it should always be carried and should be taken at the time of fasting. Therefore, the administration of the therapeutic agent may restrict the administration by the specific time and place depending on availability of the drinking water .

In the treatment of hepatitis B, the therapeutic agent has the risk of causing liver fibrosis, liver cirrhosis, liver cancer, and ultimately death if it is not taken steadily. In order to treat hepatitis B, Together they require 5-7 years of long-term treatment. Thus, the hepatitis B therapeutic agent is preferably a film formulation that contains a therapeutically effective amount of the hepatitis B therapeutic component, and which can be rapidly disintegrated in the mouth for convenient administration without the use of drinking water. Particularly, in patients who need to take drugs for a long period of time, the hepatitis B therapeutic agent is preferably a film formulation that can increase the compliance of the patient to take medication.

Conventionally, the technology relating to film formulation is disclosed in Korean Patent Application No. 2011-0075179, but there is no example in which a drug for hepatitis B treatment is contained and the formulation is a disintegrating film.

It is an object of the present invention to provide a film preparation containing entecavir, which is a hepatitis B therapeutic drug component, in the composition, and also to dissolve rapidly in the oral cavity.

The entecavir-containing oral disintegration film formulation according to the present invention is characterized by an entecavir-containing film formulation containing entecavir as an active ingredient. At this time, the entecavir-containing oral disintegration film formulation may be formed into a single-layer structure or a multi-layer structure.

In addition, the entecavir-containing oral disintegration film formulation may contain 0.001-30 wt% entecavir, more preferably 0.1-12 wt% entecavir based on 100 wt% of the total weight.

In addition, the entecavir-containing film formulation may include at least two components selected from a film forming agent, a plasticizer, a sweetener, a flavor, a taste-masking agent, a salivating stimulant, a surfactant, a pigment and an antioxidant.

The film forming agent may be at least one selected from the group consisting of pullulan, starch, modified starch (gelatinized starch), gelatin, pectin, sodium alginate, maltodextrin, polymerized rosin, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethyl Cellulose, methylcellulose, crystalline cellulose, sodium carboxymethylcellulose, colicote, eudragit, polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, hypalonic acid, hypalonic acid derivatives, chitosan, chitosan derivatives, And at least one substance selected from the group consisting of angiotensin and henan, and may be included in an amount of 20 to 80% by weight based on the total weight of the enteric-coated oral disintegration film formulation.

Wherein the plasticizer comprises at least one material selected from the group consisting of acetyl triethyl citrate, polyethylene glycol, propylene glycol, glycerin, citrate ester, triacetin and triethyl citrate, wherein the entecavir-containing oral disintegration film formulation May be contained in an amount of 0.1 to 50% by weight based on the total weight.

The sweetener may be selected from the group consisting of maltitol, isomaltooligosaccharide, sorbitol, xylitol, polyol, mannitol, sucrose, dextrose, fructose, alitame, neotame, saccharine and its salts, aspartame, glycyrrhizin, stevitene, Sodium saccharide and cyclamate, and may be included in an amount of 0.5 to 20% by weight based on the total weight of the entecavir-containing oral disintegration film formulation.

The flavor or taste-masking agent may be selected from the group consisting of natural flavors (guarana, orange, lemon, peppermint, cinnamon, menthol, peppermint oil, wintergreen mint, clove, butter scotch, maple, apricot, peach, cherry, anise, strawberry, vanillin, At least one substance selected from the group consisting of citrus flavor, licorice flavor, root beer flavor, gardenias, raspberry flavor, walnut flavor, chocolate flavor and the like) and synthetic perfume, and the whole of the entecavir-containing oral disintegrating film formulation And may be contained in an amount of 0.01 to 20% by weight based on the weight.

Wherein the saliva stimulating agent comprises at least one substance selected from the group consisting of citric acid, citric acid salt, lactic acid, malic acid, ascorbic acid, tartaric acid, and tartaric acid, To 15% by weight.

Wherein the surfactant comprises at least one material selected from the group consisting of poloxamer, sodium lauryl sulfate, benzethonium chloride, polyoxyethylene fatty acid esters, polysorbates, and sorbitan esters, wherein the entecavir-containing oral disintegration film May be included in an amount of 0.1 to 5% by weight based on the total weight of the formulation.

The pigment includes at least one substance selected from the group consisting of natural dyes and synthetic dyes, and may be included in an amount of 0.001 to 5% by weight based on the total weight of the entecavir-containing oral disintegration film formulation.

Wherein the antioxidant comprises at least one substance selected from the group consisting of sodium bisulfite, methylparaben, propylparaben, sodium benzoate, benzalkonium chloride and benzethonium chloride, the total weight of the entecavir-containing oral disintegration film formulation By weight based on the total weight of the composition.

The enteric-coated oral disintegrating film formulation according to the present invention is formed into an oral disintegrating film formulation containing a daily dose of entecavir, which is a drug component of the hepatitis B therapeutic agent, and is easy to carry and take.

In addition, the enteric-coated oral disintegrating film formulation according to the present invention is rapidly dissolved in the oral cavity with only water in the oral cavity, so that it can be conveniently taken anytime and anywhere without drinking water.

In addition, the enteric-coated oral disintegrating film formulation according to the present invention has an improved flavor peculiar to a drug formulation and can be easily taken by a patient taking a hepatitis B therapeutic.

In addition, the inventive enteric-coated oral disintegrating film formulation according to the present invention has a groove, a protrusion or a hole formed on the surface thereof, so that the patient can rub the film formulation between the tongue and the mouth of the mouth and dissolve it quickly.

The inventors of the present invention have found that the use of a mixture solution containing an edible polymer as a film former to provide a film formulation containing a therapeutically effective amount of entecavir, rapidly dissolving in the oral cavity, .

Such entecavir-containing film formulations should have pharmacological effects, rapid film dissolution in the mouth and acceptable feel of use. Thus, the entecavir-

(1) contain a daily dose of 0.5 mg to 1.0 mg of the drug in the film formulation,

(2) the film formulation would disintegrate in the mouth between 5 and 60 seconds, and

(3) a film form of a functional and thickness (preferably 30 탆 to 1000 탆) easy to take in oral cavity as an edible film form.

In the entecavir-containing oral disintegrating film formulation, the film is referred to as an edible film, a strip, an orally dissolving film, orally disintegrating film, and the like, Oral mucosa, sublingual, and the like, which rapidly dissolves or disintegrates in the oral cavity. The film formulation according to the invention has the advantage that it can be taken without drinking water.

In addition, specific expressions herein have the following meanings. "Drug" means a pharmacologically active substance that provides a therapeutic effect. "Edible" is meant to be orally administrable and pharmaceutically acceptable.

The entecavir-containing oral disintegration film formulation of the present invention is formed to contain 0.001 to 30% by weight, more preferably 0.1 to 12% by weight, and more preferably 0.4 to 5% by weight of entecavir based on 100% by weight of the total . The entecavir may be determined in terms of the area and thickness of the film formulation and the weight percentage to be mixed according to the daily dose of the drug.

The entecavir-containing oral disintegrating film formulation of the present invention may be formulated with a film former together with a plasticizer, a sweetener, a flavoring agent, a taste-masking agent, a salivating stimulant, a surfactant, a pigment, and an antioxidant. More specifically, the entecavir-containing film preparation may be formed to include at least two components selected from plasticizers, sweeteners, flavors, taste-masking agents, acupressure stimulants, surfactants, pigments and antioxidants have. In addition, the entecavir-containing oral disintegration film formulation may be mixed with a small amount of solvent such as distilled water for smooth mixing of all ingredients to be mixed.

The film forming agent may be at least one selected from the group consisting of pullulan, starch, modified starch (such as pregelatinized starch), gelatin, pectin, sodium alginate, maltodextrin, polymerized rosin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, There may be mentioned cellulose derivatives such as ethylcellulose, methylcellulose, crystalline cellulose, sodium carboxymethylcellulose, colicote, eudragit, polyethylene oxide, polyvinylpyrrolidone, polyvinyl alcohol, hypalonic acid, hypalonic acid derivatives, chitosan, chitosan derivatives, Carrageenan, and the like. These polymers may be used alone or in combination of two or more. The polymer may be contained in an amount of 20 to 80% by weight based on 100% by weight of the entecavir-containing oral disintegration film formulation.

The plasticizer used to impart flexibility and elasticity to the film formulation may be selected from the group consisting of acetyl triethyl citrate, polyethylene glycol, propylene glycol, glycerin, citrate ester, triacetin and triethyl citrate . These plasticizers may be used alone or in combination of two or more. Of the above plasticizers, polyethylene glycol or glycerin is most preferably used because of the characteristics of the present invention. The plasticizer may be contained in an amount of 0.1 to 50% by weight based on 100% by weight of the entecavir-containing oral disintegration film formulation.

The sweetener may be selected from the group consisting of maltitol, isomaltooligosaccharide, sorbitol, xylitol, polyol, mannitol, sucrose, dextrose, fructose, alitame, neotame, saccharine and its salts, aspartame, glycyrrhizin, stevitene, ≪ / RTI > sodium saccharide, and cyclic acid. These sweeteners may be used alone or in combination of two or more. The sweetener may be contained in an amount of 0.1 to 50% by weight based on 100% by weight of the entecavir-containing oral disintegration film formulation.

Examples of the flavor or taste blocking agent include natural flavoring agents (such as guarana, orange, lemon, peppermint, cinnamon, menthol, peppermint oil, wintergreen mint, clove, butter scotch, maple, apricot, peach, cherry, anise, , Citrus flavor, licorice flavor, root beer flavor, gardenias, raspberry flavor, walnut flavor, chocolate flavor), and synthetic flavor. The flavor or the taste-masking agent may be used alone or in combination of two or more. The flavor or the taste-masking agent may be contained in an amount of 0.01 to 20% by weight based on 100% by weight of the enteric-coated oral disintegration film formulation.

The saliva stimulating agent may be selected from the group consisting of citric acid, citric acid, lactic acid, malic acid, ascorbic acid, tartaric acid and tartaric acid salts. These acupuncture stimulants may be used alone or in combination of two or more. The saliva stimulating agent may be contained in an amount of 1 to 15% by weight based on 100% by weight of the entecavir-containing oral disintegration film formulation.

The surfactant may be selected from the group consisting of poloxamer, sodium lauryl sulfate, benzethonium chloride, polyoxyethylene fatty acid esters, polysorbates, and sorbitan esters. These surfactants may be used alone or in combination of two or more. The surfactant may be contained in an amount of 0.1 to 5% by weight based on 100% by weight of the entecavir-containing oral disintegration film formulation.

The dye may be selected from the group consisting of natural dyes including titanium oxide, silicon dioxide, zinc oxide, and synthetic dyes. These dyes may be used alone, or two or more dyes may be used in combination. The pigment may be contained in an amount of 0.001 to 5% by weight based on 100% by weight of the entecavir-containing oral disintegration film formulation.

The antioxidant may be selected from the group consisting of sodium hydrogen sulfite, methyl paraben, propyl paraben, sodium benzoate, benzalkonium chloride and benzethonium chloride. The antioxidant may be used alone or in combination of two or more. The antioxidant may be contained in an amount of 0.01 to 2% by weight based on 100% by weight of the entecavir-containing oral disintegration film formulation.

The entecavir-containing oral disintegration film formulation is formed into a film, and its thickness is not particularly limited, but is preferably 30 to 1000 占 퐉. If the thickness is less than 30 mu m, the strength of the film formulation is lowered and it is difficult to maintain the film shape. When the thickness exceeds 1000 mu m, it takes a long time to disintegrate in the oral cavity.

In addition, the form of the entecavir-containing oral disintegration film may be a rectangular shape, a square shape, a circular shape, an elliptical shape, but is not limited thereto. For example, the entecavir-containing oral disintegration film formulation may be formed in a square shape with rounded corners.

In addition, the entecavir-containing oral disintegration film formulation may have a concavo-convex shape such as a hole, a groove, or a projection on the surface of the film formulation. The irregular shape increases the frictional force between the surface of the film form and the upper surface of the tongue. Thus, a patient taking the entecavir-containing oral disintegrating film formulation may rub the surface of the film formulation between the tongue and the ceiling of the mouth to allow the entecavir-containing oral disintegrating film formulation to disintegrate more rapidly. In addition, the concavo-convex shape increases the contact area between the surface of the film formulation and the needles or moisture in the mouth so that the enteric-coated disintegrating film formulation breaks down more rapidly. The concavoconvex shape may be formed in a groove or a projection shape by press-fitting the surface of the film form, or may be formed into a hole shape by a means such as a needle.

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

Monolayer Film Formulation Example

The entecavir-containing oral disintegration film formulation of the present single-layer structure is a film formulation having a single-layer structure of the drug-containing layer alone.

Entecavir-containing oral disintegration film formulations of the single-layer structure of the present invention are prepared as follows.

In this film formulation, entecavir, which is a drug component, is completely dissolved in an agitator using purified water and ethanol as a solvent, and then added with a plasticizer, a sweetener, a taste-masking agent, a salivating stimulant, a surfactant, a pigment and an antioxidant, Dissolved or dispersed. The solution was then homogenized for 60 minutes using a homogenizer. Here, the polymer as the film former was added and homogenized again using the same homogenizer. Then, a flavoring agent was added thereto and mixed using a stirrer. Subsequently, the mixed solution was subjected to a cooling process at room temperature to remove the gas in the film preparation liquid under vacuum conditions at 40 to 50 DEG C, and then applied on the PP, PET, PE, and aluminum-PP films to a thickness of 30 to 1000 mu m . Subsequently, the film was dried at 80 to 105 ° C to prepare a film formulation containing entecavir.

The thickness of the film formulation, the disintegration time, the degree of bitter taste, and the like were evaluated by the following method.

(Test Example)

(1) Thickness measurement

In the present invention, the thickness of the film formulation was measured using a digital thickness meter (Mitutoyo, Japan) after drying of the film formulation, the measurement range was 0 to 10 mm, and the resolution of the measuring instrument was 0.01 mm. Thickness was measured by measuring four corners and five centers of the film formulation (4 x 4 cm 2), and in the following examples, film formulations within the range of 30 to 1000 μm were used in the same manner.

(2) Disintegration time measurement

In the present invention, in vitro The disintegration time on the film formulation was measured by stopping the time when the film formulation (2 x 2 cm 2) was put into 10 mL distilled water at 37 ° C and the disintegration time. The disintegration time was aimed at a usable 7 minutes so that the patient would not feel uncomfortable.

In order to measure the disintegration time in the oral cavity, the disintegration time required until the film (2 x 2 cm 2) disintegrated in the oral cavity of the subject (n = 6) was measured. Oral disintegration time was aimed at 5 to 60 seconds, which is commercially available so that the patient does not feel inconvenienced. In the measurement of the disintegration time, 7 minutes in distilled water was evaluated at a time similar to 60 seconds in the oral cavity.

(3) Bitter taste evaluation of film formulations

In the present invention, the degree of bitter taste improvement of the film formulations was evaluated by measuring film formulations (2 x 2) in the oral cavity of the subject (n = 6) after drying of the film formulations prepared by adjusting the blending ratio of the fragrance and the taste- Cm < 2 >) was disintegrated, and the degree of bitter taste was recorded and evaluated. For accurate evaluation of taste, subjects rinsed their mouths with drinking water before taking the film formulation.

The evaluation of the taste was evaluated as + very bitter taste, ++ slight bitter taste, +++ very bitter taste, ++++ no taste, or a shielded taste.

(4) Method of measuring physical properties of film formulations

The flexibility of the film formulation was measured with a Shimadzu universal testing machine (load cell 100N). Flexibility Measurement The size of the film formulation was 10 × 2.5 cm 2, and the film formulation was fixed with two clamps at a distance of 5 cm. The film formulation was pulled at a rate of 50 mm / min and repeated 3 times. Physical properties of film formulations such as tensile strength, elastic modulus, and elongation (%) were measured.

(Examples 1 to 8)

According to the above-mentioned method for producing a film formulation, entecavir-containing oral disintegrating film formulations were prepared with the ingredients and compositions shown in Table 1.

Ingredients Weight ratio (%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Entekavir 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Hipromelose 60 60 60 60 60 60 60 60 Hydroxypropyl
Cellulose 10 - - - _ _ _ _ Sodium carboxy
Methyl cellulose _ 10 _ - - _ _ _ Modified starch - _ 10 _ - - _ - gelatin _ - - 10 _ _ _ _ pectin _ _ - - 10 _ - _ Sodium alginate _ _ - - _ 10 _ _ Colicote _ _ _ _ _ _ 10 _ Polyvinyl alcohol _ _ _ _ _ _ _ 10 Maltitol 15 15 15 15 15 15 15 15 Sanbai Tartan 5 5 5 5 5 5 5 5 Polyethylene glycol 9 9 9 9 9 9 9 9 Sum 100 100 100 100 100 100 100 100 Disintegration time (minutes) 4 6 5 5.5 5.5 5.5 6 5 flavor ++ ++ ++ ++ ++ ++ ++ ++

Results: It was confirmed that in the oral disintegrating film formulation containing the drug component entecavir at a dose of 0.5 to 1.0 mg, the disintegration time varies depending on the kind of the film former. It was also confirmed that the film-forming agent and the plasticizer did not affect the taste.

(Examples 9 to 12)

According to the method for producing the film formulation, an enteric-bur-containing oral disintegrating film formulation was prepared with the ingredients and composition shown in Table 2.

In order to examine the effects of the film forming agent and the type of plasticizer on the disintegration time, entecavir-containing oral disintegrating film formulations were prepared as shown in Table 2 using the same method as in Examples 1 to 8 except for the same method.

Ingredients Weight ratio (%) Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Entekavir 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Hipromelose 60 60 60 60 60 60 60 60 Hydroxypropyl
Cellulose - - - - - 10 10 10 Hydroxyethyl
Cellulose 10 - - - - - - - Chitosan - 10 _ - - _ _ _ Xanthan gum - - 10 _ - - _ - Maltodextrin _ - - 10 _ _ _ _ Hyaluronic acid - - - - 10 Acetyltriethyl
Citrate _ _ - - - 9 - _ Triacetin _ _ - - - - 9 _ Triethyl
Citrate _ _ _ _ _ - - 9 Maltitol 15 15 15 15 15 15 15 15 Sanbai Tartan 5 5 5 5 5 5 5 5 Polyethylene glycol 9 9 9 9 9 - - - Sum 100 100 100 100 100 100 100 100 Disintegration time (minutes) 5 5.5 5.5 6 6 5.5 6 6 flavor ++ ++ ++ ++ ++ ++ ++ ++

Results: Film formulations were prepared by varying film formers and plasticizers in the same manner as described above. As a result, changes in disintegration time were observed. However, it was confirmed that only the film forming agent and plasticizer change did not change the taste.

(Examples 17 to 24)

According to the method of manufacturing the film formulation, an enteric-bur-containing oral disintegrating film formulation was prepared with the components and compositions shown in Table 3.

To examine the effect of the sweetener on the disintegration time in the film formulations, the entecavir-containing oral disintegrating film formulation was prepared as shown in Table 3, using the same method as in Examples 17 to 24, although the composition was different.

Ingredients Weight ratio (%) Example 17 Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Example 24 Entekavir 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Hipromelose 57 57 57 57 57 57 57 57 Hydroxypropyl
Cellulose 10 10 10 10 10 10 10 10 Isomalto
oligosaccharide 3 - - - - - - - Sorbitol - 3 _ - - _ _ _ Mannitol - - 3 _ - - _ - Sucrose _ - - 3 _ _ _ _ Dextrose - - - - 3 Fructose _ _ - - - 3 - _ Acesulfame Kay _ _ - - - - 3 _ saccharin _ _ _ _ _ - - 3 Maltitol 15 15 15 15 15 15 15 15 Sanbai Tartan 5 5 5 5 5 5 5 5 Polyethylene
Glycol 9 9 9 9 9 9 9 9 Sum 100 100 100 100 100 100 100 100 Disintegration time (minutes) 5.5 5.5 5 6 6 6.5 6 4 flavor + + + + + + + +

Results: There was only a slight difference in the disintegration time of the film formulation depending on the type of sweetener. When sorbitol and dextrose were used, disintegration time increased.

(Examples 25 to 29)

According to the production method of the film formulation, entecavir-containing oral disintegrating film formulations were prepared with the ingredients and compositions shown in Table 4.

To examine the effect of the surfactant on the disintegration time in the film formulations, the entecavir-containing oral disintegration film formulations were prepared as shown in Table 4, using the same method as in Examples 25 to 29 except that the compositions were different.

Ingredients Weight ratio (%) Example 25 Example 26 Example 27 Example 28 Example 29 Entekavir 1.0 1.0 1.0 1.0 1.0 Hipromelose 57 57 57 57 57 Hydroxypropyl
Cellulose 10 10 10 10 10 Pollock Sommer 3 - - - - Sodium Lauryl
Sulfate - 3 - - - Polyoxyethylene
ester _ - 3 - - Polysorbate - - - 3 - Sorbitan ester _ _ - - 3 Maltitol 15 15 15 15 15 Sanbai Tartan 5 5 5 5 5 Polyethylene glycol 9 9 9 9 9 Sum 100 100 100 100 100 Disintegration time (minutes) 5 3.5 4 4.5 5 flavor ++ ++ ++ ++ ++

(Examples 30 to 34)

With reference to the above examples, the composition of the film formulation is tested as shown in Table 5 so that the disintegration time can be shortened. The film formulation was prepared by adjusting the amount of the film forming agent to be used and the mixing ratio of the plasticizer, which is expected to greatly affect the disintegration speed.

Ingredients Weight ratio (%) Example 30 Example 31 Example 32 Example 33 Example 34 Entekavir 1.0 1.0 1.0 1.0 1.0 Hipromelose 57 62 55 53 53 Hydroxypropyl
Cellulose 10 5 10 10 5 Sodium Lauryl
Sulfate One One One One One saccharin One One One One One El-menthol 0.5 0.5 0.5 0.5 0.5 Citric acid 0.499 0.499 0.499 0.499 0.499 Maltitol 15 15 15 15 15 Sanbai Tartan 5 5 5 5 5 Polyethylene glycol 9 9 11 13 18 Pigment 0.001 0.001 0.001 0.001 0.001 Sum 100 100 100 100 100 Disintegration time (minutes) 4 5 4 3.5 3 flavor + + + + +

Result: The disintegration rate was shortened by appropriately adjusting the mixing ratio of the film forming agent and the plasticizer.

Multi-layered Film Formulation Example

(Examples 35 to 39)

The entecavir-containing oral disintegration film formulation of the present invention is formed of an A layer and a B layer, and the A layer is a layer having a relatively high elongation and a low hardness as compared to the B layer, and the B layer has a relatively low elongation And is formed into a layer having a high hardness.

The multi-layered entecavir-containing oral disintegration film formulation of the present invention is prepared as follows. A solution of a layer (A layer) having a relatively high elongation, that is, a solution of a layer (A layer) having a relatively low hardness and a layer having a relatively low elongation (B layer) And B-layer films, respectively. A multilayer film formulation can be prepared by incorporating a B layer film on one side of the A layer film. Further, in the film formulation of the multi-layer structure, the A film is located on the inner side of the film (A layer + B layer) so that the A layer is inwardly folded in half, . More specifically, the film formulation is formed such that when the B-layer film is comprised of at least two layers, the B-layer film is formed so as to lie on the outermost layer and the underlayer, and at least one A- So as not to be exposed to the upper portion or the lower portion. The multi-layered film formulation is such that the A-layer film and the B-layer film are each formed of at least one layer, and preferably the B-layer film is formed of at least two layers. At this time, the size (area) of the A-layer film and the B-layer film may be the same or different.

In addition, the entecavir-containing oral disintegration film formulation of the multilayer structure includes entecavir in both the A layer and the B layer. The entecavir may be contained in the same amount in each of the A layer and the B layer, and may be contained in a relatively large amount in any one layer. In addition, the entecavir may be formed only in one layer.

The single-layered film formulation is a single-layered structure. When air bubbles remain in the dried film formulation due to bubbles remaining in the preparation solution or due to moisture or solvent volatilized during drying after the application, or the like, the surface of the film formulation becomes rough, A case occurs. In this case, the problem of the inner layer can be solved by applying an outer layer which can cover both sides of the inner layer where bubbles or particles are generated. In order for the film to rapidly disintegrate or dissolve in the oral cavity, it is advantageous that the hardness of the film formulation is low, that is, the elongation rate of the film formulation is high. Conversely, it is convenient for the patient to have a high hardness for handling the film formulations easily. That is, a low elongation rate is convenient. Thus, the film formulation requires such an opposite physical property. Hardness or elongation can be controlled to a certain level even with a single-layer film formulation, but it is very limited. Therefore, in the present invention, it is possible to adjust the elongation and hardness of the film formulation by incorporating a film layer having a low hardness and a film having a high hardness so that the film can be easily handled and the disintegration of the oral cavity can be rapidly progressed. (It is judged that it is desirable to state that the multilayer structure is relatively good rather than describing the problem of the single layer structure because the previous embodiment is a single layer structure).

The thickness of the film formulation, the disintegration time, the degree of bitter taste, and the like were evaluated in the same manner as in the case of a single-layer film formulation by the following method.

Weight ratio (%) Example 35 Example 36 Example 37 Example 38 Example 39 A floor Entekavir 2.0 2.0 2.0 2.0 2.0 Hydroxypropyl cellulose 50 - - - - Hipromelose - 50 - - - Hydroxymethylcellulose - - 50 - - Polyvinylpyrrolidone - - - 50 - Polyvinyl alcohol - - - - 50 Maltitol 40 40 40 40 40 Sodium saccharin 8 8 8 8 8 Sum 100 100 100 100 100 Disintegration time (minutes) 2 4 5 7 7 Elongation (%) 150 105 110 200 180 flavor + + + + +

Results: Compared to the results of the disintegration time and elongation of the film formulations of the other film formers in the hydroxypropyl cellulose results when the entecavir content in the disintegration time and elongation of the film formulations was 2% of the total weight Showed favorable results. The taste was all the same. In the result, the film formulation of Example 35 using sodium saccharin exhibited excellent quality in terms of disintegration time, elongation, taste, and physical properties capable of mass production.

(Examples 40 to 44)

According to the production method of the film formulation, entecavir-containing film formulations were prepared with the components and compositions shown in Table 7.

In order to examine the effects of the above sweetener types on the physical properties of the film formulations, the compositions of the oral disintegrating film containing entecavir were prepared in the same manner as in Examples 40 to 44,

Weight ratio (%) Example 40 Example 41 Example 42 Example 43 Example 44 A floor Entekavir 2.0 2.0 2.0 2.0 2.0 Hydroxypropyl cellulose 50 - - - - Maltitol 40 40 40 40 40 Sorbitol 8 - - - - Mannitol - 8 - - - Dextrose - - 8 - - Acesulfame Kay - - - 8 - Sucralose - - - - 8 Sum 100 100 100 100 100 Disintegration time (minutes) 4 4 5 4 4 Elongation (%) 200 190 180 200 200 flavor ++ ++ ++ + +

Results: The results were obtained by changing the sweetener to different kinds and measuring the film formulation by the above method. As a result of comparison with Example 35, it was confirmed that the disintegration time, elongation rate, and taste of the film formulation were changed by the change of the sweetener.

(Examples 45 to 48)

According to the production method of the film formulation, entecavir-containing film formulations were prepared with the components and compositions of Table 8.

In order to examine the effect on the physical properties of the film formulations according to the types of the plasticizers, the formulation of enteric-coated disintegrating film containing entecavir was prepared as shown in Table 8, though the composition was different from those of Examples 45 to 48.

In order to improve the disintegration rate in the oral cavity and to improve the workability of mass production,

Weight ratio (%) Example 45 Example 46 Example 47 Example 48 A floor Entekavir 2.0 2.0 2.0 2.0 Hydroxypropyl cellulose 50 - - - Maltitol 38 38 38 38 Sodium saccharin 8 8 8 8 Acetyltriethyl citrate 2 - - - Triacetin - 2 - - Triethyl citrate - - 2 - Propylene glycol - - - 2 Sum 100 100 100 100 Disintegration time (minutes) 3 3.5 3 3 Elongation (%) 200 220 250 230 flavor ++ ++ ++ +

Results: The results were obtained by varying the type of plasticizer and making film formulations in the manner described above. As a result of comparison with Example 35 in which no plasticizer was used, it was confirmed that the disintegration time, elongation rate, and taste of the film formulation were changed by the change of the sweetener.

(Examples 49 to 53)

According to the production method of the film formulation, entecavir-containing film formulations were prepared with the components and compositions shown in Table 9.

In order to examine the effect on the physical properties of the film formulations according to the types of the plasticizers, the formulation of enteric-coated disintegrating film containing entecavir was prepared as shown in Table 9, though the composition was different from those of Examples 49 to 53.

In order to improve the disintegration rate in the oral cavity and to improve the workability of mass production,

Weight ratio (%) Example 49 Example 50 Example 51 Example 52 Example 53 Floor B Entekavir 1.0 1.0 1.0 1.0 1.0 Hipromelose 60.849 - - - - Hydroxypropyl cellulose - 60.849 - - - Polyvinylpyrrolidone - - 60.849 - - Polyvinyl alcohol - - - 60.849 - Starch - - - - 60.849 Maltitol 20 20 20 20 20 Polyethylene glycol 8 8 8 8 8 Titanium oxide 10 10 10 10 10 El-menthol 0.05 0.05 0.05 0.05 0.05 Polysorbate 0.05 0.05 0.05 0.05 0.05 Citric acid 0.05 0.05 0.05 0.05 0.05 Pigment 0.001 0.001 0.001 0.001 0.001 Sum 100 100 100 100 100 Disintegration time (minutes) 3 4 5 7 7 Elongation (%) 100 140 210 230 190 flavor + ++ ++ ++ ++

Results: The film formulations were prepared by changing the film formers for the B-layer films by the above-mentioned method. It was confirmed that the disintegration time, elongation rate, and taste of the film formulation change with the change of the film former. It was found that the result of Example 49 is superior to that of the B-layer film.

(Examples 54 to 57)

According to the production method of the film formulation, entecavir-containing film formulations were prepared with the ingredients and composition shown in Table 10.

To examine the effects of the plasticizer types on the physical properties of film formulations, an enteric-coated oral disintegrating film formulation was prepared as shown in Table 10 using the same method as in Examples 54 to 57 except that the composition was different.

In order to improve the disintegration rate in the oral cavity and to improve the workability of mass production,

Weight ratio (%) Example 54 Example 55 Example 56 Example 57 Floor B Entekavir 1.0 1.0 1.0 1.0 Hipromelose 60.849 60.849 60.849 60.849 Acetyltriethyl citrate 8 - - Triacetin - 8 - Triethyl citrate - - 8 Propylene glycol - - - 8 Maltitol 20 20 20 20 Titanium oxide 10 10 10 10 El-menthol 0.05 0.05 0.05 0.05 Polysorbate 0.05 0.05 0.05 0.05 Citric acid 0.05 0.05 0.05 0.05 Pigment 0.001 0.001 0.001 0.001 Sum 100 100 100 100 Disintegration time (minutes) 5 5 5 4 Elongation (%) 120 110 120 110 flavor ++ ++ ++ +

Results: The film formulations were prepared by varying the plasticizers for the B-layer films according to the type of the films. It was confirmed that the disintegration time, the elongation rate, and the taste result of the film formulation were partially changed according to the change of the plasticizer including Example 49 of the plasticizer polyethylene glycol.

(Examples 58 to 62)

According to the above-mentioned method of producing the film formulation, entecavir-containing oral disintegrating film formulations were prepared with the ingredients and composition shown in Table 11.

To examine the effects of the above sweetener types on the physical properties of the film formulation, the enteric-coated disintegrating film formulation was prepared as shown in Table 11 using the same method as in Examples 58 to 62 except that the composition was different.

In order to improve the disintegration rate in the oral cavity and to improve the workability of mass production,

Weight ratio (%) Example 58 Example 59 Example 60 Example 61 Example 62 Floor B Entekavir 1.0 1.0 1.0 1.0 1.0 Hipromelose 60.849 60.849 60.849 60.849 60.849 Polyethylene glycol 8 8 8 8 8 Sorbitol 20 - - - - Mannitol - 20 - - - Dextrose - - 20 - - Acesulfame Kay - - - 20 - Sucralose - - - - 20 Titanium oxide 10 10 10 10 10 El-menthol 0.05 0.05 0.05 0.05 0.05 Polysorbate 0.05 0.05 0.05 0.05 0.05 Citric acid 0.05 0.05 0.05 0.05 0.05 Pigment 0.001 0.001 0.001 0.001 0.001 Sum 100 100 100 100 100 Disintegration time (minutes) 5 5 5 4 4 Elongation (%) 110 110 120 110 110 flavor ++ ++ ++ + +

Results: Film formulations were prepared in the same manner as above by varying the sweeteners for the B-layer films. It was confirmed that the disintegration time, elongation rate, and taste of the film formulation change with the change of the sweetener, including Example 49 using the sweetener maltitol.

(Examples 63 to 65)

According to the preparation method of the film formulation, entecavir-containing oral decomposing film formulations were prepared with the ingredients and compositions shown in Table 12.

In order to examine the influence of the film-forming agent and the plasticizer on the physical properties of the laminate film in the composition of the A-layer film and the B-layer film in the B-layer composition, the same method as that of Examples 63 to 65 was used To prepare an oral disintegrating film formulation containing entecavir as shown in Table 12.

In order to rapidly disintegrate in the oral cavity and to be able to work in mass production,

Weight ratio (%) Example 63 Example 64 Example 65 A floor Entekavir 2.0 2.0 2.0 Hydroxypropyl cellulose 50 50 50 Maltitol 40 40 40 Sodium saccharin 8 8 8 Sum 100 100 100 Floor B Entekavir 1.0 1.0 1.0 Hipromelose 65.849 60.849 55.849 Polyethylene glycol 3 8 13 Maltitol 20 20 20 Titanium oxide 10 10 10 El-menthol 0.05 0.05 0.05 Polysorbate 0.05 0.05 0.05 Citric acid 0.05 0.05 0.05 Pigment 0.001 0.001 0.001 Sum 100 100 100 Disintegration time (minutes) 5 3 3 Elongation (%) 100 100 110 flavor + + +

Results: Entecavir was present in the A-layer film and the B-layer film, and the amounts of the film forming agent, the plasticizer and the sweetener were used in Examples 63 to 65, showing excellent disintegration time and taste of the film formulation.

From the results of Tables 1 to 12, it can be seen that the compositions of the enteric-coated oral disintegration film formulations prepared according to the present invention contain 0.001 to 30% by weight, more preferably 0.2 To 10% by weight, and when a polymer material such as hydroxypropyl cellulose and hydroxypropyl cellulose is appropriately mixed and tested in a test tube, the disintegration rate is 3 minutes. By using other sweeteners, fragrances and the like, Or an odor is improved.

Claims (13)

An enteric-coated oral disintegration film formulation comprising entecavir as an active ingredient and being formed in a single-layer structure. Wherein the entecavir-containing oral disintegration film formulation comprises entecavir and has a multi-layer structure. 3. The method according to claim 1 or 2,
Wherein the entecavir-containing oral disintegrating film formulation comprises 0.1 to 12% by weight of entecavir. 3. The method of claim 2,
The entecavir-containing oral disintegration film formulation is formed by laminating an A-layer film having a relatively high elongation and a low hardness, a B-layer film having a relatively low elongation and a high hardness,
Wherein the A-layer film and the B-layer film each contain the entecavir. 3. The method according to claim 1 or 2,
Wherein the entecavir-containing film formulation comprises at least two components selected from the group consisting of a film forming agent, a plasticizer, a sweetener, a flavoring agent, a taste-masking agent, a salivating stimulant, a surfactant, a pigment and an antioxidant. Containing disintegrating film. 6. The method of claim 5,
The film formers of the film may be selected from the group consisting of starch, gelatin, pectin, sodium alginate, maltodextrin, polymerized rosin, hydroxymethylcellulose, methylcellulose, crystalline cellulose, sodium carboxymethylcellulose, colicote, eudragit, polyethylene oxide At least one substance selected from the group consisting of polyvinyl alcohol, hyaluronic acid, hyaluronic acid derivatives, chitosan, chitosan derivatives and xanthan gum, and 20 to 80% by weight of entecavir-containing oral disintegration Film formulation. 6. The method of claim 5,
Wherein the plasticizer comprises at least one material selected from the group consisting of acetyl triethyl citrate, propylene glycol, citrate ester and triacetin, and the content of the plasticizer is 0.001 to 20% by weight. Formulation. 6. The method of claim 5,
The sweetener may be selected from the group consisting of maltitol, isomaltooligosaccharide, sorbitol, xylitol, polyol, mannitol, sucrose, dextrose, fructose, alitame, neotame, saccharine and its salts, aspartame, glycyrrhizin, stevitene, Containing disaccharide containing at least one substance selected from the group consisting of sodium saccharide, cyclodextrin, sodium saccharide, and cyclamate, and containing 0.5 to 20% by weight based on 100% by weight of the entecavir-containing oral disintegration film formulation Film formulation. 6. The method of claim 5,
Examples of the flavor or taste blocking agent include natural flavoring agents (such as guarana, orange, lemon, peppermint, cinnamon, menthol, peppermint oil, wintergreen mint, clove, butter scotch, maple, apricot, peach, cherry, anise, At least one substance selected from the group consisting of citrus flavor, licorice flavor, root beer flavor, gardenias, raspberry flavor, walnut flavor, chocolate flavor and the like) and synthetic fragrance, wherein the entecavir-containing oral cavity film formulation By weight based on 100% by weight of the total amount of the entecavir-containing oral disintegration film. 6. The method of claim 5,
Wherein the saliva stimulating agent includes at least one substance selected from the group consisting of citric acid, citric acid salt, lactic acid, malic acid, ascorbic acid, tartaric acid and tartaric acid salt, and the 100% by weight of the entecavir-containing oral disintegration film formulation By weight, based on the total weight of the oral cavity disintegrating film. 6. The method of claim 5,
Wherein the surfactant comprises at least one material selected from the group consisting of poloxamer, sodium lauryl sulfate, benzethonium chloride, polyoxyethylene fatty acid esters, polysorbates, and sorbitan esters, wherein the entecavir-containing oral disintegration Wherein the film comprises 0.1 to 5% by weight based on 100% by weight of the film formulation. 6. The method of claim 5,
Wherein the coloring matter includes at least one substance selected from the group consisting of synthetic pigments including titanium dioxide, silicon dioxide, zinc oxide, and natural pigments, and is used in an amount of from 0.001 to 100 parts by weight per 100 parts by weight of the entecavir- ≪ / RTI > 5% by weight of the composition. 6. The method of claim 5,
Wherein the antioxidant comprises at least one substance selected from the group consisting of sodium hydrogen sulfite, methyl paraben, propyl paraben, sodium benzoate, benzalkonium chloride and benzethonium chloride, wherein the entecavir-containing oral disintegration film formulation comprises 100 wt% By weight based on the total weight of the oral cavity disintegrating film.