WO2015186929A1

WO2015186929A1 - Oral disintegrating film containing tadalafil, and method of manufacturing same

Info

Publication number: WO2015186929A1
Application number: PCT/KR2015/005429
Authority: WO
Inventors: 신새벽; 최원재; 황상욱; 김훈택; 곽용규
Original assignee: 에스케이케미칼주식회사
Priority date: 2014-06-02
Filing date: 2015-05-29
Publication date: 2015-12-10
Also published as: KR20150138671A

Abstract

The present invention relates to an oral disintegrating film including Tadalafil, one or more types of solubilizer, and one or more types of film forming polymer, and to a method of manufacturing same. The oral disintegrating film according to the present invention is small in size and thin in thickness so as to be convenient to carry and is easy to take because it does not need to be taken with water. Also, the film not only disintegrates quickly inside the mouth, but can also be relied upon to exhibit favorable drug effects, as it contains a solubilizer that functions to increase the solubility of Tadalafil, and can therefore be usefully used to treat erectile dysfunction symptoms.

Description

Specification

Oral Disintegrating Film Containing Tadalafil and Manufacturing Method Thereof

Field of invention

5

The present invention relates to an orally disintegrating film containing a tadalafil and a method for manufacturing the same, and more particularly, it is possible to include a pharmacologically effective amount of tadalafil in a small size and a thin film, and is easy to handle and take. It relates to an oral disintegrating film showing high solubility and good drug expression and a method for producing the same. Background Art Tadalaf i l is a drug used to treat erectile dysfunction and is commercially available as a tablet for oral administration of Cialis 15. However, when the erectile dysfunction treatment is in the form of tablets, it is quite inconvenient to take orally without water. In addition, even after disintegrating and eluting in the gastrointestinal tract, it takes considerable time for the effective drug to be absorbed into the gastrointestinal tract and reach the site of action.

On the other hand, oral disintegrating film containing the drug is easy to carry and take, can be expected to disintegrate rapidly in the oral cavity and rapid expression of the active ingredient. Accordingly, attempts have been made to prepare erectile dysfunction drugs in the form of oral disintegrating films. However, tadalafil is poorly soluble drugs is because commercial ^■ 1: Tablets (commercially available reference product) of Cialis passions indicate the efficacy expressed the same level of 25 to the mouth as to maintain different other with drugs equivalent contrast the solubility of the necessary forms A disintegrating film should be prepared. Accordingly, the inventors have found that the solubility of tadalafil is equivalent to that of the reference drug. As a result of intensive studies to develop an orally disintegrating film that can maintain and have excellent physical properties such as size, physical properties, and disintegration rate, the present invention has been completed by developing a tadalafil-containing oral disintegrating film that can satisfy the above requirements. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide an oral disintegrating film comprising a tadalafil and a method for producing the same. The present invention to achieve the above object is tadalafil; One or more solubilizers; And it provides an oral disintegrating film comprising at least one film-forming polymer.

The present invention to achieve the above another object,

(1) dissolving at least one solubilizer and at least one film-forming polymer in a solvent and dispersing tadalafil therein to prepare a coating stock solution; And

(2) It provides a method for producing an oral disintegrating film comprising the step of degassing the coating stock solution prepared above, applied to a process film (processing film) and dried to produce an oral disintegrating film. According to the present invention, it is possible to include a pharmacologically effective amount of tadalafil in a small-sized and thin film, thereby making it easy to handle and take, and to produce an orally disintegrating film that exhibits high solubility and shows bioequivalence with a reference drug. have. Therefore, the oral disintegrating film of the present invention can be usefully used to treat erectile dysfunction. BRIEF DESCRIPTION OF THE DRAWINGS The above and other objects and features of the present invention are described in conjunction with the accompanying drawings. It will be apparent from the description of the invention:

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing the results of a Cialis definition comparative dissolution test that is an orally disintegrating film of the present invention and a commercial tablet. Detailed Description of the Invention The present invention relates to tadalafil; One or more solubilizers; And at least one film forming polymer.

Oral disintegration film in the present invention refers to a formulation to be taken by disintegrating in the oral cavity after being placed on the tongue, it can be easily taken without water. Oral disintegrating film of the present invention contains tadalafil as a pharmacologically active ingredient. The tadalafil is a drug of the phosphodiesterase (PDE5) inhibitor family and is used as a erectile dysfunction treatment agent. Tadalafil, a selective, reversible inhibitor of cGMP-specific PDE5, increases levels of cGMP in the cavernous body when it causes local release of nitric oxide by sexual stimulation. This causes erect ions by leading to smooth muscle relaxation and the influx of blood into the penis tissue. Tadalafil is currently marketed as Cialis tablets. Therefore, the oral disintegrating film of the present invention can be usefully used to treat erectile dysfunction.

The tadalafil may be included in an amount of 0.1 to 100 mg, preferably 2.5 to 20 mg per sheet of 10 cm ² film.

The tadalafil may be included in an amount of 5 to 75% by weight, preferably 10 to 30% by weight based on the total weight of the film. The oral disintegrating film of the present invention includes at least one solubilizer. The solubilizer serves to increase the solubility of tadalafil to increase the bioavailability. The solubilizing agent is preferably a plastic cap polylactam polyvinyl acetate-polyethylene glycol copolymer (commercial product name: Plus solution (Soluplus) ^®; Manufacturer: BASF Corporation).

The solubilizer may be included in the film in a weight ratio of 1: 0.25 to 1: 10, preferably in a weight ratio of 1: 1 to 1: 6 based on the tadalafil.

The solubilizer may be included in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, based on the total weight of the film.

The oral disintegrating film of the present invention comprises at least one film forming polymer. The film forming polymer is preferably a hydrophilic polymer, more preferably carboxymethylsalose sodium.

The film forming polymer may be included in an amount of 10 to 80% by weight, preferably 20 to 40% by weight, based on the total weight of the film.

In addition to the above components, the oral disintegrating film of the present invention may further include other pharmaceutically acceptable additives within a range not impairing the object of the present invention.

The pharmaceutically acceptable additive may be selected from the group consisting of excipients, plasticizers, emulsifiers, sweeteners, fragrances, antioxidants, and combinations thereof, the amount of which may be appropriately adjusted according to needs and purposes.

As the excipient, one or more components selected from the group consisting of calcium phosphate, microcrystalline salose, lactose pregelatinized starch, and mixtures thereof may be used, for example, calcium phosphate. The excipient may be used in an amount of 2 to 50 weight percent>, preferably 5 to 30 weight percent based on the total weight of the film.

Plasticizers serve to give flexibility and flexibility to films made of polymers so that they are not easily broken. Examples of the plasticizer include glycerin, propylene glycol, ethylene glycol, polyethylene glycol, sorbbi, xylyl, malty, erythri, tributyl citrate, triethyl citrate, triacetin, and glycerol triacetate. One or more components selected from the group consisting of acceptable alcohols (e.g. ethanol), mannites and combinations thereof may be used. For example, glycerin. The plasticizer may be used in an amount of 5 to 40 wt%, preferably 10 to 30 wt%, based on the total weight of the film. As the emulsifier, one or more components selected from the group consisting of polysorbate, sorbitan oleate, sodium lauryl sulfate, polyoxyethylene hardened castor oil, polyoxyethylene octylphenyl 5 ether, and mixtures thereof may be used. For example polysorbate. The emulsifier may be used in an amount of 0.01 to 8% by weight, preferably 0.2 to 4% by weight based on the total weight of the film.

Sweeteners play a role in controlling taste. As the sweetening agent, one or more ingredients selected from the group consisting of sucralose, 10 aspartame, sodium saccharin, stevioside, riboudioside, tomatin (thaumat in ^" acesulfame potassium and combinations thereof) may be used. It may be for example sucralose. The sweetener may be used in an amount of 0.1 to 10% by weight, preferably 0.5 to 5% by weight, based on the total weight of the film.

Fragrances have the right fragrance to reduce discomfort. The fragrance may be one or more ingredients selected from the group consisting of men, camphor, peppermint and mixtures thereof, for example, men. The fragrance is based on the total weight of the film, from 0.01 to 10 weight ¾. , Preferably in an amount of 0.5 to 5 weight ¾.

20 The antioxidants include butyl ated hydroxytoluene (BHT), butyl ated hydroxy ani sole (BHA), ascorbyl palmitate, ascorbic acid, tocopherol and its One or more components selected from the group consisting of mixtures may be used, for example ΒΗΤ. The antioxidant may be used in an amount of 0.001 to 5% by weight, preferably 25 to 0.01% by weight, based on the total weight of the film. According to one embodiment of the present invention, one oral disintegrating film of the present invention containing about 20 mg of tadalafil in a size of 10 cm ² was dissolved in about 10 mL of water. At 20 to 200 ug / mL, preferably 40 to 100 yg / mL of tadalafil solubility. The solubility and bioavailability of the oral disintegrating film of the present invention shows bioequivalence at a level similar to that of commercial tablets Cialis tablets. In addition, the oral disintegrating film of the present invention has a weight of 80 to 160 mg after the drying of the film based on the size of about 10 cm ² , the thickness is 0.05 to 0.5 mm, small size and thin thickness, easy to carry Do. In addition, the present invention comprises the steps of (1) dissolving at least one solubilizer and at least one film-forming polymer in a solvent, dispersing tadalafil therein to prepare a coating stock solution; And (2) degassing the coating stock solution prepared above, applying it to a process film, and then drying to prepare an oral disintegrating film. Hereinafter, the manufacturing method of the oral disintegrating film according to the present invention will be described in detail.

In step (1) of the production method of the present invention, the coating stock solution is prepared by dissolving at least one solubilizer and at least one film-forming polymer in a solvent, and dispersing tadalafil therein.

The solvent used in the step (1) is water; an organic solvent selected from the group consisting of ethanol, acetone, ethyl acetate and a mixture thereof; Or a mixed solvent thereof, and preferably a water, or a mixed solvent of water and ethanol. The solvent may be used in an amount of 200 mg to 500 mg based on the case of producing a film of about 10 cm ² size.

The type and amount of solubilizer and film forming polymer used in step (1) are the same as described above.

The step (1) may further include a pharmaceutically acceptable additive in the coating stock solution, the pharmaceutically acceptable additive is in the group consisting of excipients, plasticizers, emulsifiers, sweeteners, fragrances, antioxidants and mixtures thereof Can be selected. Specific types and usage amounts of the additives are the same as described above. In step (2) of the production method of the present invention, the coating 5 undiluted solution prepared in step (1) is degassed, coated on a process film, and dried to prepare an oral disintegrating film.

In the step (2), first, the coating stock solution is applied to the process film in a thickness of 100 to 1,000 μηι according to a conventional method of preparing a film formulation. Subsequently, the process film to which the coating ^' stock solution is applied is dried for 5 minutes to 1 hour to evaporate the solvent. Then, if necessary, the oral disintegrating film of the present invention can be prepared by peeling the dried film and then cutting it to an appropriate size, for example, about 2 to 15 cm ² .

The process film may be a suitable process film used in the pharmaceutical field, such as polyethylene terephthalate process film, polyethylene terephthalate film coated with silicone or Teflon, polyethylene 5 film. The oral disintegrating film of the present invention is small in size and thin in thickness, which is convenient to carry, and does not need to be ingested with water, and is easy to take. In addition, since it contains a solubilizer that dissolves rapidly in the oral cavity and serves to increase the solubility of tadalafil, it can be expected to express the same efficacy as a commercially available control drug. Accordingly, it will be useful in the treatment of erectile _dysfunction: on the basis of the following examples to the present invention will be described in more detail. The following examples are only for illustrating the present invention, but the scope of the present invention is not limited to these five. Example 1: Preparation of Oral Disintegrating Film Containing Tadalafil Oral disintegrating film was prepared according to the ingredients and contents shown in Table 1 below. Specifically, carboxymethyl salolose sodium (CMC-Na, obtained by Ashland) as a polymer and polyvinyl caprolactam-polyvinylacetate- polyethylene glycol copolymer (Soluplus, obtained by BASF) as a solubilizer Was dissolved in water, glycerin as a plasticizer (from LG H & H), calcium phosphate as an excipient (Cal ipharm A, obtained from Innophos), polysorbate as an emulsifier (Tween 80, obtained from Merck) And sucralose (available from Splenda) as a sweetener was added and mixed uniformly. A tadalafil was added thereto and dispersed to prepare a coating stock solution.

The coating solution thus prepared was degassed by stirring under vacuum, and the film was coated with polyethylene terephthalate process (obtained by SKC Co., Ltd.) using a film-coating apparatus manufactured by ENT. The thickness was applied uniformly. Then, the solvent was removed by drying for 10 to 20 minutes at a temperature of 8C C or more. The dried film was peeled from the polyethylene terephthalate process film and cut to a size of about 10 cm ² to prepare an oral disintegrating film of the present invention. It was then packaged using an aluminum pouch. The weight after drying of the thus prepared film was about 120 mg. Comparative Examples 1 and 2: Preparation of oral disintegrating film containing tadalafil According to the components and contents shown in Table 1 below was prepared oral disintegrating film in the same manner as in Example 1. At this time, the solubilizer was not used in Comparative Example 1, and HPC was used instead of SoluPlus in Comparative Example 2.

TABLE 1

Experimental Example 1 Comparative Dissolution Test of Oral Disintegrating Film and Commercial Tablet A comparative dissolution test of 20 mg of Cialis tablet, a commercial tablet of oral disintegrating films prepared according to Examples 1 and 1 and tadalafil, was as follows. Was carried out.

Elution was performed by using 500 mL of 0.5% sodium lauryl sulfate (SLS) as a eluent and a paddle method at a rotational speed of 50 rpm. The oral disintegrating film was put into a sinker and tested. The results are shown in FIG.

As shown in Figure 1, Comparative Example 1 and Example 1 can be seen that the dissolution rate is faster than commercial tablets due to the nature of the oral disintegrating film. Experimental Example 2 Solubility Comparison Test of Oral Disintegrating Film and Commercial Tablet A solubility comparison test of 20 mg of Cialis tablets, which are commercial tablets of oral disintegrating films prepared according to Examples 1 and Comparative Examples 1 and 2 and tadalafil, was performed as follows. It was carried out as follows. It also comes with solubility for 20 mg of tadalafil for comparison Compared.

One oral disintegrating film, one tablet of commercial tablets and 20 mg of tadalafil were added to 10 mL of water, and then completely disintegrated for 10 minutes, and then the solubility was measured. When measuring solubility, about 2 mL of the dispersion was taken, centrifuged, the supernatant was obtained, filtered, and measured by liquid chromatography. In addition, the remaining dispersion was placed in a shaking incubator (37 ^° C.) incubator for 60 minutes and the solubility was measured again in the same manner as above. The results are shown in Table 2 below.

TABLE 2

As shown in Table 2, the orally disintegrating film of Example 1 exhibited similar tadalafil solubility as Cialis tablets. On the other hand, oral disintegrating films of Comparative Examples 1 and 2 exhibited solubility of only about 1/10 of the film of Example 1. Experimental Example 3 Bioavailability Evaluation Test of Oral Disintegrating Films and Commercial Tablets A bioavailability evaluation test of 20 mg of Cialis tablets, a commercial tablet of oral disintegrating films prepared according to Examples 1 and 1 and Comparative Example 1, was given below. It was carried out as follows.

Six healthy adult men were cross-tested with a five day washout period. At this time, oral disintegrating film was taken to disintegrate in the oral cavity without water when taking, and Cialis tablets to be taken with 250 mL of water. It was. Pharmacokinetic parameters were calculated by measuring the tadalafil concentration in plasma obtained through the test, and the geometric mean ratio of the test drug / cialis definition was obtained. The results were shown in Table 3.

TABLE 3

As shown in Table 3, the orally disintegrating film of the present invention exhibits a similar bioavailability as Cialis tablets and can be expected to be equivalent to the expression of the drug. Therefore, it can be usefully used for the treatment of erectile dysfunction symptoms.

Claims

Scope of claim

1. tadalafil; One or more solubilizers; And at least one film forming polymer.

2. The method of paragraph 1,

The solubilizing agent is a polyvinyl caprolactam-polyvinylacetate-polyethylene glycol copolymer, oral disintegrating film.

3. The method of paragraph 1,

The solubilizer is included in a weight ratio of 1: 0.25 to 1: 10 based on tadalafil, oral disintegrating film.

4. The method of paragraph 1,

Or solubilizing agent is included in an amount of 1 to 50 weight ¾ based on the total weight of the film.

5. The method of clause 1, wherein

Oral disintegrating film, wherein the film forming polymer is carboxymethylsalose sodium. .

6. The method of paragraph 1,

The tadalafil is contained in an amount of 2.5 to 20 mg per one film of the size of 10 cm ² , oral disintegrating film.

7. Paragraph 1 according to claim 1,

The oral disintegrating film comprises 20 mg of tadalafil in a size of 10 cm ² , An oral disintegrating film exhibiting a tadalafil solubility of 20 to 200 g / mL when dissolved in 10 mL of water.

8. (1) dissolving at least one solubilizer and at least one film-forming polymer in a solvent and dispersing tadalafil therein to prepare a coating stock solution; And

(2) degassing the coating solution prepared above, and applying it to a processing film (processing f lm), followed by drying to prepare an oral disintegrating film

Method for producing oral disintegrating film comprising a.

9. The method of clause 8, wherein

In the step (1), characterized in that it further comprises a pharmaceutically acceptable additive in the coating stock solution.

10. The method of clause 8,

The solvent of step (1) is water; Organic solvents selected from the group consisting of ethanol, acetone, ethyl acetate and mixtures thereof; Or a mixed solvent thereof.