Preparation, comprising inclusion complex of varenicline or pharmaceutically acceptable salt thereof, for oral administration

Abstract

The present disclosure relates to an orally administered pharmaceutical formulation containing an inclusion complex formed as varenicline or a pharmaceutically acceptable salt thereof is included in cyclodextrin. The pharmaceutical formulation can improve convenience of medication by effectively masking the bitter taste of the drug and the irritation during swallowing, can provide the oxidation stability of varenicline and can improve the solubility of the drug.

Claims

1. An orally administered pharmaceutical formulation, comprising an inclusion complex formed as varenicline salicylate included in cyclodextrin, wherein the formulation further comprises one or more acids selected from the group consisting of tartaric acid, salicylic acid, benzoic acid, acetic acid, and phosphoric acid, wherein the pharmaceutical formulation is prepared by a method comprising (S1) a step of preparing a mixture of varenicline salicylate and a solvent; (S2) a step of forming a mixture comprising a cyclodextrin inclusion complex by adding cyclodextrin to the mixture and forming a cyclodextrin inclusion complex by heating and stirring the same; (S3) a step of preparing solution for preparing a formulation by mixing a pharmaceutically acceptable additive in the mixture comprising the cyclodextrin inclusion complex; and (S4) a step of preparing the solution for preparing a formulation into the formulation, wherein, in step (S2), the cyclodextrin inclusion complex is formed by using an acid during the stirring and the inclusion complex of the varenicline salicylate and the cyclodextrin is formed at pH 2.5 to 5.5 by adding the acid, and wherein the acid is one or more acids selected from the group consisting of tartaric acid, salicylic acid, benzoic acid, acetic acid, and phosphoric acid.

2. The orally administered pharmaceutical formulation according to claim 1, wherein the cyclodextrin is β-cyclodextrin.

3. The orally administered pharmaceutical formulation according to claim 1, wherein the formulation is a film formulation comprising the varenicline salicylate and the cyclodextrin at a weight ratio of 2:1 to 1:230 (varenicline salicylate: cyclodextrin).

4. The orally administered pharmaceutical formulation according to claim 1, wherein the formulation is a rapidly disintegrating tablet comprising the varenicline salicylate and the cyclodextrin at a weight ratio of 1:4 to 1:520 (varenicline salicylate: cyclodextrin).

5. The orally administered pharmaceutical formulation according to claim 1, wherein the formulation masks the bitter taste of the varenicline salicylate and exhibits improved stability of the drug in the formulation.

6. The orally administered pharmaceutical formulation according to claim 1, wherein the formulation is an orally dissolving film or a disintegrating tablet, wherein 80% or more of the disintegrating tablet dissolves, disperses, or disintegrates within 10 minutes after oral administration.

7. A method for preparing an orally administered formulation of varenicline salicylate, comprising: (S1) a step of preparing a mixture of varenicline salicylate and a solvent; (S2) a step of forming a mixture comprising a cyclodextrin inclusion complex by adding cyclodextrin to the mixture and forming a cyclodextrin inclusion complex by heating and stirring the same; (S3) a step of preparing solution for preparing a formulation by mixing a pharmaceutically acceptable additive in the mixture comprising the cyclodextrin inclusion complex; and (S4) a step of preparing the solution for preparing a formulation into the formulation, wherein, in step (S2), the cyclodextrin inclusion complex is formed by using an acid during the stirring and the inclusion complex of the varenicline salicylate and the cyclodextrin is formed at pH 2.5 to 5.5 by adding the acid, and wherein the acid is one or more acids selected from the group consisting of tartaric acid, salicylic acid, benzoic acid, acetic acid, and phosphoric acid.

8. The method for preparing a formulation according to claim 7, wherein the cyclodextrin is β-cyclodextrin.

9. The method for preparing a formulation according to claim 7, wherein the formulation is an orally administered film and, in the step (S4), the film is prepared by homogenizing a film-forming polymer and the mixture of the inclusion complex and the pharmaceutically acceptable additive and then drying the same.

10. The method for preparing a formulation according to claim 7, wherein, in the step (S2), the inclusion complex of the varenicline salicylate and the cyclodextrin is formed by mixing the varenicline salicylate and the cyclodextrin at a weight ratio of 2:1 to 1:230 (varenicline or pharmaceutically acceptable salt thereof: cyclodextrin) at pH 2.5-5.5 by adding the acid.

11. A smoking cessation aid, comprising an inclusion complex wherein varenicline salicylate is included in cyclodextrin, which is prepared by the preparation method according to claim 7.

Description

DETAILED DESCRIPTION

(1) Hereinafter, the present disclosure will be explained in detail with reference to Examples. The following examples may, however, be embodied in many different forms and should not be construed as limited to the exemplary embodiments set forth therein. Rather, these exemplary embodiments are provided so that the present disclosure will be thorough and complete, and will fully convey the scope of the present disclosure to those skilled in the art.

Example 1. Preparation of Film Containing Salt of Varenicline as Active Ingredient

(2) (1) Preparation of Film Formulation with Bitter Taste of Varenicline Tartrate Masked

(3) A film formulation containing varenicline tartrate as an active ingredient was prepared using the ingredients described in Table 1 by the method described below and the taste-masking effect and physical properties of the film depending on the addition ratio of β-CD and the drug was investigated.

(4) TABLE-US-00001 TABLE 1 Comparative example Example (mg/unit) 1 1 2 3 4 5 6 7 8 API : TM agent   10:1 2:1 1:4 1:20 1:50 1:100 1:200 1:500 Varenicline Tartrate 0.85 (0.5 mg as varenicline) Beta-Cyclodextrin   0.05 0.25 2.00 10.00 25.00 50.00 100.00 250.00 Excipients (%) Pullulan 50.0 Glycerin 12.0 Sucralose 3.0 Ferric oxide red 2.0 TiO.sub.2 10.0 Peppermint powder 3.0 Water q.s.

(5) After adding β-cyclodextrin to a liquid varenicline tartrate solution, the mixture was stirred for 1 hour or longer while heating to 60-70° C. Then, after adding glycerin, sucralose, ferric oxide red, TiO.sub.2 and peppermint to purified water and then 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.

(6) (2) Preparation of Film Formulation with Bitter Taste of Varenicline Salicylate Masked

(7) A film formulation containing varenicline salicylate as an active ingredient was prepared using the ingredients described in Table 2 by the method described below and the taste-masking effect and physical properties of the film depending on the addition ratio of β-CD and the drug was investigated.

(8) TABLE-US-00002 TABLE 2 Comparative example Example (mg/unit) 2 9 10 11 12 13 14 15 16 API : TM agent   10:1 2:1 1:4 1:20 1:50 1:100 1:200 1:500 Varenicline Salicylate 0.82 (0.5 mg as varenicline) Beta-Cyclodextrin   0.05 0.25 2.00 10.00 25.00 50.00 100.00 250.00 Excipients (%) Pullulan 50.0 Glycerin 12.0 Sucralose 3.0 Ferric oxide red 2.0 TiO.sub.2 10.0 Peppermint powder 3.0 Water q.s.

(9) After adding β-cyclodextrin to a liquid varenicline salicylate solution, the mixture was stirred for 1 hour or longer while heating to 60-70° C. Then, after adding glycerin, sucralose, ferric oxide red, TiO.sub.2 and peppermint powder to purified water and then 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.

(10) (3) Investigation of Taste-Masking Effect and Physical Properties of Film Depending on Addition Ratio of β-CD and Drug

(11) The following experiment was conducted to investigate the taste-masking effect and physical properties of the film depending on the addition ratio of β-CD and the drug and the result is given in Table 6.

(12) The taste-masking effect of the film formulation was investigated as follows. The TM sensory test was performed with the formulation of the same amount. 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 unpleasant 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 unpleasant taste longer than 3 hours was excluded from the next test. The detailed evaluation criteria were as follows.

(13) TABLE-US-00003 TABLE 3 1-poor Retention time of unpleasant taste: NLT 60 min. 2-not good Retention time of unpleasant taste: NLT 20 min. 3-not bad Retention time of unpleasant taste: NMT 20 min. 4-excellent Retention time of unpleasant taste: NMT 5 min. (NLT: no less than, NMT: no more than)

(14) Tensile strength was tested by the following method. 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.

(15) Universal testing machine: LLOYS LS-1

(16) Load cell (N): 100 N

(17) Grips: Pneumatic vice grips

(18) Testing speed (mm/min): 200

(19) Distance between grips (mm): 2

(20) Air pressure of grip: (MPa): 0

(21) The tensile strength was calculated from the measurement results according to the following equation.
Tensile strength=load value (N)/sample area (mm.sup.2)

(22) TABLE-US-00004 TABLE 4 1-poor Tensile strength value: NMT 5 N/mm.sup.2 2-not good Tensile strength value: NMT 10 N/mm.sup.2 3-not bad Tensile strength value: NLT 10 N/mm.sup.2 4-excellent Tensile strength value: NLT 15 N/mm.sup.2

(23) 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.

(24) TABLE-US-00005 TABLE 5 1-poor Maximum folding angle without breaking NMT 60° 2-not good Maximum folding angle without breaking NMT 90° 3-not bad Maximum folding angle without breaking: NLT 90° 4-excellent Maximum folding angle without breaking: NLT 150°

(25) The measurement result is as follows.

(26) TABLE-US-00006 TABLE 6 Comparative Example No. Evaluation Example 1 1 2 3 4 5 6 7 8 parameter Weigh Score = Each parameter value × Weigh Effect of 3 3 3 6 9 9 9 9 9  9 taste masking Tensile 1 4 4 4 4 4 4 4 3  1 strength Flexibility 1 4 4 4 4 4 4 4 3  2 Total score 11 11 14 17 17 17 17 15 12 Comparative Example No. Evaluation Example 2 9 10 11 12 13 14 15 16 parameter Weigh Score = Each parameter value × Weigh Effect of 3 3 3 6 9 9 9 9 9  9 taste masking Tensile 1 4 4 4 4 4 4 4 3  1 strength Flexibility 1 4 4 4 4 4 4 4 3  2 Total score 11 11 14 17 17 17 17 15 12

(27) As can be seen from Table 6, the taste-masking effect was different depending on the ratio of the varenicline salt and the β-cyclodextrin. The best taste-masking effect was achieved when the β-cyclodextrin was added at a ratio of 1:4 or higher. When the mixing ratio was 1:500 or higher, the addition of the β-cyclodextrin negatively affected the flexibility and tensile strength of the film.

(28) In Table 6, ‘weigh’ refers to the weight applied to each parameter value. To take Comparative Example 1 for example, the weight 3 was applied to the taste masking value-1 (poor) [1 (taste masking value)*3 (weigh)=3].

Example 2. Preparation of Rapidly Disintegrating Tablet Containing Salt of Varenicline as Active Ingredient

(29) (1) Preparation of Rapidly Disintegrating Tablet with Bitter Taste of Varenicline Tartrate Masked

(30) A rapidly disintegrating tablet containing varenicline tartrate as an active ingredient was prepared using the ingredients described in Table 7 by the method described below and the taste-masking effect and hardness of the tablet depending on the addition ratio of β-CD and the drug was investigated.

(31) After adding β-CD to a liquid varenicline tartrate solution, the mixture was stirred for 1 hour or longer.

(32) Then, a solid was obtained from the mixture through filtration or evaporation of the solvent under reduced pressure. After adding a binder, a disintegrant, an excipient and a lubricant to the obtained solid and then mixing the same, a tablet was prepared using a tablet-making machine.

(33) TABLE-US-00007 TABLE 7 Comparative example Example (mg/unit) 2-1 2-1 2-2 2-3 2-4 2-5 2-6 2-7 2-8 2-9 API : TM agent   10:1 2:1 1:4 1:20 1:50 1:100 1:250 1:500 1:1000 Varenicline Tartrate 0.85 (0.5 mg as varenicline) Beta-Cyclodextrin   0.05 0.25 2.00 10.00 25.00 50.00 125.00 250.00 500.00 Excipients (%) Mannitol 30.0 Avicell 10.0 HPC-L 3.0 Magnesium stearate 0.5 Sucralose 2.0 Peppermint powder 2.0 Water q.s.

(34) (2) Preparation of Rapidly Disintegrating Tablet with Bitter Taste of Varenicline Salicylate Masked

(35) A rapidly disintegrating tablet containing varenicline salicylate as an active ingredient was prepared using the ingredients described in Table 8 by the method described below and the taste-masking effect and hardness of the tablet depending on the addition ratio of β-CD and the drug was investigated.

(36) After adding β-CD to a liquid varenicline salicylate solution, the mixture was stirred for 1 hour or longer.

(37) Then, a solid was obtained from the mixture through filtration or evaporation of the solvent under reduced pressure. After adding a binder, a disintegrant, an excipient and a lubricant to the obtained solid and then mixing the same, a tablet was prepared using a tablet-making machine.

(38) TABLE-US-00008 TABLE 8 Comparative example Example (mg/unit) 2-2 2-10 2-11 2-12 2-13 2-14 2-15 2-16 2-17 2-18 API : TM agent   10:1 2:1 1:4 1:20 1:50 1:100 1:250 1:500 1:1000 Varenicline Salicylate 0.82 (0.5 mg as varenicline) Beta-Cyclodextrin   0.05 0.25 2.00 10.00 25.00 50.00 125.00 250.00 500.00 Excipients (%) Mannitol 30.0 Avicell 10.0 HPC-L 3.0 Magnesium stearate 0.5 Sucralose 2.0 Peppermint powder 2.0 Water q.s.

(39) (3) Investigation of Taste-Masking Effect and Formability of Rapidly Disintegrating Tablet Depending on Addition Rate of β-CD and Drug

(40) The following experiment was conducted to investigate the taste-masking effect and formability of the tablet depending on the addition rate of the β-CD and the drug. The result is given in Table 9.

(41) The taste-masking effect of the tablet was measured in the same manner as the measurement of the taste-masking effect of the film.

(42) The tablet formability was measured based on the hardness of the tablet. The evaluation criteria were as follows.

(43) The hardness was measured using a tablet harness tester (Vankel VK 200). While gradually increasing the force applied to the tablet, the force at the time when the tablet was broken was recorded.

(44) TABLE-US-00009 TABLE 9 1-poor Tablet not formed 2-not good Hardness: NMT 3 3-not bad Hardness: 3-10 4-excellent Hardness: NLT 10

(45) The result is as follows.

(46) TABLE-US-00010 TABLE 10 Comparative example Example No. 2-1 2-1 2-2 2-3 2-4 2-5 2-6 2-7 2-8 2-9 Evaluation parameter Weigh Score = Each parameter value × Weigh Effect of taste masking 3 3 3 6 9 9 9 9 9 9 9 Hardness 1 4 4 4 4 4 4 4 4 3 1 Total score 7 7 10 13 13 13 13 13 12 10 Comparative example Example No. 2-2 2-10 2-11 2-12 2-13 2-14 2-15 2-16 2-17 2-18 Evaluation parameter Weigh Score = Each parameter value × Weigh Effect of taste masking 3 3 3 6 9 9 9 9 9 9 9 Hardness 1 4 4 4 4 4 4 4 4 3 1 Total score 7 7 10 13 13 13 13 13 12 10

(47) As can be seen from Table 10, the taste-masking effect was different depending on the ratio of the varenicline salt and the β-cyclodextrin. The best taste-masking effect was achieved when the β-cyclodextrin was added at a ratio of 1:4 or higher. When the addition amount of the β-cyclodextrin was 1:1000 or higher, the hardness of the prepared orally disintegrating tablet was decreased.

Example 3. Preparation of Suspension Formulation Containing Salt of Varenicline as Active Ingredient

(48) 1) After adding β-cyclodextrin to a liquid varenicline tartrate solution, the mixture was stirred for 1 hour or longer while heating to 60-70° C.

(49) 2) Then, after adding a flavor, a colorant, a stabilizer, a preservative, a buffer or an excipient to purified water, a suspension formulation was prepared by dissolving or mixing the same through stirring.

(50) TABLE-US-00011 TABLE 11 Comparative Example Examples (mg/unit) 3-1 3-1 3-2 3-3 3-4 3-5 3-6 3-7 3-8 3-9 API: TM agent — 10:1 2:1 1:4 1:20 1:50 1:100 1:250 1:500 1:1000 Varenicline Tartrate 0.85 (0.5 mg as varenicline) Beta-Cyclodextrin — 0.05 0.25 2.00 10.00 25.00 50.00 125.00 250.00 500.00 Excipients (%) Sucralose 3 Mannitol 15 Xanthan gum 0.1 Sodium CMC 5.0 Propyl paraben 0.02 Methyl paraben 0.08 Peppermint powder 3.0 Water q.s. Comparative Example Examples No. 3-1 3-1 3-2 3-3 3-4 3-5 3-6 3-7 3-8 3-9 Evaluation parameter Score = Each parameter value × Weigh Effect of taste masking 3 3 6 9 9 9 9 9 9 9

Example 4. Preparation of Granule Containing Salt of Varenicline as Active Ingredient

(51) 1) After adding β-cyclodextrin to a liquid varenicline tartrate solution, the mixture was stirred for 1 hour or longer while heating to 60-70° C.

(52) 2) Then, a solid was obtained by precipitating the solution, followed by filtering and drying. 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 spry-dried to prepare a granule.

(53) TABLE-US-00012 TABLE 12 Comparative Example Examples (mg/unit) 4-1 4-1 4-2 4-3 4-4 4-5 4-6 4-7 4-8 4-9 API: TM agent — 10:1 2:1 1:4 1:20 1:50 1:100 1:250 1:500 1:1000 Varenicline Tartrate 0.85 (0.5 mg as varenicline) Beta-Cyclodextrin — 0.05 0.25 2.00 10.00 25.00 50.00 125.00 250.00 500.00 Excipients (%) MCC 10 Mannitol 160C 35 HPC-SL 2 Peppermint powder 3.0 Sucralose q.s. Water q.s. Comparative Example Examples No. 4-1 4-1 4-2 4-3 4-4 4-5 4-6 4-7 4-8 4-9 Evaluation parameter Score = Each parameter value × Weigh Effect of taste masking 3 3 6 9 9 9 9 9 9 9

(54) Also for Examples 3 and 4, taste-masking effect could be achieved by adding the β-cyclodextrin.

Example 5. Investigation of Effect of Adding Acidifier

(55) (1) Film Formulation Containing Varenicline Salt

(56) A film formulation was prepared in the same manner as in Example 1 under an acidic condition by adding an acidifier as described in Tables 13 and 14. Then, taste-masking effect and film formability were measured. Table 13 shows the composition of a film formulation containing varenicline tartrate and Table 14 shows the composition of a film formulation containing varenicline salicylate.

(57) Preparation method: After dissolving varenicline tartrate or salicylate and β-cyclodextrin in water, the mixture was stirred for 1 hour while heating to 60-70° C. Then, after adding glycerin, sucralose, a sweetener and a flavor, the mixture was dissolved by stirring and then homogenized using a homogenizer (Ultra-Turrax T-24, IKA). Then, after adding pullulan as a film-forming agent and then homogenizing using the same homogenizer, a diluted acidifier solution (tartaric acid 5 mg/mL) was added to the solution for preparing a film little by little until the pH described in Tables 13 and 14 was reached. After removing a gas from the solution in vacuo, the solution was coated on a PET film to an appropriate thickness. Then, a film formulation containing the varenicline salt was prepared by drying the same at 60-80° C.

(58) TABLE-US-00013 TABLE 13 Comparative Example Examples (mg/mL) 5-1 5-2 5-3 5-4 5-5 5-6 5-1 5-2 5-3 5-4 5-5 5-6 Controlled pH Not pH 2 pH 6 pH 3 pH 4 pH 5 controlled (± 10%) (± 10%) (± 10%) (± 10%) (± 10%) API: TM agent 1:4 1:1 1:4 1:1 1:4 1:1 1:4 1:1 1:4 1:1 1:4 1:1 00 00 00 00 00 Varenicline Tartrate 0.85 (0.5 mg as varenicline) Beta-Cyclodextrin 2 50 2 50 2 50 2 50 2 50 2 50 Excipients (%) Pullulan 50.0 Glycerin 12.0 Sucralose 3.0 Ferric oxide red 2.0 TiO.sub.2 10.0 Peppermint powder 3.0 pH control agent q.s. (Tartaric acid) Water q.s. Comparative Example Examples No. Evaluation 5-1 5-2 5-3 5-4 5-5 5-6 5-1 5-2 5-3 5-4 5-5 5-6 parameter Weigh Score = Each parameter value × Weigh Effect of 3 9 9 9 9 9 9 12 12 12 12 12 12 taste masking Film Forming 1 4 4 4 4 4 4 4 4 4 4 4 4 Total score 13 13 13 13 13 13 13 16 16 16 16 16

(59) TABLE-US-00014 TABLE 14 Comparative Example Examples (mg/mL) 5-7 5-8 5-9 5-10 5-11 5-12 5-7 5-8 5-9 5-10 5-11 5-12 Controlled pH Not pH 2 pH 6 pH 3 pH 4 pH 5 controlled (± 10%) (± 10%) (± 10%) (± 10%) (± 10%) API: TM agent 1:4 1:100 1:4 1:10 1:4 1:10 1:4 1:10 1:4 1:10 1:4 1:100 0 0 0 0 Varenicline Salicylate 0.82 (0.5 mg as varenicline) Beta-Cyclodextrin 2 50 2 50 2 50 2 50 2 50 2 50 Excipients (%) Pullulan 50.0 Glycerin 12.0 Sucralose 3.0 Ferric oxide red 2.0 TiO.sub.2 10.0 Peppermint powder 3.0 pH control agent q.s. (Tartaric acid) Water q.s. Comparative Example Examples No. Evaluation 5-7 5-8 5-9 5-10 5-11 5-12 5-7 5-8 5-9 5-10 5-11 5-12 parameter Weigh Score = Each parameter value × Weigh Effect of 3 9 9 9 9 9 9 12 12 12 12 12 12 taste masking Film Forming 1 4 4 4 4 4 4 4 4 4 4 4 4 Total score 13 13 13 13 13 13 16 16 16 16 16 16

(60) Film formability was evaluated according to the following criteria.

(61) TABLE-US-00015 TABLE 15 1-poor Film is not formed 2-not good Formed, but having lots of cracks 3-not bad Formed, but a little crack 4-excellent Film is formed well

(62) (2) Rapidly Disintegrating Tablet Containing Varenicline Salt

(63) A tablet was prepared in the same manner as in Example 2 under an acidic condition by adding an acidifier as described in Tables 16 and 17. Then, taste-masking effect and film formability were measured. Table 16 shows the composition of a rapidly disintegrating tablet containing varenicline tartrate and Table 17 shows the composition of a rapidly disintegrating tablet containing varenicline salicylate.

(64) TABLE-US-00016 TABLE 16 Comparative Example Examples (mg/unit) 6-1 6-2 6-3 6-4 6-5 6-6 6-1 6-2 6-3 6-4 6-5 6-6 Controlled pH Not pH 2 pH 6 pH 3 pH 4 pH 5 controlled (± 10%) (± 10%) (± 10%) (± 10%) (± 10%) API: TM agent 1:4 1:250 1:4 1:250 1:4 1:250 1:4 1:250 1:4 1:250 1:4 1:250 Varenicline Tartrate 0.85 (0.5 mg as varenicline) Beta-Cyclodextrin 2 125 2 125 2 125 2 125 2 125 2 125 Excipients (%) Mannitol 30.0 Avicell 10.0 HPC-L 3.0 Magnesium stearate 0.5 Sucralose 2.0 Peppermint powder 2.0 pH control agent q.s. (Tartaric acid) Water q.s. Comparative Example Examples No. 6-1 6-2 6-3 6-4 6-5 6-6 6-1 6-2 6-3 6-4 6-5 6-6 Evaluation parameter Weigh Score = Each parameter value × Weigh Effect of 3 9 9 9 9 9 9 12 12 12 12 12 12 taste masking Hardness 1 4 4 4 4 4 4 4 4 4 4 4 4 Total score 13 13 13 13 13 13 16 16 16 16 16 16

(65) TABLE-US-00017 TABLE 17 Comparative Example Examples (mg/mL) 6-7 6-8 6-9 6-10 6-11 6-12 6-7 6-8 6-9 6-10 6-11 6-12 Controlled pH Not pH 2 pH 6 pH 3 pH 4 pH 5 controlled (± 10%) (± 10%) (± 10%) (± 10%) (± 10%) API: TM agent 1:4 1:250 1:4 1:250 1:4 1:250 1:4 1:250 1:4 1:250 1:4 1:250 Varenicline Tartrate 0.82 (0.5 mg as varenicline) Beta-Cyclodextrin 2 125 2 125 2 125 2 125 2 125 2 125 Excipients (%) Mannitol 30.0 Avicell 10.0 HPC-L 3.0 Magnesium stearate 0.5 Sucralose 2.0 Peppermint powder 2.0 pH control agent q.s. (Tartaric acid) Water q.s. Comparative Example Examples No. 6-7 6-8 6-9 6-10 6-11 6-12 6-7 6-8 6-9 6-10 6-11 6-12 Evaluation parameter Weigh Score = Each parameter value × Weigh Effect of 3 9 9 9 9 9 9 12 12 12 12 12 12 taste masking Hardness 1 4 4 4 4 4 4 4 4 4 4 4 4 Total score 13 13 13 13 13 13 16 16 16 16 16 16

Example 6. Effect of Acid Addition on Stabilization

Test Example

(66) Stability Test Method

(67) Assay (%) and total impurities (%) were investigated by HPLC (high-performance liquid chromatography). A test solution for conducting HPLC was prepared as follows.

(68) Preparation of Test Solution

(69) A film containing 1 mg of a varenicline salt was put in a 10-mL flask and mixed with a mobile phase. The mixture was centrifuged for 20 minutes. The centrifugate was filtered through a 0.45-μm filter (water-soluble PVDF). As a result, a test solution (0.1 mg/mL) was obtained.

(70) Preparation of Standard Solution

(71) 20 mg of a varenicline salt was added to a 200-mL flask together with a mobile phase. The mixture was sonicated and then stirred. As a result, a standard solution (0.1 mg/mL) was obtained.

(72) HPLC Condition

(73) Detector: UV (237 nm)

(74) Column: ODS, 150×4.6 mm, 5 μm

(75) Flow rate: 1.0 mL/min

(76) Mobile Phase

(77) A: ACN:buffer (88:12)

(78) B: ACN Buffer=1.3606 g of KH.sub.2PO.sub.4 dissolved in 1 L of distilled water.

(79) <Gradient Condition>

(80) TABLE-US-00018 TABLE 18 Time (min) Mobile phase A Mobile phase B 0 100 0 3 100 0 15 80 20 58 35 65 60 100 0 70 100 0

(81) Assay (%)
Assay (%)=A.sub.t/A.sub.s×C.sub.s/C.sub.t×P

(82) A.sub.t: area response of varenicline in test sample solution

(83) A.sub.s: area response of varenicline in standard sample solution

(84) C.sub.t: varenicline concentration of test sample solution

(85) C.sub.s: varenicline concentration of standard sample solution

(86) P: purity of desmopressin acetate standard (%)

(87) Total Impurities (%)
Total impurities=sum total of individual impurities
Individual impurity (%)=A.sub.i/A.sub.t×100

(88) A.sub.i: area response of impurity in test sample solution

(89) A.sub.t: area response of varenicline in test sample solution

(90) LOD (Loss on Drying)

(91) LOD was tested according to the method described in USP 731 at 105° C. for 4 hours.

(92) The assay and impurity evaluation criteria were as follows.

(93) TABLE-US-00019 TABLE 19 Change amount Assay judgement Very good ≤±0.5%   Good −0.5% to −1.0% Bad −1.0% to −2.0% Poor ≥−5.0%   Impurity judgement Very good ≤0.3% Good 0.3% to 0.6% Bad 0.6% to 1.0% Poor ≥1.0%

(94) Stability was tested under an accelerated condition (40±2° C., relative humidity 60±5%). In order to prevent contact with external water, the test was conducted after putting the pharmaceutical formulation in a multi-layered aluminum foil container and sealing the same.

(95) The assay (%) is the amount of varenicline retained in the pharmaceutical formulation and change amount (%) is the change of the assay (%) value depending on time, reflecting the change in the amount of varenicline in the pharmaceutical formulation with time. The assay (%) was measured 0, 4 and 8 weeks later and the difference between the assay (%) at week 0 and the assay (%) at week 8 was recorded as the change amount (%).

(96) The total impurities (%) is the amount of varenicline-derived related substances in the pharmaceutical formulation and the change amount (%) is the change of the total impurities (%) value depending on time, reflecting the change in the amount of the varenicline related substances in the pharmaceutical formulation with time. The total impurities (%) was measured at weeks 0, 4 and 8 and the difference between the total impurities (%) at week 0 and the total impurities (%) at week 8 was recorded as the change amount (%).

(97) 6-1. Effect of Organic Acid on Stabilization of Film Formulation Containing Varenicline Tartrate

(98) The stability of a varenicline salt was investigated after adjusting the pH of the solution for preparing a film formulation to 4 using different organic acids.

(99) Preparation method: After dissolving varenicline tartrate and β-cyclodextrin in water, the mixture was stirred for 1 hour while heating to 60-70° C. Then, after adding glycerin, sucralose, a sweetener and a flavor, the mixture was dissolved by stirring and then homogenized using a homogenizer (Ultra-Turrax T-24, IKA). Then, after adding pullulan and homogenizing using the same homogenizer, a diluted acidifier solution (tartaric acid 5 mg/mL) was added to the solution for preparing a film little by little until the pH described in Tables 20 and 21 was reached. After removing a gas from the solution in vacuo, 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.

(100) TABLE-US-00020 TABLE 20 Comparative Example Examples 7-1 7-1 7-2 7-3 7-4 7-5 7-6 7-7 7-8 Varenicline 1.00 Tartrate Beta- 50.00 Cyclodextrin Citric acid — Add until — — — — — — — pH 4.0 Tartaric acid — — Add until — — — — — pH 4.0 Salicylic — — — Add until — — — — — acid pH 4.0 Benzoic — — — — Add until — — — — acid pH 4.0 Acetic acid — — — — — Add until — — pH 4.0 Phosphoric — — — — — — Add until — — acid pH 4.0 pyruvic acid — — — — — — — Add until — pH 4.0 Gallic acid — — — — — — — — Add until pH 4.0 Excipients (%) Pullulan 50.00 Glycerin 8.00 TiO.sub.2 10.00 Sucralose 3.000 Ferric oxide q.s. (red) Peppermint powder q.s. Water q.s. LOD (%) 9.1 9.8 10.1 9.3 9.6 9.8 9.5 9.8 9.7 LOD test condition: 105° C., 4 hrs.

(101) TABLE-US-00021 TABLE 21 Examples Period Ref Contents (weeks) 7-1 7-1 7-2 7-3 7-4 7-5 7-6 7-7 7-8 Assay (%) 0 100.4 100.9 100.4 100.6 101.3 100.7 101.6 100.9 100.7 4 95.4 100.7 100.3 100.5 101.4 100.5 101.4 100.7 100.6 8 95.1 100.7 100.2 100.8 101.3 100.6 101.5 100.7 100.5 Change amount (%) −5.3 −0.2 −0.2 0.2 0.0 −0.1 −0.1 −0.2 −0.2 Judgement Poor Very Very Very Very Very Very Very Very Good good good good good good good good Total 0 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 impurity 4 ≤1.5 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.3 ≤0.3 (%) 8 ≤1.9 ≤0.5 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.5 ≤0.5 Change amount (%) 1.8 0.4 0.1 0.1 0.1 0.1 0.1 0.4 0.4 Judgement Poor Good Very Very Very Very Very Good Good good good good good good - Storage condition: Accelerated condition (40° C., 60% RH) - Storage container: Multi-layer aluminum foil

(102) The change in the contents of varenicline and related substances depending on the organic acids added could be confirmed. In particular, the films prepared at pH 4.0 by adding tartaric acid, salicylic acid, benzoic acid, acetic acid or phosphoric acid showed superior stability with decreased change in varenicline content and less generation of related substance with time.

(103) In addition, it was confirmed that the taste-masking effect was excellent and the solubility was higher when tartaric acid was added.

(104) 6-2. Effect of Organic Acid on Stabilization of Film Formulation Containing Varenicline Salicylate

(105) The stability of a varenicline salt was investigated after adjusting the pH of the solution for preparing a film formulation to 4 using different organic acids.

(106) TABLE-US-00022 TABLE 22 Examples (mg/unit) 7-2 7-9 7-10 7-11 7-12 7-13 7-14 7-15 7-16 Ingredients Ref. Varenicline 1.00 Salicylate Beta- 50.00 Cyclodextrin Citric acid — Add until — — — — — — — pH 4.0 Tartaric acid — — Add until — — — — — pH 4.0 Salicylic — — — Add until — — — — — acid pH 4.0 Benzoic — — — — Add until — — — — acid pH 4.0 Acetic acid — — — — — Add until — — pH 4.0 Phosphoric — — — — — — Add until — — acid pH 4.0 Pyruvic acid — — — — — — — Add until — pH 4.0 Gallic acid — — — — — — — — Add until pH 4.0 Excipients (%) Pullulan 50.00 Glycerin 8.00 TiO.sub.2 10.00 Sucralose 3.000 Ferric oxide q.s. (red) Peppermint powder q.s. Water q.s. LOD (%) 9.3 9.4 9.6 9.4 9.5 9.8 9.9 9.5 9.6

(107) TABLE-US-00023 TABLE 23 Examples Period Ref Contents (weeks) 7-2 7-9 7-10 7-11 7-12 7-13 7-14 7-15 7-16 Assay (%) 0 100.4 100.9 100.3 100.5 101.4 100.6 101.4 100.8 100.8 4 95.5 100.8 100.2 100.4 101.2 100.6 101.7 100.6 100.5 8 95.7 100.6 100.5 100.6 101.4 100.7 101.2 100.5 100.6 Change amount (%) −4.7 −0.3 0.2 0.1 0.0 0.1 −0.2 −0.3 −0.2 Judgement Poor Very Very Very Very Very Very Very Very Good good good good good good good good Total impurity (%) 0 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 4 ≤1.5 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.3 ≤0.3 8 ≤20 ≤0.5 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.5 ≤0.5 Change amount (%) 1.9 0.4 0.1 0.1 0.1 0.1 0.1 0.4 0.4 Judgement Poor Good Very Very Very Very Very Good Good good good good good good Storage condition: Accelerated condition (40° C., 60% RH) Storage container: multi-layered aluminum foil

(108) The change in the contents of varenicline and related substances depending on the organic acids added could be confirmed. In particular, the films prepared at pH 4.0 by adding tartaric acid, salicylic acid, benzoic acid, acetic acid or phosphoric acid showed superior stability with decreased change in varenicline content and less generation of related substance with time.

(109) 6-3. Effect of pH on Stabilization of Film Formulation Containing Varenicline Tartrate

(110) TABLE-US-00024 TABLE 24 8-1 8-1 8-2 8-3 8-4 8-5 8-6 8-7 8-8 8-9 8-10 8-11 8-12 Ingredients Ref Adjust pH 3.0 (± 10%) Adjust pH 4.0 (± 10%) Adjust pH 5.0 (± 10%) Adjust pH 6.0 (± 10%) Varenicline Tartrate 1.00 Beta-Cyclodextrin 50.00 Tartaric acid — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ — — Salicylic acid — — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ — Acetic acid — — — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ Excipients (%) Pullulan 50.00 Glycerin 8.00 TiO.sub.2 5.00 Sucralose 0.10 Ferric oxide (red) 0.30 Peppermint powder q.s. Flavor q.s. Water q.s. LOD (%) 9.5 9.4 9.6 9.5 9.8 9.9 9.4 9.5 9.3 9.6 10.1 9.5 9.8

(111) TABLE-US-00025 TABLE 25 Examples Period Ref. Contents (weeks) 8-1 8-1 8-2 8-3 8-4 8-5 8-6 8-7 8-8 8-9 8-10 8-11 8-12 Assay (%) 0 100.4 100.7 100.3 100.3 101.4 100.7 101.6 101.2 100.7 101.3 101.4 100.9 100.9 4 95.4 100.5 100.1 100.2 101.3 100.6 101.3 101.1 100.6 101.1 100.5 100.3 100.2 8 95.1 100.3 100.4 100.1 101.2 100.5 101.2 100.9 100.8 100.9 99.8 99.5 99.8 Change −5.3 −0.4 0.1 −0.2 −0.2 −0.2 −0.4 −0.3 0.1 −0.4 −1.6 −1.4 -1.1 amount (%) Judgement Poor Very Very Very Very Very Very Very Very Very bad bad bad good good good good good good good good good Total 0 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 0.1 0.1 0.1 impurity (%) 4 ≤1.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 1.0 1.0 1.0 8 ≤1.9 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤0.3 1.3 1.6 1.7 Change 1.8 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 1.2 1.5 1.6 amount (%) Judgement Poor Very Very Very Very Very Very Very Very Very poor poor poor good good good good good good good good good

(112) It was confirmed that superior stability with less change in varenicline content and less generation of related substances was achieved when the pH of the solution for preparing a film was 3-5.

(113) 6-4. Effect of pH on Stabilization of Film Formulation Containing Varenicline Salicylate

(114) TABLE-US-00026 TABLE 26 9-1 9-1 9-2 9-3 9-4 9-5 9-6 9-7 9-8 9-9 9-10 9-11 9-12 Ref Adjust pH 3.0 Adjust pH 4.0 Adjust pH 5.0 Adjust pH 6.0 Ingredients (± 10%) (± 10%) (± 10%) (± 10%) Varenicline 1.00 Salicylate Beta- 50.00 Cyclodextrin Tartaric acid — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ — — Salicylic acid — — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ — Acetic acid — — — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ — — — — — — — — — — — — — — — ◯ Excipients (%) Pullulan 50.00 Glycerin 8.00 TiO.sub.2 5.00 Sucralose 0.10 Ferric oxide 0.30 (red) Peppermint q.s. powder Flavor q.s. Water q.s. LOD (%) 9.6 9.4 9.5 9.3 9.6 9.7 9.4 9.1 9.8 9.6 9.4 9.5 9.6

(115) TABLE-US-00027 TABLE 27 Period Examples Contents (weeks) 9-1 9-1 9-2 9-3 9-4 9-5 9-6 9-7 9-8 9-9 9-10 9-11 9-12 Assay (%) 0 100.4 100.6 100.4 100.2 101.5 100.5 101.4 101.5 100.6 101.3 101.3 100.9 100.8 4 95.4 100.3 100.3 100.6 101.4 100.4 101.3 101.4 100.4 101 100.7 100.4 100.1 8 95.1 100.4 100.4 100.4 101.5 100.5 101.6 101.2 100.4 100.9 99.7 99.6 99.7 Change amount (%) −5.3 −0.2 0.0 0.2 0.0 0.0 0.2 −0.3 −0.2 −0.4 −1.6 −1.3 −1.1 Judgement Poor Very Very Very Very Very Very Very Very Very bad bad bad good good good good good good good good good Total 0 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 ≤0.1 impurity 4 ≤1.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤0.2 ≤1.0 ≤1.0 ≤1.0 (%) 8 ≤1.9 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤0.3 ≤1.4 ≤1.5 ≤1.6 Change amount (%) 1.8 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 1.3 1.4 1.5 Judgement Poor Very Very Very Very Very Very Very Very Very poor poor poor good good good good good good good good good

(116) It was confirmed that superior stability with less change in varenicline content and less generation of related substances was achieved when the pH of the solution for preparing a film was 3-5.

INDUSTRIAL APPLICABILITY

(117) A formulation the present disclosure is a superior orally administered formulation which masks the bitter taste of varenicline or a pharmaceutically acceptable salt thereof and improves swallowing.

(118) The formulation the present disclosure may be used as a smoking cessation aid.