TASTE-MASKED AND ORALLY ADMINISTERED PHARMACEUTICAL PREPARATION CONTAINING VARENICLINE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

Abstract

The present disclosure relates to a pharmaceutical preparation having varenicline or a pharmaceutically acceptable salt thereof as an active ingredient. More particularly, it relates to an orally administered pharmaceutical preparation which allows limited use of a sweetening agent or a flavoring agent by effectively masking the unique taste of varenicline, particularly bitterness, which is a bitter and burning taste, and ensures convenience in taking the pharmaceutical preparation by being orally administrable without irritation, while containing a pharmaceutically effective amount of varenicline or a pharmaceutically acceptable salt thereof, and a method for preparing the same.

Claims

1. A bitterness-masked orally administered pharmaceutical preparation comprising varenicline or a pharmaceutically acceptable salt thereof as an active ingredient and comprising both an anionic polymer comprising carboxyl groups and a cationic polymer comprising amino groups.

2. The bitterness-masked orally administered pharmaceutical preparation according to claim 1, wherein the active ingredient is one or more selected from a group consisting of varenicline tartrate, varenicline salicylate, varenicline sulfate, varenicline fumarate, varenicline oxalate, varenicline hydrochloride, varenicline hydrobromide, varenicline citrate, varenicline maleate, varenicline succinate, varenicline phosphate, varenicline tosylate, varenicline free base and varenicline mesylate.

3. The bitterness-masked orally administered pharmaceutical preparation according to claim 1, wherein the anionic polymer comprising carboxyl groups is a polyacryl-based anionic polymer, a polystyrene-based anionic polymer or a mixture thereof.

4. The bitterness-masked orally administered pharmaceutical preparation according to claim 1, wherein the anionic polymer comprising carboxyl groups is one or more of a crosslinked polymer of methacrylic acid and divinylbenzene, a crosslinked polymer of styrene and divinylbenzene, a crosslinked polymer of acrylic acid and divinylbenzene or a mixture thereof.

5. The bitterness-masked orally administered pharmaceutical preparation according to claim 1, wherein the cationic polymer comprising amino groups is a copolymer polymerized from methacrylic acid, acrylic acid or styrene as a monomer and comprising amino groups.

6. The bitterness-masked orally administered pharmaceutical preparation according to claim 1, wherein the weight ratio of the total weight of the cationic polymer comprising amino groups based on the total weight of the anionic polymer comprising carboxyl groups is 5:1 to 1:4.

7. The bitterness-masked orally administered pharmaceutical preparation according to claim 1, wherein the weight ratio of the total weight of the anionic polymer comprising carboxyl groups and the cationic polymer comprising amino groups based on the total weight of the varenicline or a pharmaceutically acceptable salt thereof is 10:1 to 1:100.

8. The bitterness-masked orally administered pharmaceutical preparation according to claim 1, wherein the weight ratio of the total weight of the varenicline or a pharmaceutically acceptable salt thereof, the total weight of the anionic polymer comprising carboxyl groups and the total weight of the cationic polymer comprising amino groups is 1:8:2.

9. The bitterness-masked orally administered pharmaceutical preparation according to claim 1, wherein the orally administered pharmaceutical preparation is a smoking cessation aid.

10. The bitterness-masked orally administered pharmaceutical preparation according to claim 1, wherein the orally administered pharmaceutical preparation is dissolved or disintegrated in the mouth.

11. The bitterness-masked orally administered pharmaceutical preparation according to claim 10, wherein the orally administered pharmaceutical preparation is a rapidly disintegrating tablet or a film formulation.

Description

DETAILED DESCRIPTION

[0052] Hereinafter, the present disclosure will be described in detail with reference to the following examples. However, it should be understood that the following examples are not intended to limit the scope of the present disclosure and various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the following claims. It will be apparent that these exemplary embodiments are provided so that the present disclosure will be complete and understood easily by those skilled in the art.

Example 1. Preparation of Film Formulation Containing Varenicline Tartrate as Active Ingredient

[0053] After adding an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups to varenicline tartrate dissolved in a solution, the mixture was stirred for at least 1 hour.

[0054] Then, after adding a plasticizer, a flavoring agent, a coloring agent, a sweetening agent, a surfactant and an excipient (diluent) to purified water and dissolving or dispersing by stirring, the mixture was homogenized using a homogenizer (Ultra-Turrax T-25, IKA). Then, after adding a polymer (pullulan) and then homogenizing using the same homogenizer, a gas was removed from the solution for preparing a film in vacuo and the solution was coated on a PET film to an appropriate thickness. Then, a film formulation containing varenicline tartrate was prepared by drying the same at 60-80 C.

Example 2. Preparation of Film Formulation Containing Varenicline Salicylate as Active Ingredient

[0055] After adding an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups to varenicline salicylate dissolved in a solution, the mixture was stirred for at least 1 hour.

[0056] Then, after adding a plasticizer, a flavoring agent, a coloring agent, a sweetening agent, a surfactant and an excipient (diluent) to purified water and dissolving or dispersing by stirring, the mixture was homogenized using a homogenizer (Ultra-Turrax T-25, IKA). Then, after adding a polymer (pullulan) and then homogenizing using the same homogenizer, a gas was removed from the solution for preparing a film in vacuo and the solution was coated on a PET film to an appropriate thickness. Then, a film formulation containing varenicline salicylate was prepared by drying the same at 60-80 C.

Example 3. Preparation of Rapidly Disintegrating Tablet Containing Varenicline Tartrate as Active Ingredient

[0057] After adding an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups to varenicline tartrate dissolved in a solution, the mixture was stirred for at least 1 hour.

[0058] Then, a solid was obtained by filtering and drying the solution. After adding a binder, a disintegrant, an excipient (diluent) and a lubricant to the obtained solid and then mixing the same, a tablet was prepared using a tablet-making machine.

Example 4. Preparation of Rapidly Disintegrating Tablet Containing Varenicline Salicylate as Active Ingredient

[0059] After adding an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups to varenicline salicylate dissolved in a solution, the mixture was stirred for at least 1 hour.

[0060] Then, a solid was obtained by filtering and drying the solution. After adding a binder, a disintegrant, an excipient (diluent) and a lubricant to the obtained solid and then mixing the same, a tablet was prepared using a tablet-making machine.

Example 5. Preparation of Granule Containing Varenicline Tartrate as Active Ingredient

[0061] After adding an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups to varenicline tartrate dissolved in a solution, the mixture was stirred for at least 1 hour.

[0062] Then, a solid was obtained by filtering and drying the solution. Separately from this, a solution containing a binder, a disintegrant and an excipient (diluent) was prepared and the obtained solid was added into a fluidized-bed granulator and then spray-dried to prepare a granule.

Example 6. Preparation of Granule Containing Varenicline Salicylate as Active Ingredient

[0063] After adding an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups to varenicline salicylate dissolved in a solution, the mixture was stirred for at least 1 hour.

[0064] Then, a solid was obtained by filtering and drying the solution. Separately from this, a solution containing a binder, a disintegrant and an excipient (diluent) was prepared and the obtained solid was added into a fluidized-bed granulator and then spray-dried to prepare a granule.

Example 7. Preparation of Suspension Containing Varenicline Tartrate as Active Ingredient

[0065] After adding an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups to varenicline tartrate dissolved in a solution, the mixture was stirred for at least 1 hour. Then, after adding a flavoring agent, a coloring agent, a sweetening agent, a surfactant and a viscosity increasing agent to purified water, a suspension was prepared by stirring the mixture.

Example 8. Preparation of Suspension Containing Varenicline Salicylate as Active Ingredient

[0066] After adding an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups to varenicline salicylate dissolved in a solution, the mixture was stirred for at least 1 hour. Then, after adding a flavoring agent, a coloring agent, a sweetening agent, a surfactant and a viscosity increasing agent to purified water, a suspension was prepared by stirring the mixture.

Test Example 1. Test of Bitterness Masking Effect of Film Formulation Containing Varenicline Tartrate as Active Ingredient when Anionic Polymer Containing Carboxyl Groups and Cationic Polymer Containing Amino Groups are Used

[0067] A film formulation containing varenicline tartrate as an active ingredient was prepared in the same manner as in Example 1, using an anionic polymer containing carboxyl groups alone, a cationic polymer containing amino groups alone or a combination of an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as described in Table 1.

[0068] The bitterness masking effect of the film formulation was tested as follows. The TM sensory test was performed for the formulations of the same weight. A test subject put the formulation sample containing varenicline tartrate of the same amount in the mouth, dissolved it for the same time period, spitted it out and then lightly rinsed the mouth with the same amount of water. Then, the time for which bitter and burning taste was maintained was recorded. The time between tests for each formulation sample was set to 3 hours or longer and the subject who felt the bitter and burning taste longer than 3 hours was excluded from the next test.

[0069] The result is shown in Table 1.

TABLE-US-00001 TABLE 1 Compar- ative Example Example (%) 1 2 3 4 5 6 7 Varenicline Tartrate 0.24 Taste (anionic polymer) Purolite C108DR 2.33 2.31 2.31 masking (anionic polymer) Eudragit L100 2.33 2.31 2.31 agent (cationic polymer) Purolite 0.93 0.93 A830EMR (cationic polymer) Eudragit EPO 0.930 0.93 Pullulan 13.0 Plasticizer 7.0 Aspartame 3.0 Pigment 10.0 Diluent Q.S Flavor Q.S Water to 100% Taste masking value 1 2 2 4 4 3 3 * Taste masking value 1poor Retention time of Bitter, burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effects: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. (NLT: no less than, NMT: no more than)

[0070] As seen from Table 1, the bitterness masking effect was remarkably superior when the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups were used together as compared to when the anionic polymer containing carboxyl groups was used alone.

Test Example 2. Test of Bitterness Masking Effect of Film Formulation Containing Varenicline Tartrate as Active Ingredient Depending on Weight Ratio of Anionic Polymer Containing Carboxyl Groups and Cationic Polymer Containing Amino Groups

[0071] A film formulation containing varenicline tartrate as an active ingredient was prepared in the same manner as in Example 1, using a combination of an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as described in Table 2 by varying their weight ratio.

[0072] The bitterness masking effect of the film formulation was tested in the same manner as described in Test Example 1.

[0073] The result is shown in Table 2.

TABLE-US-00002 TABLE 2 Com- par- ative Ex- ample Example % 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Ratio 10:1 1:10 1:100 (API:TM agent) Ratio of TM agent 1:10 5:1 4:1 1:4 20:1 1:10 5:1 4:1 1:4 20:1 1:10 5:1 4:1 1:4 20:1 (Anionic polymer: Cationic polymer) Varenicline Tartrate 0.25 0.24 0.23 0.19 Taste Purolite 0.002 0.019 0.019 0.005 0.019 0.210 1.941 1.867 0.467 2.220 1.751 16.049 15.426 3.857 18.359 masking C108DR agent Eudragit 0.021 0.004 0.005 0.019 0.001 2.100 0.387 0.467 1.867 0.107 17.513 3.202 3.857 15.426 0.918 EPO Pullulan 13.0 Plasticizer 7.0 Aspartame 3.0 Pigment 10.0 Diluent Q.S Flavor Q.S Water to 100% Effect of taste 1 2 3 3 3 1 3 4 4 4 2 3 4 4 4 3 masking * Taste masking value 1poor Retention time of Bitter, burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effects: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. (NLT: no less than, NMT: no more than)

[0074] As seen from Table 2, superior bitterness masking effect was achieved for the varenicline tartrate (API) when the weight ratio of the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups used as the bitter taste masking agents was in the range from 5:1 to 1:4.

Test Example 3. Test of Bitterness Masking Effect of Rapidly Disintegrating Tablet Containing Varenicline Tartrate as Active Ingredient Depending on Weight Ratio of Anionic Polymer Containing Carboxyl Groups and Cationic Polymer Containing Amino Groups

[0075] A rapidly disintegrating tablet containing varenicline tartrate as an active ingredient was prepared in the same manner as in Example 1, using a combination of an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as described in Table 3 by varying their weight ratio.

[0076] The bitterness masking effect of the rapidly disintegrating tablet was tested in the same manner as described in Test Example 1.

[0077] The result is shown in Table 3.

TABLE-US-00003 Com- par- ative Ex- ample Example % 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Ratio 10:1 1:10 1:100 (API:TM agent) Ratio of TM agent 1:10 5:1 4:1 1:4 20:1 1:10 5:1 4:1 1:4 20:1 1:10 5:1 4:1 1:4 20:1 (Anionic polymer: Cationic polymer) Varenicline 0.25 0.24 0.23 0.19 Tartrate Taste Purolite 0.002 0.019 0.019 0.005 0.019 0.210 1.941 1.867 0.467 2.220 1.751 16.049 15.426 3.857 18.359 masking C108DR agent Eudragit 0.021 0.004 0.005 0.019 0.001 2.100 0.387 0.467 1.867 0.107 17.513 3.202 3.857 15.426 0.918 EPO Binder & Disintegration agent & Diluent 60.0 Aspartame 7.0 Flavor (If needed) Q.S Lubricant (If Q.S needed) Water to 100% Effect of taste 1 2 3 3 3 1 3 4 4 4 3 3 4 4 4 3 masking * Taste masking value 1poor Retention time of Bitter, burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effects: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. (NLT: no less than, NMT: no more than)

[0078] As seen from Table 3, superior bitterness masking effect was achieved for the varenicline tartrate (API) when the weight ratio of the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups used as the bitter taste masking agents was in the range from 5:1 to 1:4.

Test Example 4. Test of Film Formulation Depending on Weight Ratio of Anionic Polymer Containing Carboxyl Groups and Cationic Polymer Containing Amino Groups Based on Varenicline Tartrate

[0079] A film formulation containing varenicline tartrate as an active ingredient was prepared in the same manner as in Example 1, by varying the weight ratio of varenicline tartrate, an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as described in Table 4.

[0080] The upper weight ratio limit and the lower weight ratio limit of the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups, which are bitterness masking agents, were set to 1:100:100 and 10:1:1, respectively.

[0081] The bitterness masking effect of the prepared film formulation was tested in the same manner as described in Test Example 1.

[0082] Tensile strength was tested by the following method.

[0083] After coating the solution for forming a film on a support film and cutting to a predetermined size, the formed film was detached from the support film and tensile strength was measured using a universal testing machine (texture analyzer) under the following condition.

TABLE-US-00004 Universal testing machine LLOYD LS-1 Load cell (N) 100N Grips Pneumatic vice grips Testing speed (mm/min) 200 Distance between the grips (mm) 2 Air pressure of the grip (MPa) 0

[0084] The tensile strength was calculated from the measurement results according to the following equation.

Tensile strength=load value(N)/sample area(mm.sup.2)

[0085] Flexibility was evaluated as follows. After coating the solution for forming a film on a support film and cutting to a predetermined size, the formed film was detached from the support film. After folding the formed film, the maximum angle at which the film was not broken was measured.

[0086] The result is shown in Table 4.

TABLE-US-00005 TABLE 4 Comparative Example Example (%) 1 2 3 4 5 6 Ratio 10:1:1 5:4:1 1:100:100 1:8:2 1:40:10 (API:Anionic polymer: Cationic polymer) Varenicline Tartrate 0.25 0.25 0.24 0.23 0.22 0.17 Taste Purolite 0.02 0.19 1.87 8.36 17.00 masking C108DR agent Eudragit 0.02 0.05 0.47 2.21 17.00 EPO Pullulan 13.00 Plasticizer 7.00 Aspartame 3.00 Pigment 10.00 Diluent Q.S Flavor Q.S Water to 100% Evaluation Example No. parameter Weigh 1 2 3 4 5 6 Effect of taste 2 2 4 6 8 8 6 masking Tensile strength 1 4 4 4 4 3 2 Flexibility 1 4 4 4 4 3 2 Total score 10 12 14 16 14 10 * Taste masking value 1poor Retention time of Bitter, burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effects: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. * Tensile strength 1poor Tensile strength value: NMT 5 N/mm.sup.2 2not good Tensile strength value: NMT 10 N/mm.sup.2 3not bad Tensile strength value: NLT 10 N/mm.sup.2 4excellent Tensile strength value: NLT 15 N/mm.sup.2 * Flexibility 1poor Maximised folding angle without breaking NMT 60 2not good Maximised folding angle without breaking NMT 90 3not bad Maximised folding angle without breaking: NLT 90 4excellent Maximsed folding angle without breaking: NLT 150 (NLT: no less than, NMT: no more than)

[0087] As seen from Table 4, the most superior effect was achieved in terms of the bitterness masking effect, tensile strength and flexibility considered together when the weight ratio was 1:8:2.

Test Example 5. Test of Rapidly Disintegrating Tablet Depending on Weight Ratio of Anionic Polymer Containing Carboxyl Groups and Cationic Polymer Containing Amino Groups Based on Varenicline Tartrate

[0088] A rapidly disintegrating tablet containing varenicline tartrate as an active ingredient was prepared in the same manner as in Example 3, by varying the weight ratio of varenicline tartrate, an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as described in Table 5.

[0089] The upper weight ratio limit and the lower weight ratio limit of the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups, which are bitterness masking agents, were set to 1:100:100 and 10:1:1, respectively.

[0090] The bitterness masking effect of the prepared rapidly disintegrating tablet was tested in the same manner as described in Test Example 1.

[0091] Disintegration time was tested according to the Korean Pharmacopoeia General Test Method.

[0092] The result is shown in Table 5.

TABLE-US-00006 TABLE 5 Comparative Example Example (%) 1 2 3 4 5 6 Ratio 10:1:1 5:4:1 1:8:2 1:40:10 1:100:100 (API:Anionic polymer: Cationic polymer) Varenicline Tartrate 0.25 0.25 0.24 0.23 0.22 0.17 Taste Purolite 0.02 0.19 1.87 8.36 17.00 masking C108DR agent Eudragit 0.02 0.05 0.47 2.21 17.00 EPO Binder & Disintegration 60.00 agent & Diluent Aspartame 7.00 Flavor (If needed) Q.S Lubricant (If needed) Q.S Water to 100% Evaluation Example No. parameter Weigh 1 2 3 4 5 6 Effect of taste 2 2 4 6 8 8 6 masking Distintegration 1 4 4 4 4 3 2 Total score 6 8 10 12 11 8 * Taste masking value 1poor Retention time of Bitter, burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effects: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. * Disintegration time 1poor Retention time of ODT in sinker: NLT 2 min 2not good Retention time of ODT in sinker: NLT 1 min 3not bad Retention time of ODT in sinker: NMT 1 min 4excellent Retention time of ODT in sinker: NMT 30 sec *The test is performed using disintegration tester (NLT: no less than, NMT: no more than)

[0093] As seen from Table 5, the most superior effect was achieved in terms of the bitterness masking effect and disintegration time considered together when the weight ratio was 1:8:2.

Test Example 6. Test of Bitterness Masking Effect of Film Formulation Containing Varenicline Salicylate as Active Ingredient Depending on Weight Ratio of Anionic Polymer Containing Carboxyl Groups and Cationic Polymer Containing Amino Groups

[0094] A film formulation containing varenicline salicylate as an active ingredient was prepared in the same manner as in Example 2, using a combination of an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as described in Table 6 by varying their weight ratio.

[0095] The bitterness masking effect of the film formulation was tested in the same manner as described in Test Example 1.

[0096] The result is shown in Table 6.

TABLE-US-00007 TABLE 6 Com- para- tive Ex- ample Example % 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Ratio 10:1 1:10 1:100 (API:TM agent) Ratio of TM agent 1:10 5:1 4:1 1:4 20:1 1:10 5:1 4:1 1:4 20:1 1:10 5:1 4:1 1:4 20:1 (Anionic polymer: Cationic polymer) Varenicline 0.26 0.26 0.25 0.21 Salicylate Taste Purolite 0.002 0.019 0.019 0.005 0.019 0.210 1.941 1.867 0.467 2.220 1.751 16.049 15.426 3.857 18.359 masking C108DR agent Eudragit 0.021 0.004 0.005 0.019 0.001 2.100 0.387 0.467 1.867 0.107 17.513 3.202 3.857 15.426 0.918 EPO Pullulan 13.0 Plasticizer 7.0 Aspartame 3.0 Pigment 10.0 Diluent Q.S Flavor Q.S Water to 100% Effect of taste 1 2 3 3 3 2 3 4 4 4 3 3 4 4 4 3 masking * Taste masking value 1poor Retention time of Bitter, burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effecs: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. (NLT: no less than, NMT: no more than)

[0097] As seen from Table 6, superior bitterness masking effect was achieved for the varenicline salicylate (API) when the weight ratio of the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups used as the bitter taste masking agents was in the range from 5:1 to 1:4.

Test Example 7. Test of Bitterness Masking Effect of Rapidly Disintegrating Tablet Containing Varenicline Salicylate as Active Ingredient Depending on Weight Ratio of Anionic Polymer Containing Carboxyl Groups and Cationic Polymer Containing Amino Groups

[0098] A rapidly disintegrating tablet containing varenicline salicylate as an active ingredient was prepared in the same manner as in Example 2, using a combination of an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as described in Table 7 by varying their weight ratio.

[0099] The bitterness masking effect of the film formulation was tested in the same manner as described in Test Example 1.

[0100] The result is shown in Table 7.

TABLE-US-00008 TABLE 7 Com- para- tive Ex- ample Example % 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Ratio 10:1 1:10 1:100 (API:TM agent) Ratio of TM agent 1:10 5:1 4:1 1:4 20:1 1:10 5:1 4:1 1:4 20:1 1:10 5:1 4:1 1:4 20:1 (Anionic polymer: Cationic polymer) Varenicline 0.26 0.26 0.25 0.21 Salicylate Taste Purolite 0.002 0.019 0.019 0.005 0.019 0.210 1.941 1.867 0.467 2.220 1.751 16.049 15.426 3.857 18.359 masking C108DR agent Eudragit 0.021 0.004 0.005 0.019 0.001 2.100 0.387 0.467 1.867 0.107 17.513 3.202 3.857 15.426 0.918 EPO Binder & 60.0 Disintegration agent & Diluent Aspartame 7.0 Flavor (If needed) Q.S Lubricant Q.S (If needed) Water to 100% Effect of taste 1 2 3 3 3 2 3 4 4 4 3 3 4 4 4 3 masking * Taste masking value 1poor Retention time of Bitter, burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effects: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. (NLT: no less than, NMT: no more than)

[0101] As seen from Table 7, superior bitterness masking effect was achieved for the varenicline salicylate (API) when the weight ratio of the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups used as the bitter taste masking agents was in the range from 5:1 to 1:4.

Test Example 8. Test of Film Formulation Depending on Weight Ratio of Anionic Polymer Containing Carboxyl Groups and Cationic Polymer Containing Amino Groups Based on Varenicline Salicylate

[0102] A film formulation containing varenicline salicylate as an active ingredient was prepared in the same manner as in Example 2, by varying the weight ratio of varenicline salicylate, an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as described in Table 8.

[0103] The upper weight ratio limit and the lower weight ratio limit of the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups, which are bitterness masking agents, were set to 1:100:100 and 10:1:1, respectively.

[0104] The bitterness masking effect of the prepared film formulation was tested in the same manner as described in Test Example 1.

[0105] Tensile strength was tested by the following method.

[0106] After coating the solution for forming a film on a support film and cutting to a predetermined size, the formed film was detached from the support film and tensile strength was measured using a universal testing machine (texture analyzer) under the following condition.

TABLE-US-00009 Universal testing machine LLOYD LS-1 Load cell (N) 100N Grips Pneumatic vice grips Testing speed (mm/min) 200 Distance between the grips (mm) 2 Air pressure of the grip (MPa) 0

[0107] The tensile strength was calculated from the measurement results according to the following equation.

Tensile strength=load value(N)/sample area(mm.sup.2)

[0108] Flexibility was evaluated as follows. After coating the solution for forming a film on a support film and cutting to a predetermined size, the formed film was detached from the support film. After folding the formed film, the maximum angle at which the film was not broken was measured.

[0109] The result is shown in Table 8.

TABLE-US-00010 TABLE 8 Comparative Example Example (%) 1 2 3 4 5 6 Ratio 10:1:1 5:4:1 1:8:2 1:40:10 1:100:100 (API:Anionic polymer: Cationic polymer) Varenicline Salicylate 0.26 0.27 0.26 0.25 0.24 0.19 Taste Purolite 0.02 0.19 1.87 8.36 17.00 masking C108DR agent Eudragit 0.02 0.05 0.47 2.21 17.00 EPO Pullulan 13.00 Plasticizer 7.00 Aspartame 3.00 Pigment 10.00 Diluent Q.S Flavor Q.S Water to 100% Evaluation Example No. parameter Weigh 1 2 3 4 5 6 Effect of taste 2 2 4 6 8 8 8 masking Tensile strength 1 4 4 4 4 3 2 Flexibility 1 4 4 4 4 3 2 Total score 10 12 14 16 14 12 * Taste masking value 1poor Retention time of Bitter, burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effects: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. * Tensile strength 1poor Tensile strength value : NMT 5 N/mm.sup.2 2not good Tensile strength value : NMT 10 N/mm.sup.2 3not bad Tensile strength value : NLT 10 N/mm.sup.2 4excellent Tensile strength value : NLT 15 N/mm.sup.2 * Flexibility 1poor Maximised folding angle without breaking NMT 60 2not good Maximised folding angle without breaking NMT 90 3not bad Maximised folding angle without breaking: NLT 90 4excellent Maximsed folding angle without breaking: NLT 150 (NLT: no less than, NMT: no more than)

[0110] As seen from Table 8, the most superior effect was achieved in terms of the bitterness masking effect, tensile strength and flexibility considered together when the weight ratio was 1:8:2.

Test Example 9. Test of Rapidly Disintegrating Tablet Depending on Weight Ratio of Anionic Polymer Containing Carboxyl Groups and Cationic Polymer Containing Amino Groups Based on Varenicline Salicylate

[0111] A rapidly disintegrating tablet containing varenicline salicylate as an active ingredient was prepared in the same manner as in Example 4, by varying the weight ratio of varenicline salicylate, an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as described in Table 9.

[0112] The upper weight ratio limit and the lower weight ratio limit of the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups, which are bitterness masking agents, were set to 1:100:100 and 10:1:1, respectively.

[0113] The bitterness masking effect of the prepared rapidly disintegrating tablet was tested in the same manner as described in Test Example 1.

[0114] Disintegration time was tested according to the Korean Pharmacopoeia General Test Method.

[0115] The result is shown in Table 9.

TABLE-US-00011 TABLE 9 Comparative Example Example (%) 1 2 3 4 5 6 Ratio 10:1:1 5:4:1 1:100:100 1:8:2 1:40:10 (API:Anionic polymer Cationic polymer) Varenicline Salicylate 0.27 0.27 0.26 0.25 0.24 0.19 Taste Purolite 0.02 0.19 1.87 8.36 17.00 masking C108DR agent Eudragit 0.02 0.05 0.47 2.21 17.00 EPO Binder & Disintegration 60.00 agent & Diluent Aspartame 7.00 Flavor (If needed) Q.S Lubricant (If needed) Q.S Water to 100% Evaluation Example No. parameter Weigh 1 2 3 4 5 6 Effect of taste 2 2 4 6 8 8 8 masking Distintegration 1 4 4 4 4 3 2 Total score 6 8 10 12 11 10 * Taste masking value 1poor Retention time of Bitter burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effects: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. * Disintegration time 1poor Retention time of ODT in sinker: NLT 2 min 2not good Retention time of ODT in sinker: NLT 1 min 3not bad Retention time of ODT in sinker: NMT 1 min 4excellent Retention time of ODT in sinker: NMT 30 sec *The test is performed using disintegration tester (NLT: no less than, NMT: no more than)

[0116] As seen from Table 9, the most superior effect was achieved in terms of the bitterness masking effect and disintegration time considered together when the weight ratio was 1:8:2.

Test Example 10. Test of Difference in Bitterness Masking Effect of Film Formulation Depending on Change in Varenicline Salts

[0117] A film formulation was prepared in the same manner as in Example 1 and Example 2, by varying the varenicline salt as described in Table 10 and using an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as bitterness masking agents.

[0118] The bitterness masking effect of the prepared film formulation was tested in the same manner as described in Test Example 1.

[0119] The result is shown in Table 10.

TABLE-US-00012 TABLE 10 Comparative Example (%) Example (%) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Varenicline 0.23 0.23 Tartrate Varenicline 0.23 0.23 Salicylate Varenicline 0.23 0.23 Sulfate Varenicline 0.23 0.23 Fumarate Varenicline 0.23 0.23 Oxalate Varenicline 0.23 0.23 Hydrochloride Varenicline 0.23 0.23 Hydiobromide Varenicline 0.23 0.23 Citrate Varenicline 0.23 0.23 Malate Varenicline 0.23 0.23 Succinate Varenicline 0.23 0.23 Phosphate Varenicline 0.23 0.23 Tosylate Varenicline 0.23 0.23 Free Base Varenicline 0.23 0.23 Mesylate TM Purolite 1.87 agent C108DR Eudragit 0.47 EPO Pullulan 13 Plasticizer 7 Aspartame 3 Pigment 10 Diluent Q.S Flavor Q.S Water up to 100% Effect of taste 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4 4 4 4 4 3 3 4 4 4 3 4 3 4 masking * Taste masking value 1poor Retention time of Bitter, burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effects: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. (NLT: no less than, NMT: no more than)

[0120] As a result, superior bitterness masking effect was achieved for all of varenicline tartrate, varenicline salicylate, varenicline sulfate, varenicline fumarate, varenicline oxalate, varenicline hydrochloride, varenicline hydrobromide, varenicline citrate, varenicline maleate, varenicline succinate, varenicline phosphate, varenicline tosylate, varenicline free base and varenicline mesylate, when the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups were used as bitterness masking agents.

Test Example 11. Test of Difference in Bitterness Masking Effect of Rapidly Disintegrating Tablet Depending on Change in Varenicline Salts

[0121] A rapidly disintegrating tablet was prepared in the same manner as in Example 3 and Example 4, by varying the varenicline salt as described in Table 11 and using an anionic polymer containing carboxyl groups and a cationic polymer containing amino groups as bitterness masking agents.

[0122] The bitterness masking effect of the prepared rapidly disintegrating tablet was tested in the same manner as described in Test Example 1.

[0123] The result is shown in Table 11.

TABLE-US-00013 TABLE 11 Comparative Example (%) Example (%) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Varenicline 0.23 0.23 Tartrate Varenicline 0.23 0.23 Salicylate Varenicline 0.23 0.23 Sulfate Varenicline 0.23 0.23 Fumarate Varenicline 0.23 0.23 Oxalate Varenicline 0.23 0.23 Hydrochloride Varenicline 0.23 0.23 Hydrobromide Varenicline 0.23 0.23 Citrate Varenicline 0.23 0.23 Malate Varenicline 0.23 0.23 Succinate Varenicline 0.23 0.23 Phosphate Varenicline 0.23 0.23 Tosylate Varenicline 0.23 0.23 Free Base Varenicline 0.23 0.23 Mesylate TM Purolite 1.87 agent C108 DR Eudra- 0.47 git EPO Binder & 60 Disintegration agent & Diluent Aspartame 7 Flavor Q.S (If needed) Lubricant Q.S (If needed) Water up to 100% Effect of taste 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4 4 4 4 4 3 3 4 4 4 3 4 3 4 masking * Taste masking value 1poor Retention time of Bitter, burning effects: NLT 60 min. 2not good Retention time of Bitter, burning effects: NLT 20 min. 3not bad Retention time of Bitter, burning effects: NMT 20 min. 4excellent Retention time of Bitter, burning effects: NMT 5 min. (NLT: no less than, NMT: no more than)

[0124] As a result, superior bitterness masking effect was achieved for all of varenicline tartrate, varenicline salicylate, varenicline sulfate, varenicline fumarate, varenicline oxalate, varenicline hydrochloride, varenicline hydrobromide, varenicline citrate, varenicline maleate, varenicline succinate, varenicline phosphate, varenicline tosylate, varenicline free base and varenicline mesylate, when the anionic polymer containing carboxyl groups and the cationic polymer containing amino groups were used as bitterness masking agents.