KR102291180B1 - Oral dissolving film and preparation method thereof - Google Patents

Abstract

The present invention relates to a fast-disintegrating film-type preparation in the oral cavity and a method for preparing the same, wherein the film-type preparation contains furosemide or a pharmaceutically acceptable salt thereof as an active ingredient, and is easy to take for companion animals. Easy.

Description

Intraoral fast-dissolving film-type formulation and its manufacturing method {Oral dissolving film and preparation method thereof}

The present invention relates to an oral fast-disintegrating film-type preparation comprising furosemide or a pharmaceutically acceptable salt thereof as an active ingredient, and a method for preparing the same.

Furosemide is a well-known diuretic, inhibiting the reabsorption of sodium and chlorine in the ascending loop of Henle and the distal tubule, and interfering with the air transport system where chlorine binds, thereby excreting water and sodium, chlorine, magnesium, and calcium. It is used for the purpose of alleviating edema and fluid retention caused by various diseases such as heart disease, liver disease, and kidney disease by removing unnecessary water or salt from the body through urine.

On the other hand, various administration routes such as intravenous administration, sublingual administration, oral administration, etc. are known as drug administration routes in human or veterinary medicine. However, except for oral administration in veterinary medicine, it is difficult for guardians to apply at home care, and the existing oral administration also has some problems. For example, when it is necessary to manage oral administration of tablets for a long time, some guardians have difficulties in taking oral tablets due to the low cooperation of animal patients, and the administration route is limited in stressful situations such as breathing difficulties due to acute pulmonary edema.

Although furosemide is a widely used drug in the field of veterinary medicine, home administration is limited from the point of view of parents for the above reasons, and discomfort is complained about. Accordingly, there is a need for the development of a new formulation that can provide the convenience and safety of taking drugs to the veterinarian's prescription for animals and companion animals and their guardians.

An object of the present invention is to provide an oral fast-disintegrating film-type formulation having excellent ease of administration and stability in order to solve the above problems.

In addition, an object of the present invention is to provide a method for preparing a fast-disintegrating film-type formulation in the oral cavity.

Another object of the present invention is to provide an oral fast-disintegrating film-type formulation for companion animals comprising furosemide or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a method for treating companion animals other than humans using an oral fast-disintegrating film-type formulation comprising furosemide or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention provides a fast-disintegrating film-type formulation in the oral cavity comprising furosemide or a pharmaceutically acceptable salt thereof as an active ingredient, and comprising a film former, a plasticizer, a solubilizer, a disintegrant and a sweetener .

The film-type formulation is characterized in that it is for companion animals.

The film forming agent includes alginic acid or alginate, and any alginate may be used as the alginate, but an alkali of alginate, such as sodium or potassium alginate

Particular preference is given to using lithium metal salts. Most preferably, it contains sodium alginate, the disintegrant includes crospovidone, and the particle size of the disintegrant is 10 to 20 μm.

The plasticizer is a combination of glycerin and polyethylene glycol 400, and glycerin: polyethylene glycol 400 is characterized in that the weight ratio is 1:1.

The solubilizing agent comprises polysorbate 80, and the sweetening agent is characterized in that it comprises D-sorbitol.

The oral rapidly disintegrating film-type formulation comprises 40 parts by weight of furosemide, 28 parts by weight of a film former, 16 parts by weight of a plasticizer, 2 parts by weight of a solubilizer, 12 parts by weight of a disintegrant, and 2 parts by weight of a sweetener .

In addition, in another aspect, the present invention comprises the steps of: 1) dissolving furosemide and a plasticizer in a chamber at 80° C. and then dissolving them in heated ethanol to prepare an ethanol phase solution; 2) maintaining the ethanol phase solution by leaving it in a chamber at 40°C; 3) preparing an aqueous solution by dissolving a film-forming agent, a solubilizer and a sweetener in water; 4) dispersing a disintegrant in the aqueous solution; 5) maintaining the aqueous solution at 40°C; 6) adding the ethanol phase solution to the aqueous phase solution, stirring and mixing; 7) degassing; 8) forming the mixed solution into a film form; and 9) drying the film.

In the manufacturing method, the film forming agent includes sodium alginate, the particle size of the disintegrant is 10 to 20 μm, and the ethanol:water is 3:7 by volume.

The oral fast-disintegrating film-type formulation according to the present invention can provide safe dosing, stress relief, and convenience to companion animals that are difficult to take tablets or in an emergency due to pulmonary edema at home.

In addition, the formulation according to the present invention has the effect of increasing the efficiency of animal management by allowing the companion animal to consume furosemide without any objection.

1 shows a photograph of a film for each film forming agent according to an embodiment of the present invention.
Figure 2 shows the performance evaluation results of the film for each film forming agent according to an embodiment of the present invention.
3 shows the film performance evaluation results of F-7 according to an embodiment of the present invention.
Figure 4 shows the film photograph and film performance evaluation results of F-8 to F-10 according to an embodiment of the present invention.
Figure 5 shows the film photograph and film performance evaluation results of F-11 to F-13 according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail. In describing the present invention, if it is determined that a detailed description of a related known configuration or function may obscure the gist of the present invention, the detailed description thereof will be omitted.

The present invention provides a fast-disintegrating film-type formulation in the oral cavity comprising furosemide or a pharmaceutically acceptable salt thereof as an active ingredient, and comprising a film former, a plasticizer, a solubilizer, a disintegrant and a sweetener .

The film-type formulation is preferably for companion animals as an animal drug.

The film forming agent is preferably sodium alginate.

The disintegrant is preferably crospovidone, and the particle size of the disintegrant is preferably 10 to 20 μm. If the particle size of the disintegrant is out of the above range, the film may be non-uniform because the density of the film is low, and the particles are dried in a suspended state or aggregation between the particles occurs.

The plasticizer is preferably a combination of glycerin and polyethylene glycol 400, and glycerin: polyethylene glycol 400 is preferably 1:1 by weight.

The solubilizing agent is preferably polysorbate 80, and the sweetening agent is preferably D-sorbitol.

The oral rapidly disintegrating film-type formulation preferably contains 40 parts by weight of furosemide, 28 parts by weight of a film former, 16 parts by weight of a plasticizer, 2 parts by weight of a solubilizer, 12 parts by weight of a disintegrant, and 2 parts by weight of a sweetener.

In addition, in another aspect, the present invention comprises the steps of: 1) dissolving furosemide and a plasticizer in a chamber at 80° C. and then dissolving them in heated ethanol to prepare an ethanol phase solution; 2) maintaining the ethanol phase solution by leaving it in a chamber at 40°C; 3) preparing an aqueous solution by dissolving a film-forming agent, a solubilizer and a sweetener in water; 4) dispersing a disintegrant in the aqueous solution; 5) maintaining the aqueous solution in a chamber at 40°C; 6) adding the ethanol phase solution to the aqueous phase solution, stirring and mixing; 7) degassing; 8) forming the mixed solution into a film form; and 9) drying the film.

In the preparation method, the film forming agent is preferably sodium alginate, the particle size of the disintegrant is preferably 10 to 20 μm, and the ethanol:water is preferably 3:7 by weight. do.

Hereinafter, examples of the present invention will be described in detail, but the present invention is not limited to the following examples.

The constituents of the films according to Examples of the present invention are shown in Table 1 below, and all examples were prepared on the basis of a total amount of 5 films.

Classification Ingredient name standard manufacturer chief ingredient Furosemide 6-EOD-170-1 TRC canada film former HPMC 60SH-4000 Shin-Etsu Chemical PVP Kollidon 25 D-BASF PVA PVA 1500 DUKSAN CMC-Na 7HF PHARM ASHLAND Sodium alginate GQ7505504 FMC Biopolymer Pullulan USP/NF, JP Hayashibara plasticizer Glycerin GAIL61 DUKSAN PEG 400 74328568 D-BASF solubilizer Tween 80 0016472491 D-BASF sweetener D-Sorbitol E337J Roquette disintegrant Crospovidone Kollidon CL-SF D-BASF

* HPMC: hydroxypropyl methylcellulose

PVP: polyvinyl pyrrolidone

PVA: polyvinyl alcohol

CMC-Na: carboxymethylcellulose Na

In an embodiment of the present invention, an in vitro disintegration test and a bending test were performed to evaluate the film performance. The in vitro disintegration test is to predict the disintegration rate in the oral cavity after taking, and after pouring 5 mL of distilled water into a Petri dish, the prepared film is floated on it to measure the time it takes for the film to disintegrate (Eur. J. Pharm. See Biopharm 2009;73(1):195-201). The bending test is to evaluate the flexibility of the film, and when the prepared film is repeatedly folded in half using two fingers, the number of folds until split in half was measured. All tests were repeated three times and expressed as the average value.

Example One. film former comparative evaluation

Film comparative evaluation was performed according to six types of film forming agents.

First, 100 mg of furosemide, 5 mg of a plasticizer, 5 mg of a solubilizer, and 60 mg of a sweetener are put into a 10 mL vial, 5 mL of water is added, stirred at 300 rpm for 5 minutes, and then a film is formed under water bath conditions at 40°C. 150 mg of No. 150 mg was added in small portions several times to completely dissolve. 25 mg of disintegrant was added and homogeneously dispersed, and then the vial was placed in a sonicator to remove air bubbles in the mixed solution and degassed for 10 minutes. Considering the area (diameter 9 cm, area 63.585 cm ² ) of the Petri dish, the mixture corresponding to the theoretical weight was weighed and uniformly applied to the Petri dish. Put the Petri dish in a drying oven set at 100 ° C, and completely dry the mixture for about 35 to 40 minutes until a film is formed, then the formed film was peeled off and cut into a rectangular shape of 2 cm × 3 cm standard. .

^* Theoretical weight (mg): 1,070 mg × experience correction factor × 63.585/6

^* Experience value correction factor: weight considering the loss rate during application (1.10~1.20)

Table 2 below shows manufacturing conditions based on one film according to Example 1.

Classification Formulation F-1 F-2 F-3 F-4 F-5 F-6 Main ingredient (mg) Furosemide 20.0 Film former (mg) HPMC 30.0 - - - - - PVP - 30.0 - - - - PVA - - 30.0 - - - CMC-Na - - - 30.0 - - Sodium alginate - - - - 30.0 - Pullulan - - - - - 30.0 plasticizer (mg) Glycerin 1.0 PEG 400 1.0 Solubilizer (mg) Tween 80 1.0 Sweetener (mg) D-Sorbitol 12.0 Disintegrant (mg) Crospovidone 5.0 Solvent (mL) D.W. 1.0 (density 1 g/mL) Total weight of solids (mg) 70.0 Total weight of crude liquor per film 1,070 mg/film Drying temperature (℃) 100

Referring to FIG. 1 , as a result of preparing a film by adding the same amount of six kinds of film forming agents, a film was not formed in PVA and PVP, and a film was formed in HPMC, but it was strongly attached to the bottom of the Petri dish and did not separate. and CMC-Na film was formed, but the film surface was non-uniform. In the case of Pullulan, the film itself had low strength and high adhesion, so the shape was not maintained. On the other hand, in the case of sodium alginate, the film strength was high and the surface was prepared homogeneously.

Referring to FIG. 2 , the disintegration time was the fastest for Pullulan at 15 seconds, 22 seconds for CMC-Na, and 28 seconds for sodium alginate. In the bending test, sodium alginate showed the best results.

From the above results, it was confirmed that sodium alginate was most suitable in terms of viscosity, disintegration time and formulation stability of the solution.

Example 2. solubilization condition comparison evaluation

Put 1.5 mL of ethanol in a vial, leave it in a chamber at 80° C. to warm it, add 100 mg of furosemide and 20 mg each of a plasticizer, and repeat vortex mixing twice for 1 minute to dissolve (ethanol phase solution). 70 mg of sodium alginate, 5 mg of a solubilizer, and 5 mg of a sweetener were placed in a new 10 mL vial, added with 3.5 mL of water, stirred for 5 minutes to completely dissolve, and then 30 mg of the disintegrant was suspended and stirred to disperse (aqueous solution). The ethanol phase solution was added to the aqueous phase solution, stirred and mixed, and then degassed by sonication for 10 minutes. In the same manner as in Example 1, the mixture corresponding to the theoretical weight was weighed and uniformly applied to the Petri dish. The petri dish was put in a drying oven set at 80° C., and the mixture was completely dried for about 40 to 45 minutes until a film was formed, and then the formed film was peeled off, cut into 2 cm × 3 cm dimensions, and characteristic evaluation was performed.

Table 3 below shows manufacturing conditions based on one film according to Example 2.

Classification Formulation F-7 Main ingredient (mg) Furosemide 20.0 Film former (mg) Sodium alginate 14.0 plasticizer (mg) Glycerin 4.0 PEG 400 4.0 Solubilizer (mg) Tween 80 1.0 Sweetener (mg) D-Sorbitol 1.0 Disintegrant (mg) Crospovidone 6.0 Solvent (mL) 30% EtOH 1.0 Total weight of solids (mg) 50.0 Total weight of crude liquor per film 1,050 mg/film Drying temperature (℃) 80

Referring to FIG. 3 , as a result of completely dissolving furosemide in ethanol by dividing it into an aqueous phase and an ethanol phase, the suspended and agglomerated particles generated during mixing were sufficiently finely formed to prepare a film with a homogeneous surface. The moisture content in the film was controlled by preventing overdrying of the film by setting it to 80°C appropriate for the drying temperature. Due to the unique properties of sodium alginate, a film with excellent strength and a disintegration time of less than 1 minute could be produced.

Example 3. ethanol supernatant Comparative evaluation according to the mixing temperature of the aqueous phase

Put 1.5 mL of ethanol in a vial, leave it in a chamber at 80 ℃ to warm it, add 100 mg of furosemide and 20 mg each of a plasticizer, and repeat vortex mixing twice for 1 minute to dissolve, 25 ℃, 40 ℃, 80 ℃, respectively The temperature was reached to equilibrium (solution in ethanol) by storage in the chamber for 30 minutes. 70 mg of sodium alginate, 5 mg of a solubilizer, and 5 mg of a sweetener were placed in a new 10 mL vial, added with 3.5 mL of water, stirred for 5 minutes to completely dissolve, and then 30 mg of the disintegrant was suspended and stirred to disperse (aqueous solution). The aqueous solution was stored in chambers at 25°C, 40°C, and 80°C for 30 minutes, respectively, to achieve temperature equilibrium. Each of the ethanol phase solutions at different storage temperatures was added to the aqueous phase solutions stored at the same temperature, stirred and mixed, followed by sonication for 10 minutes to degas. In the same manner as in Example 1, the mixture corresponding to the theoretical weight was weighed and uniformly applied to the Petri dish. The petri dish was put in a drying oven set at 80° C., and the mixture was completely dried for about 40 to 45 minutes until a film was formed, and then the formed film was peeled off, cut into 2 cm × 3 cm dimensions, and characteristic evaluation was performed.

Table 4 below shows manufacturing conditions based on one film according to Example 3.

Classification Formulation F-8 F-9 F-10 Main ingredient (mg) Furosemide 20.0 Film former (mg) Sodium alginate 14.0 plasticizer (mg) Glycerin 4.0 PEG 400 4.0 Solubilizer (mg) Tween 80 1.0 Sweetener (mg) D-Sorbitol 1.0 Disintegrant (mg) Crospovidone 6.0 Solvent (mL) 30% EtOH 1.0 Total weight of solids (mg) 50.0 Total weight of crude liquor per film 1,050 mg/film Drying temperature (℃) 80 Storage temperature (℃) before mixing water/ethanol phase 25 40 80

Referring to FIG. 4 , in the case of room temperature (25° C.), the degree of aggregation between particles increased and the film surface was non-homogeneous. In the case of 80° C., bubbles were generated due to the high temperature and the film surface was non-homogeneous. On the other hand, in the case of 40 ℃, the strength and surface homogeneity of the film showed the best results. As a result, it was confirmed that the aspect of the film surface was changed according to the mixing temperature of the aqueous phase and the ethanol phase. No significant difference was found in disintegration rate and film strength.

Example 4. disintegrant Comparative evaluation according to particle size

Put 1.5 mL of ethanol in a vial, leave it in a chamber at 80 ℃ to warm it, add 100 mg of furosemide and 20 mg each of a plasticizer, repeat vortex mixing twice for 1 minute to dissolve, and store in a chamber at 40 ℃ for 30 minutes to temperature reached equilibrium (solution in ethanol). Sodium alginate 70 mg, solubilizer 5 mg, and sweetener 5 mg were placed in a new 10 mL vial, added 3.5 mL of water, stirred for 5 minutes to completely dissolve, and then 30 mg of each disintegrant having a different particle size was suspended and stirred and dispersed ( aqueous solution). The aqueous solution was stored in a chamber at 40° C. for 30 minutes to bring the temperature to equilibrium. The ethanol phase solution was added to the aqueous solution, stirred and mixed, followed by sonication for 10 minutes to degas. In the same manner as in Example 1, the mixture corresponding to the theoretical weight was weighed and uniformly applied to the Petri dish. The petri dish was put in a drying oven set at 80° C., and the mixture was completely dried for about 40 to 45 minutes until a film was formed, and then the formed film was peeled off, cut into 2 cm × 3 cm dimensions, and characteristic evaluation was performed.

Table 5 below shows manufacturing conditions based on one film according to Example 4.

Classification Formulation F-11 F-12 F-13 Main ingredient (mg) Furosemide 20.0 Film former (mg) Sodium alginate 14.0 plasticizer (mg) Glycerin 4.0 PEG 400 4.0 Solubilizer (mg) Tween 80 1.0 Sweetener (mg) D-Sorbitol 1.0
Disintegrant (mg)
Crospovidone Average particle size of disintegrant (㎛) 3-10 10-20 20-40 6.0 Solvent (mL) 30% EtOH 1.0 Total weight of solids (mg) 50.0 Total weight of crude liquor per film 1,050 mg/film Drying temperature (℃) 80 Storage temperature (℃) before mixing water/ethanol phase 25 40 80

5 and the following Table 6, it can be seen that the properties and disintegration rate of the film surface vary according to the particle size of the disintegrant in the same composition. When the particle size of the disintegrant is 3 to 10 ㎛, it can be seen that the density is low and the particles are biased toward drying in a suspended state. appeared the fastest with 35 seconds. When the particle size of the disintegrant was 20 to 40 μm, it was heterogeneous due to aggregation between the particles. Through the above results, it was confirmed that the most suitable disintegrant particle size in terms of disintegration rate and properties was 10 to 20 μm.

Classification Formulation F-11 F-12 F-13 Film weight (mg) N=1 50.6 51.5 48.5 N=2 52.4 50.4 46.0 N=3 54.0 48.5 49.5 N=4 53.7 52.8 51.4 N=5 47.9 47.1 49.7 Aver. 51.7±2.2 50.0±2.0 49.7±2.4 disintegration time 57 seconds 35 seconds 1 minute 7 seconds bending test 5 5 5 drying time 51 minutes 53 minutes 50 minutes

Example 5. Reproducibility evaluation

A film was prepared in the same manner as in Example 4 by setting the particle size of the disintegrant to 10 to 20 μm, and the characteristic evaluation results are shown in Table 7 below.

Classification Formulation F-14 Film weight (mg) N=1 54.4 N=2 53.1 N=3 52.2 N=4 56.5 N=5 51.7 Aver. 53.5±1.9 disintegration time 32 seconds bending test 5 drying time 56 minutes

As a result of testing with n=3 through HPLC quantitative analysis specified in the Korean Pharmacopoeia (KP), the furosemide content was 98.30±3.01%, 99.63±4.38%, and 99.01±1.31%, respectively, and the average content was 98.9±0.6 %, and the content deviation compared to the standard solution was within 2%, and the reproducibility was excellent. It was found that furosemide was well dispersed in the film.

Above, the present invention has been described by way of example, and various modifications will be possible without departing from the essential characteristics of the present invention by those of ordinary skill in the art to which the present invention pertains. Accordingly, the embodiments disclosed in the present specification are intended to illustrate, not to limit the present invention, and the spirit and scope of the present invention are not limited by these embodiments. The protection scope of the present invention should be construed by the following claims, and all technologies within the scope equivalent thereto should be construed as being included in the scope of the present invention.

Claims (15)

Contains furosemide or a pharmaceutically acceptable salt thereof as an active ingredient, and includes a film former, a plasticizer, a solubilizer, a disintegrant and a sweetener,
The film-forming agent comprises alginic acid or alginic acid salt. Oral fast-disintegrating film-type formulation
delete According to claim 1, wherein the disintegrant is a fast-disintegrating film-type formulation in the oral cavity, characterized in that it comprises crospovidone (crospovidone).
According to claim 1, wherein the particle size of the disintegrant is 10 to 20 ㎛ oral fast-disintegrating film-type formulation, characterized in that
According to claim 1, wherein the plasticizer is glycerin (glycerin) and polyethylene glycol (polyethylene glycol) 400, characterized in that the combination of the oral fast-disintegrating film-type formulation
According to claim 5, wherein the glycerin: polyethylene glycol 400 is a fast-disintegrating film-type formulation in the oral cavity, characterized in that 1:1 weight ratio.
According to claim 1, wherein the solubilizing agent is a fast-disintegrating film-type formulation in the oral cavity, characterized in that it comprises polysorbate (polysorbate) 80.
According to claim 1, wherein the sweetening agent D-sorbitol (D-sorbitol) is characterized in that the oral rapidly disintegrating film-type formulation
The method according to claim 1, comprising 40 parts by weight of the furosemide, 28 parts by weight of the film former, 16 parts by weight of the plasticizer, 2 parts by weight of the solubilizer, 12 parts by weight of the disintegrant, and 2 parts by weight of the sweetener based on the total formulation. Oral fast-disintegrating film-type formulation characterized by
Contains furosemide or a pharmaceutically acceptable salt thereof as an active ingredient, and includes a film former, a plasticizer, a solubilizer, a disintegrant and a sweetener,
The film-forming agent comprises alginic acid or alginic acid salt. Oral fast-disintegrating film-type preparation for veterinary medicine.
1) preparing an ethanol phase solution by dissolving furosemide and a plasticizer in ethanol heated to 80°C;
2) maintaining the ethanol phase solution at 40°C;
3) preparing an aqueous solution by dissolving a film-forming agent, a solubilizer and a sweetener in water;
4) dispersing a disintegrant in the aqueous solution;
5) maintaining the aqueous solution at 40°C;
6) adding the ethanol phase solution to the aqueous phase solution, stirring and mixing;
7) degassing;
8) forming the mixed solution into a film form; and
9) drying the film;
Method for producing a fast-disintegrating film-type formulation in the oral cavity, characterized in that the film-forming agent comprises alginic acid or alginic acid salt
delete The method of claim 11, wherein the particle size of the disintegrant is 10 to 20 μm.
The method of claim 11, wherein the ethanol:water is in a weight ratio of 3:7 by weight.
Treatment method for companion animals other than humans using an oral fast-disintegrating film formulation comprising furosemide or a pharmaceutically acceptable salt thereof as an active ingredient, and containing alginic acid or alginic acid salt as a film forming agent

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