VILAZODONE INCLUSION COMPLEXES, COMPOSITIONS AND PREPARATION THEREOF

Abstract

Disclosed herein are inclusion complexes comprising vilazodone or a pharmaceutically acceptable salt thereof and an inclusion material, compositions and pharmaceutical formulations comprising the inclusion complexes, and methods for preparing the inclusion complexes, compositions or pharmaceutical formulations.

Claims

1. A composition comprising an active ingredient contained in an inclusion material, wherein the active ingredient is vilazodone or a pharmaceutically acceptable salt thereof, the inclusion material is hydroxypropyl--cyclodextrin, and the weight ratio of the active ingredient to the inclusion material is from 1:5 to 1:45.4.

2. The composition of claim 1, wherein the weight ratio of the active ingredient to hydroxypropyl--cyclodextrin is from 1:6.5 to 1:45.4.

3. The composition of claim 1, wherein the weight ratio of the active ingredient to hydroxypropyl--cyclodextrin is from 1:7 to 1:20.

4. The composition of claim 1, wherein the weight ratio of the active ingredient to hydroxypropyl--cyclodextrin is from 1:8 to 1:10.

5. The composition of claim 1, wherein the weight ratio of the active ingredient to hydroxypropyl--cyclodextrin is 1:9.

6. The composition of claim 1, further comprising a stabilizing agent, optionally comprising an acid reagent.

7. The composition of claim 6, wherein the stabilizing agent is a water-soluble polymer.

8. The composition of claim 7, wherein the water-soluble polymer comprises at least one selected from a group consisting of a vinylpyrrolidone based copolymer, a methacrylic acid based copolymer, a hydroxyalkylcellulose, a hydroxyalkylalkylcellulose, a cellulose phthalate, and a cellulose succinate.

9. The composition of claim 7, wherein the water-soluble polymer comprises at least one selected from a group consisting of polyvinylpyrrolidone, copovidone, hypromellose, carboxymethyl cellulose sodium, hypromellose succinate, and hypromellose acetate succinate.

10. The composition of claim 7, wherein the water-soluble polymer is hydroxypropylmethylcellulose.

11. The composition of claim 6, based on the total weight of the composition, wherein the composition comprises 0.1% to 10% stabilizing agent, optionally comprises 1% to 10% acid reagent.

12. The composition of claim 6, wherein the composition comprises an acid reagent.

13. The composition of claim 12, wherein the acid reagent comprises at least one selected from a group consisting of an organic acid, a water-soluble acidic amino acid, a water-soluble inorganic acid and an acid salt.

14. The composition of claim 13, wherein the organic acid comprises at least one selected from a group consisting of citric acid, citric acid monohydrate, D-tartaric acid, L-tartaric acid, D-malic acid, L-malic acid, fumaric acid, maleic acid, succinic acid, oxalic acid and ascorbic acid.

15. The composition of claim 12, wherein the acid reagent is citric acid and/or citric acid monohydrate.

16. The composition of claim 12, wherein the composition comprises 1% to 10% acid reagent, based on the total weight of the composition.

17. The composition of claim 1, comprising hydroxypropylmethylcellulose, and at least one of citric acid and citric acid monohydrate.

18. The composition of claim 6, further comprising one or more pharmaceutically acceptable excipients.

19. The composition of claim 18, wherein the pharmaceutically acceptable excipient includes one or more of fillers, disintegrants, and lubricants.

20. The composition of claim 18, based on the total weight of the composition, comprising 0.1% to 10% hydroxypropylmethylcellulose, optionally 1% to 10% citric acid and/or citric acid monohydrate.

21. A method for preparing the composition of claim 6, comprising mixing vilazodone or a pharmaceutically acceptable salt thereof and hydroxypropyl--cyclodextrin to form the inclusion complex, then adding the stabilizing agent and optionally adding an acid reagent.

22. The method of claim 21, wherein the method comprises: 1) mixing vilazodone or a pharmaceutically acceptable salt thereof, hydroxypropyl--cyclodextrin and water to form the inclusion complex under heating; 2) mixing the stabilizing agent and optional an acid reagent with the inclusion complex to obtain a mixture; 3) solidifying the mixture and optional a pharmaceutically acceptable excipient into particles by fluidized bed or spray drying; 4) optionally mixing the particles and other pharmaceutically acceptable excipients, and forming a formulation.

23. The method of claim 22, wherein the temperature of heating is from 80 C. to 90 C.

24. A method for treating a patient in need comprising orally administering to said patient a therapeutically effective amount of the composition of claim 18.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0149] FIG. 1 is an average plasma concentration-time curve of the composition detected in example 19.

EXAMPLES

[0150] It will be understood by those skilled in the art that the following examples are intended to be illustrative of the invention and are not to be construed as limiting the disclosure. Persons skilled in the art may modify, adjust, substitute or vary the examples. Unless specifically stated otherwise, specific techniques or conditions that are not expressly described in the following examples may be ascertained by conventional techniques or conditions in the art or in accordance with the product specifications. The drugs, reagents or instruments used without specific indications of the manufacturer are commercially available products.

[0151] Among them, the reference listed drug VIIBRYD used in the examples was 10 mg vilazodone hydrochloride tablet which was prepared by Merck KGaA Germany.

[0152] Unless specifically stated, the following testing methods were used in the following examples:

[0153] HPLC: Agilent 1260;

[0154] Chromatographic conditions: UV 242 nm detection wavelength, chromatographic column:kromasil 100-5 C18 4.6 mm*150 mm, 5 microns, mobile phase: 0.02 M pH 6.0 potassium hydrogen phosphate and acetonitrile at 54:46 (V/V), flow rate: 1.0 mL/minute, injection volume: 10 microliters, runtime: 4.5 minutes.

Comparative Example 1

[0155] In Comparative Example 1, vilazodone was micronized without addition of cyclodextrin. The micronized vilazodone was mixed with lactose, microcrystalline cellulose, silicon dioxide and magnesium stearate according to Table 1 to form total mixed granules, which were compressed into 100.0 mg vilazodone tablets (C1).

TABLE-US-00001 TABLE 1 Ingredients of Comparative Example Tablets C1 Ingredient Weight (g) Vilazodone hydrochloride 5.00 (From IV) Lactose 25.00 Microcrystalline cellulose 18.50 Silicon dioxide 1.00 Magnesium stearate 0.50

[0156] Vilazodone tablets C1 were put in a 0.1% acetic acid dissolution medium having a pH of 3.1 which is in vitro simulation of fed conditions, a 0.1 N HCl dissolution medium simulating fasted conditions, and a dissolution medium having a pH of 6.8 simulating the intestinal conditions. Drug dissolution was detected by a dissolution apparatus using the US Pharmacopoeia paddle method (USP II) at a speed of 60 RPM. An aliquot of the solution of each time point was taken, and filtered with a 0.45 micron microporous membrane. The filtrate of each sample was analyzed by HPLC. The results are shown in Tables 11-13.

Comparative Example 2

[0157] In Comparative Example 2, vilazodone hydrochloride was mixed with lactose monohydrate, and -cyclodextrin in Table 2, and the mixture was milled to a particle size of about 20 m, mixed with other excipients in Table 2, and compressed into vilazodone tablets having a total weight of 100.0 mg (C2). The tablets were subjected to in vitro dissolution test according to the method described in Comparative Example 1. The results are shown in Tables 11-13.

TABLE-US-00002 TABLE 2 Ingredients of Comparative Example Tablets C2 Ingredient Weight (%, w/w) Vilazodone hydrochloride 10.00 (From IV) Lactose monohydrate 25.00 -Cyclodextrin 25.00 Microcrystalline cellulose 29.00 Sodium carboxymethyl starch 5.00 Silicon dioxide 3.00 Magnesium stearate 3.00 Total 100.00

Comparative Example 3

[0158] In Comparative Example 3, vilazodone hydrochloride was mixed with hydroxypropyl--cyclodextrin, and the mixture was milled to a particle size of about 5 m. The particles were dispersed in an aqueous solution of polysorbate 80, dried and blended evenly with other excipients in Table 3, and directly compressed into tablets (C3). The tablets were subjected to in vitro dissolution test according to the method described in Comparative Example 1. The results are shown in Tables 11-13.

TABLE-US-00003 TABLE 3 Ingredients of Comparative Example Tablets C3 Ingredient Weight (%, w/w) Vilazodone hydrochloride 10.00 (From IV) Hydroxypropyl--cyclodextrin 10.00 Starch 29.95 Lactose monohydrate 40.00 Sodium carboxymethylcellulose 5.00 Sodium lauryl sulfate 3.00 Polysorbate 80 0.05 Silicon dioxide 1.00 Magnesium stearate 1.00 Total 100.00

Example 1

[0159] In Example 1, vilazodone hydrochloride (API) and betadex sulfobutyl ether sodium (SBE--CD) in ratios according to Table 4 were stirred in water at 80 C. in a water bath for 4 hours, to form inclusion complex solutions, which were lyophilized to obtain inclusion complex compositions as powders.

TABLE-US-00004 TABLE 4 Ratios of Vilazodone Hydrochloride and Betadex Sulfobutyl Ether Sodium Molar Ratio Weight Ratio API SBE--CD SBE--CD No. (mol) (mol) API (g) (g) Water (g) 0 1.0 0.2 1.0 1.0 1.387 1 1.0 0.5 1.0 2.4 3.329 2 1.0 0.8 1.0 3.5 4.855 3 1.0 1.4 1.0 6.5 9.016 4 1.0 2.5 1.0 11.4 15.812 5 1.0 10.0 1.0 45.4 62.970

[0160] A sample of each inclusion complex solution was filtered through a 0.45 micron filter membrane and the subsequent filtrate was subjected to HPLC testing to determine the content of the dmg in the inclusion complex solution. Inclusion rate=included dmg amount/total dmg amount100%. The results are shown in Table 5.

TABLE-US-00005 TABLE 5 Inclusion Amounts and Rates Volume Total API API Inclusion Inclusion API:SBE--CD No. (mL) amount (g) Amount (g) Rate (%) Weight Ratio (%) 1-0 25.0 8.626 1.811 21.0 1:1 1-1 25.0 3.620 1.245 34.4 1:2.4 1-2 25.0 2.475 1.175 47.5 1:3.5 1-3 25.0 1.142 1.062 93.0 1:6.5 1-4 25.0 0.762 0.709 93.0 1:11.4 1-5 25.0 0.190 0.187 98.4 1:45.4

[0161] Vilazodone inclusion complexes 1-0 to 1-5, C1, and reference listed drug (RLD) (10 mg each) were subjected to in vitro dissolution tests in a 0.1 N HCl and a pH 6.8 buffer according to the method described in Comparative Example 1. The results are shown in Tables 6-7.

TABLE-US-00006 TABLE 6 Cumulative Dissolution Rate in 0.1N HCl 10 min 15 min 20 min 30 min 45 min No. (%) (%) (%) (%) (%) 0 31 34 38 44 48 1.15 0.58 1.00 1.00 1.15 1 47.0 1.0 53.0 3.5 59.0 0.6 64.0 1.0 67.0 1.2 2 56.0 3.6 61.0 2.3 66.0 2.1 71.0 2.3 74.0 3.0 3 76.0 2.5 81.0 1.5 81.0 2.5 81.0 1.0 79.0 2.6 4 90.0 2.0 96.0 1.5 98.0 0.0 98.0 0.0 98.0 0.6 5 96.0 2.5 102.0 0.6 100.0 0.6 102.0 0.6 101.0 0.6 C1 14.0 3.1 21.0 1.0 24.0 1.2 30.0 1.0 35.0 0.6 RLD 25.0 2.9 33.0 2.1 38.0 1.2 46.0 4.2 56.0 1.5

TABLE-US-00007 TABLE 7 Cumulative Dissolution Rate in pH 6.8 Buffer 10 min 15 min 20 min 30 min 45 min No. (%) (%) (%) (%) (%) 0 20 1.15 23 0.58 24 1.00 23 0.00 22 0.58 1 31 2 38 5 47 1.7 54 3.5 58 3 2 36 2.5 45 4 48 3.6 50 6.7 56 2.9 3 65 1 75 2.5 76 3.8 66 3.2 77 4.4 4 81 4.5 93 1 94 1 95 1.2 95 0.6 5 89 2.1 94 3.5 98 1 98 1.5 98 2.1 C1 0 0 0 0 0 0 1 0 1 0 RLD 2 0.6 4 0.6 4 0.6 5 0 6 0.6

[0162] Results

[0163] When the weight ratio of vilazodone hydrochloride to SBE--CD is 1:1 (1-0), the dissolution of the API in 0.1 N HCl was low and the bioavailability was not significantly improved. In comparison, when the weight ratio of vilazodone hydrochloride to SBE--CD was 1:2.4 to 45.4 (1-1 to 1-5), and the inclusion rate of vilazodone hydrochloride increased from 34.4% to 98.4%. When the weight ratio of vilazodone hydrochloride to SBE--CD was 1:45.4, the inclusion rate reached about 100% (1-5). Further increases in the amount of SBE--CD did not increase the cumulative release of the drug, but would increase the production cost as more SBE--CD would be used.

[0164] In summary, when the weight ratio of vilazodone hydrochloride to SBE--CD was 1:2.4 to 1:45.4, the inclusion and dissolution rates as well as the production costs were optimized The solubility of the drug was improved significantly under simulated fasted conditions. Considering production cost and solubility, the effect was better when the weight ratio of vilazodone hydrochloride to SBE--CD is 1:6.5 to 1:11.5. The test results show that encapsulating vilazodone hydrochloride in the cavity of the inclusion material could result in a good solubility at 0.1 N HCl and pH 6.8, leading to complete release of the drug.

Example 2

[0165] In Example 2, vilazodone hydrochloride and -cyclodextrin according to Table 8 were added to purified water with stirring. The mixture was stirred at 80 C. for 4 hours to form a clear inclusion complex solution. The inclusion complex solution was spray dried to form vilazodone hydrochloride inclusion complex composition as a solid powder. The vilazodone hydrochloride inclusion complex composition was mixed with microcrystalline cellulose, lactose, crospovidone and magnesium stearate according to Table 8 to obtain blended granules, which were compressed into tablets having a total weight of 381.2 mg (A1).

TABLE-US-00008 TABLE 8 Ingredients of Tablets A1 Comprising Inclusion Complex Ingredient Weight (g) Vilazodone hydrochloride (From IV) 0.65 -cyclodextrin 10.50 Purified water 31.34 Microcrystalline Cellulose 6.63 Lactose 2.57 Crospovidone 2.29 Magnesium stearate 0.23

[0166] In Example 2, the dissolution rate of vilazodone hydrochloride inclusion complex tablets was accessed in a pH 3.1 dissolution medium (0.1% acetic acid), a 0.1 N HCl dissolution medium and a pH 6.8 dissolution medium according to the test conditions of Comparative Example 1. After the in vitro dissolution test, the test solution was filtered through a 0.45 micron microfiltration membrane and the filtrate was subjected to HPLC analysis. The results are shown in Tables 11-13.

Example 3

[0167] In Example 3, the tablet formulation (A2) shown in Table 9 comprising vilazodone inclusion complex having a total tablet weight of 200.0 mg/tablet was prepared and tested as described in Example 2. The results are shown in Tables 11-13.

TABLE-US-00009 TABLE 9 Ingredients of Tablets A2 Comprising Inclusion Complex Ingredient Weight (g) Vilazodone hydrochloride (From IV) 5.00 -cyclodextrin 40.00 Purified water 40.00 Microcrystalline cellulose 29.00 Lactose 15.00 Crospovidone 10.00 Magnesium stearate 1.00

Example 4

[0168] In Example 4, the vilazodone tablets (A3) were prepared as described in Example 3 with the exception that -cyclodextrin was replaced with hydroxypropyl--cyclodextrin. The in vitro dissolution of the tablets A3 was tested as described in Example 2 and the results are shown in Tables 11-13.

Example 5

[0169] In Example 5, the specific formulation of the vilazodone tablet (A4) was shown in Table 10. Vilazodone hydrochloride and betadex sulfobutyl ether sodium were added to purified water at 80 C. with stirring, and the mixture was stirred for 4 hours to form a clear solution. The inclusion complex solution was used as the granulating solution, microcrystalline cellulose and croscarmellose sodium were used as the substrate in a subsequent granulating process to form granules. The granules were dried by fluid bed to form dry granules. The dry granules were mixed with extragranular excipients crospovidone and magnesium stearate to form blended granules, and the blended granules were compressed to form vilazodone tablets weighing 216.2 mg each. The drug dissolution of the vilazodone inclusion complex tablets A4 was assessed in dissolution mediums having pH 3.1 (0.1% acetic acid), 0.1 N HCl or pH 6.8. After in vitro dissolution test, the test solution was filtered through a 0.45 micron microfiltration membrane and the filtrate was analyzed by HPLC. The results are shown in Tables 11-13.

TABLE-US-00010 TABLE 10 Ingredients of Tablets A4 Comprising Inclusion Complex Ingredient Weight (g) Vilazodone hydrochloride (FromIV) 40.00 Sulfobutyl--cyclodextrin 320.00 Purified water 400.00 Microcrystalline cellulose (intragranular) 300.00 Croscarmellose sodium (intragranular) 100.00 Crospovidone (extragranular) 100.00 Magnesium stearate (extragranular) 4.80

[0170] Results

[0171] Tables 11-13 show the results of the dissolution test of the formulations A1-A4 of Examples 2-5,

[0172] Comparative Examples C1-C3, and RLD in dissolution mediums having a pH of 3.1 (0.1% acetic acid), 0.1 N HCl or a pH of 6.8, respectively.

TABLE-US-00011 TABLE 11 Cumulative Dissolution at pH 3.1 Formula- 10 min 15 min 20 min 30 min 45 min tion (%) (%) (%) (%) (%) A1 56.0 1.5 79.0 3.2 99.0 4.6 104.0 0.6 104.0 1.0 A2 89.0 3.1 92.0 1.0 94.0 1.5 93.0 1.0 91.0 4.2 A3 83.0 6.6 95.0 1.7 94.0 1.5 95.0 2.1 95.0 3.5 A4 69.0 12.1 95.0 4.4 101.0 3.4 102.0 1.3 101.0 3 C1 68.0 11.0 82.0 5.6 89.0 2.0 91.0 1.5 92.0 3.6 C2 97 97 97 97 97 1.00 1.00 1.53 2.00 1.53 C3 56 63 67 75 81 1.73 0.58 0.58 1.00 1.53 RLD 87.0 2.3 93.0 1.0 93.0 1.0 93.0 1.7 93.0 0.6

TABLE-US-00012 TABLE 12 Cumulative Dissolution in 0.1N HCl Formula- 10 min 15 min 20 min 30 min 45 min tion (%) (%) (%) (%) (%) A1 39.0 2.3 60.0 2.5 76.0 1.5 95.0 0.0 97.0 0.0 A2 88.0 0.0 93.0 0.6 92.0 1.0 93.0 0.6 93.0 1.0 A3 92.0 1.5 97.0 0.6 99.0 1.0 98.0 1.0 98.0 2.1 A4 71.0 9.7 97.0 7.2 99.0 2.3 100.0 1.8 100.0 1.6 C1 14.0 3.1 21.0 1.0 24.0 1.2 30.0 1.0 35.0 0.6 C2 51 53 57 61 64 1.00 2.52 0.58 0.00 0.00 C3 55 43 36 28 19 1.15 2.00 3.06 2.00 1.00 RLD 25.0 2.9 33.0 2.1 38.0 1.2 46.0 4.2 56.0 1.5

TABLE-US-00013 TABLE 13 Cumulative Dissolution at pH 6.8 For- mu- la- 45 tion 10 min (%) 15 min (%) 20 min (%) 30 min (%) min (%) A1 26 3.5 48 11.1 69 25.6 75 9 77 3.8 A2 54 3.5 70 7.5 76 5.3 77 1 74 5.1 A3 69 10.7 81 3.6 86 3.2 88 2.5 83 3.5 A4 70 2.6 80 1.5 81 1.5 82 3.5 82 3.1 C1 0 0 0 0 0 0 1 0 1 0 C2 13 0.58 15 0.58 16 0.58 16 0.58 16 0.00 C3 15 8.72 23 2.31 24 3.00 26 1.53 26 1.00 RLD 2 0.6 4 0.6 4 0.6 5 0 6 0.6

[0173] As shown in Tables 11-13, the dissolution rates of A1-A4 were similar to C1-C3 and RLD at pH 3.1 (0.1% acetic acid) with cumulative dissolution rates of more than 93% at 45 min. The cumulative release of C1 (micronized) and RLD in 0.1 N HCl was only 35% and 56% at 45 min, respectively. The cumulative release of C2-C3, which are formulations prepared in accordance with CN104116741A, was 64% and 19%, respectively. By comparison, the cumulative release of A1-A4 reached 93% to 100% at 45 min, with the cumulative dissolution rate at each time point being significantly higher than that of C1 and RLD. The results show that the dissolution improvement of the formulations A1-A4 disclosed herein over C2-C3 was more prominent at 0.1 N HCl. At pH 6.8, the cumulative release rates of A1-A4 at 45 min were about 3 times or higher of the mere 1%-26% of C1-C3 and 6% of RLD.

Example 6

[0174] The specific formulation of vilazodone formulation of Example 6 is shown in Table 14. Vilazodone and sulfobutyl--cyclodextrin were added to purified water at 80 C. with stirring, and the mixture was stirred for 4 hours to form a clear inclusion complex solution. The inclusion complex solution was used as the granulating solution, and microcrystalline cellulose as the substrate in the subsequent granulating process to form granules, which were dried by a fluid bed granulator to form dry vilazodone granules. The dry granules were mixed with extragranular excipient magnesium stearate to form total mixed granules, which were compressed to tablets each comprising 40 mg vilazodone hydrochloride. Alternatively, the total mixed granules were filled into hard capsules to form capsules. Dissolution of the vilazodone tablets was determined in dissolution mediums having 0.1 N HCl, pH 3.1 or pH 6.8, respectively, using the procedure described in Example 2. The results are shown in Table 15. As the results show, the dissolution of the vilazodone tablets in 0.1 N HCl, pH 3.1 and pH 6.8 mediums are similar and not affected by the pH value, reaching to nearly 100% in 15 minutes.

TABLE-US-00014 TABLE 14 Ingredients of Formulation of Example 6 Comprising Inclusion Complex Ingredient Weight (g) Vilazodone hydrochloride (From IV) 100.00 SBE--CD 900.00 Purified water 900.00 Microcrystalline cellulose 300.00 Magnesium stearate (extragranular) 10.00

TABLE-US-00015 TABLE 15 Cumulative Dissolution of Tablets of Example 6 Disso- lution 5 min 10 min 15 min 20 min 30 min 45 min Medium (%) (%) (%) (%) (%) (%) 0.1N 53 87 1.41 98 0.00 98 0.00 98 0.00 98 0.00 HCl 2.12 pH 3.1 52 85 0.58 97 0.58 98 0.00 98 0.58 98 0.00 2.00 pH 6.8 46 78 1.00 93 0.00 95 0.00 95 0.58 95 0.58 0.58

Example 7

[0175] The specific formulation of Example 7 is shown in Table 16. Vilazodone and sulfobutyl--cyclodextrin were added to purified water at 80 C. with stirring and the mixture was stirred for 4 hours to form a clear inclusion complex solution. The inclusion complex solution was used as a granulating solution, and sucrose as the substrate in the subsequent granulation process to form granules which were dried by a fluid bed granulator to form dry vilazodone granules.

TABLE-US-00016 TABLE 16 Ingredients of Formulation of Example 7 Comprising Inclusion Complex Ingredient Weight (g) Vilazodone hydrochloride (From IV) 100.00 SBE--CD 900.00 Purified water 900.00 Sucrose 3200.00

Example 8

[0176] The specific formulation of Example 8 is shown in Table 17. Vilazodone (Crystalline From XVI) and sulfobutyl--cyclodextrin were added to purified water at 80 C. with stirring, and the mixture was stirred for 4 hours to form a clear inclusion complex solution. The inclusion complex solution was used as the granulating solution, and microcrystalline cellulose and lactose as the substrate in the subsequent granulation process and the resulting granules were dried by a fluid bed granulator to form dry vilazodone granules. The dry vilazodone granules were mixed with extragranular excipients to form total mixed granules, and the total mixed granules were compressed to form tablets. Vilazodone tablets were subjected to dissolution tests in dissolution mediums having 0.1 N HCl, a pH of 3.1 or a pH of 6.8 respectively under conditions as describe in Example 2. The in vitro dissolution test results are shown in Table 19.

TABLE-US-00017 TABLE 17 Ingredients of Formulation of Example 8 Comprising Inclusion Complex Ingredient Weight (g) Vilazodone hydrochloride (From XVI) 53.90 SBE--CD 511.50 Microcrystalline cellulose 312.29 Lactose 80.74 Vilazodone hydrochloride (From X VI) 23.10 (extragranular) Crospovidone (extragranular) 107.69 Sodium stearyl fumarate (extragranular) 10.78

Comparative Example 4

[0177] In Comparative Example 4, vilazodone (Form XVI) was micronized without addition of cyclodextrin. The micronized vilazodone was mixed with lactose, microcrystalline cellulose, silicon dioxide and magnesium stearate according to Table 18 to form total mixed granules. The total mixed granules were compressed into 100.0 mg vilazodone tablets (C4). The vilazodone tablets were subjected to dissolution tests in dissolution mediums having 0.1 N HCl, a pH of 3.1 or a pH of 6.8 respectively under test conditions as described in Example 2. The in vitro dissolution test results are shown in Table 19.

TABLE-US-00018 TABLE 18 Ingredients of Formulation of Comparative Example 4 Ingredient Weight (g) Vilazodone hydrochloride (From XVI) 5.00 Lactose 25.00 Microcrystalline cellulose 18.50 Silicon dioxide 1.00 Magnesium stearate 0.50

TABLE-US-00019 TABLE 19 Cumulative Dissolution Percentage Comparison of Tablets of Example 8, Comparative Example 4 and RLD Disso- lution 10 medium Exp. min 15 min 20 min 30 min 45 min pH 3.1 Exp. 8 85 96 2.00 98 1.53 98 2.08 99 2.08 9.07 C4 63 73 2.1 79 1.7 85 2.1 88 2.9 4.7 RLD 87 93 1.00 93 1.00 93 1.70 93 0.60 2.30 0.1N HCl Exp. 8 81 90 1.73 91 2.08 95 0.58 97 0.00 0.58 C4 11 15 0.6 19 0.6 22 0.6 27 1.2 0.6 RLD 25 33 2.10 38 1.20 46 4.20 56 1.50 2.90 pH 6.8 Exp. 8 70 73 0.58 74 1.15 74 0.58 75 0.58 0.58 C4 0 0 0 0 0 1 0.6 1 0 0 RLD 2 4 0.60 4 0.60 5 0 6 0.60 0.60

[0178] In Example 8, Form XVI of vilazodone hydrochloride reported in U.S. Pat. No. 8,673,921 was used. As shown by the results of C4 and RLD in Table 19, the crystalline forms of vilazodone also have an effect on the dissolution. Using the inclusion technology, vilazodone exhibited good solubility and a higher bioavailability regardless of the crystalline forms.

Example 9

[0179] Six beagle dogs were randomly divided into two groups in double crossover experiments under fasted and fed conditions. The dogs were given orally A4 (10 mg tablet) or C1. Whole blood samples were taken at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 24 hours. Plasma samples were prepared as follows: whole blood 200-400 L was placed in a centrifuge tube, K.sub.2EDTA was added as an anticoagulant, and centrifuged for 60 min. The plasma samples were kept at 70 C. The concentration of vilazodone in the blood plasma was measured by a validated LC-MS/MS method and pharmacokinetic parameters were assessed with non-compartment model using WinNonlin 6.3 software. The results are shown in Table 20.

TABLE-US-00020 TABLE 20 Pharmacokinetics Parameters in Fasted and Fed Dogs Pharmacokinetic AUC.sub.last parameters (n = 3) T.sub.max (h) C.sub.max (ng/mL) (h * ng/mL) A4, fasted Mean 0.9 116 398 CV % 22 45 71 A4, fed Mean 1.8 90.1 341.4 CV % 58 66 77 C1, fasted Mean 1.0 25.4 105.2 CV % 0 57 55 C1, fed Mean 1.7 67.8 293.8 CV % 31 48 86

[0180] As shown in Table 20, the plasma concentration-time curve (AUC.sub.last) and the peak plasma concentration (C.sub.max) of A4 (tablets prepared in example 5) under fasted conditions were higher than under fed conditions, achieving the purpose of improving the bioavailability under fasted conditions. By comparison, the C.sub.max of C1 under fasted conditions was only about 37.5% of the C.sub.max under fed conditions and the AUC.sub.last of C1 under fasted conditions was only about 35.8% of the AUC.sub.last under fed conditions.

Example 10

[0181] Six Beagle dogs were randomly divided into two groups in double crossover experiments under fasted and fed conditions, respectively. The dogs were given orally A4 (10 mg tablet) or RLD (10 mg). Whole blood samples of the dogs were analyzed according to the procedure described in Example 9 and the results are shown in Table 21.

TABLE-US-00021 TABLE 21 Pharmacokinetics Parameters in Fasted and Fed Dogs Pharmacokinetic AUC.sub.last parameter (n = 3) T.sub.max (h) C.sub.max (ng/mL) (h * ng/mL) A4, fasted Mean 0.8 148.7 451.7 CV % 31.0 41.6 54.0 A4, fed Mean 1.0 106.2 343.3 CV % 54.8 30.8 37.5 RLD, fasted Mean 1.5 24.6 109.3 CV % 36.5 77.1 85.6 RLD, fed Mean 2.3 76.7 267.2 CV % 79.8 74.1 70.4

[0182] As shown in Table 21, the AUC.sub.last and C.sub.max of A4 under fasted conditions were higher than the AUC.sub.last and C.sub.max under fed conditions, achieving the purpose of improving the bioavailability under fasted conditions. By comparison, the C.sub.max of RLD under fasted conditions was only about 32.1% of the C.sub.max of RLD under fed conditions, and the AUC.sub.last of RLD under fasted conditions was about 41% of the AUC.sub.last of RLD under fed conditions.

Example 11

[0183] According to the inclusion technology disclosed herein, 10 mg vilazodone coated tablets comprising the inclusion complex were prepared according to the formulation of Example 8, and given to three Beagle dogs orally under fasted or fed conditions in a double crossover experiment. Whole blood samples were collected and analyzed as described in Experiment 9. The results are shown in Table 22.

TABLE-US-00022 TABLE 22 Pharmacokinetics Parameters in Fasted and Fed Dogs Pharmacokinetic AUC.sub.last parameters (n = 3) T.sub.max (h) C.sub.max (ng/mL) (h * ng/mL) fasted Mean 0.67 111.04 382.91 CV % 43.3 43.1 54.0 fed Mean 2.0 96.52 382.64 CV % 86.5 63.43 59.6

[0184] As shown in Table 22, AUC.sub.last and C.sub.max of the coated tablets were similar under fasted and fed conditions, achieving bioequivalence under fasted and fed conditions.

[0185] As shown in Experiments 9-11, the formulations comprising the vilazodone inclusion complex exhibited improved absorption of vilazodone when taken with or without food, which reduces variability in therapeutic effect due to food effect, and ensures drug performance and improves patients' flexibility and compliance. In addition, vilazodone inclusion complex and formulations comprising the complex can be prepared conveniently with low production cost and under industrial manufactural conditions.

Example 12

[0186] According to the formulations in Table 23, the prescribed amount of hydroxypropyl--cyclodextrin (HP-(3-CD) was added to purified water, stirred to dissolve; then vilazodone hydrochloride (API) was added, heated to 85 C., stirred until the solution was clear to obtain an inclusion complex solution. According to the dissolution method in Comparative Example 1, the dissolution of 40 mg strength inclusion complex solution samples in a pH 6.8 medium was measured respectively. The specific results are shown in Table 24.

TABLE-US-00023 TABLE 23 Formulations of inclusion complexes with different amounts of HP--CD (unit: g) Formu- Formu- Formu- Formu- Formu- Formu- lation lation lation lation lation lation Component 1 2 3 4 5 6 Vilazodone 40.00 40.00 40.00 40.00 40.00 40.00 hydrochloride HP--CD 360.00 520.00 600.00 800.00 280.00 320.00 Purified Water.sup.1 360.00 520.00 600.00 800.00 280.00 320.00

TABLE-US-00024 TABLE 24 Dissolution data of inclusion complex samples with different ratios of HP--CD in pH 6.8 media HP-- CD: API 5 min 10 min 15 min 20 min 30 min (w/w) Formu- 79 1.41 83 2.83 80 1.41 79 1.41 68 13.44 9:1 lation 1 Formu- 88 0.71 91 3.54 93 4.95 91 2.12 85 4.24 13:1 lation 2 Formu- 85 1.41 89 0.71 96 7.78 88 2.12 82 2.12 15:1 lation 3 Formu- 93 3.54 96 2.83 95 1.41 94 0.00 84 2.12 20:1 lation 4 Formu- 84 2.65 86 4.51 81 11.24 65 20.95 35 22.01 7:1 lation 5 Formu- 91 2.83 93 1.41 95 4.24 94 0.71 86 1.41 8:1 lation 6

[0187] The above results show that when the weight ratio of HP--CD to API is greater than 7:1, the dissolution of the prepared inclusion complex is significantly higher than that of the RLD, indicating that, the solubility of vilazodone hydrochloride was significantly improved after being prepared into an inclusion complex. As the dissolution rate of vilazodone hydrochloride has been significantly improved, its dissolution in the pH 6.8 medium has also appeared unstable, and the dissolution platform has decreased. But by increasing the amount of hydroxypropyl--cyclodextrin, the dissolution stability of the prepared inclusion complex solution in a pH 6.8 medium has been improved to a certain extent, with a downward trend slowed down. When the weight ratio of HP--CD to API is greater than 13:1, further increasing the amount of HP--CD will not significantly increase the dissolution stability.

Example 13

[0188] According to the formulations in Table 25, the prescribed amount of hydroxypropyl--cyclodextrin was added to purified water and stirred to dissolve; then vilazodone hydrochloride was added, heated to 85 C., stirred until the solution was clear to obtain an inclusion complex solution; then water-soluble polymers were added, stirred and dissolved to obtain a mixture of vilazodone hydrochloride. According to the dissolution method in Comparative Example 1, the dissolution of 40 mg strength samples in pH 6.8 medium was measured. The specific results are shown in Table 26.

TABLE-US-00025 TABLE 25 Formulations of samples with different water-soluble polymers (unit: g) Formu- Formu- Formu- Formu- Formu- Formu- tion tion tion tion tion tion Component 1 7 8 9 10 11 Vilazodone 40.00 40.00 40.00 40.00 40.00 40.00 hydrochloride HP--CD 360.00 280.00 320.00 360.00 360.00 360.00 Purified Water.sup.1 360.00 280.00 320.00 360.00 360.00 360.00 Hypromellose E5 4.20 4.80 15.20 Povidone K30 15.20 Carboxymethyl 15.20 cellulose sodium

TABLE-US-00026 TABLE 26 Dissolution data of samples with different water-soluble polymers in pH 6.8 media 5 min 10 min 15 min 20 min 30 min 45 min Formu- 79 83 2.83 80 1.41 79 1.41 68 13.44 lation 1.41 1 Formu- 85 90 5.86 90 6.11 90 3.21 95 4.04 89 4.73 lation 5.69 7 Formu- 87 91 7.00 90 12.12 93 9.02 94 8.50 94 6.11 lation 7.23 8 Formu- 88 88 2.12 85 1.41 87 5.66 85 1.41 84 0.71 lation 2.12 9 Formu- 83 88 0.71 89 1.41 89 4.24 87 2.12 86 0.71 lation 0.71 10 Formu- 83 86 0.71 86 0.71 84 0.71 87 0.71 87 6.36 lation 0.71 11

[0189] The data of example 12 and example 13 shows that when the stabilizing agent water-soluble polymer is combined with the inclusion complex, the dissolution stability of the prepared composition in the pH 6.8 medium is significantly improved. Compared with formulation 1, after adding the stabilizing agent water-soluble polymer, the dissolution platform of the prepared composition at 45 minutes did not significantly decrease. When the weight ratio of HP--CD to API is 7:1 to 9:1 and after adding 1.30% to 3.66% (w/w, excluding water) of stabilizing agent to the composition, the dissolution platform of the prepared composition has been improved in the pH 6.8 medium.

Example 14

[0190] According to the formulations in Table 27, the prescribed amount of hydroxypropyl--cyclodextrin, was added to purified water, stirred to dissolve, then vilazodone hydrochloride was added, heated to 85 C., stirred until the solution was clear to obtain an inclusion complex solution. The inclusion complex solution was sprayed on microcrystalline cellulose in a fluidized bed granulator and granulated to obtain dry granules; then the water-soluble polymer and sodium stearyl fumarate were added, mixed evenly and compressed into tablets. According to the dissolution method in Comparative Example 1, the dissolution of 40 mg strength tablet samples in 0.1N HCl and a pH 6.8 medium was measured respectively. The specific results are shown in Table 28.

TABLE-US-00027 TABLE 27 Formulations of tablets with different water-soluble polymers (unit: g) Formu- Formu- Formu- Formu- Component lation 12 lation 13 lation 14 lation 15 Vilazodone 40.00 40.00 40.00 40.00 hydrochloride HP--CD 360.00 360.00 360.00 360.00 Purified Water.sup.1 360.00 360.00 360.00 360.00 Microcrystalline 109.00 109.00 109.00 109.00 cellulose Colloidal silicon 3.00 3.00 3.00 3.00 dioxide Hypromellose E5 30.00 Carboxymethyl 4.00 cellulose sodium (CMC-Na) Copovidone 30.00 Sodium stearyl 8.00 4.00 4.00 4.00 fumarate Total 520 546 520 546 Remarks: The purified water in 1 is removed during fluidized bed granulation and drying.

TABLE-US-00028 TABLE 28 Dissolution data of tablets with different water-soluble polymers Formu- Medium lation 5 min 10 min 15 min 20 min 30 min 45 min 0.1N Formu- 36 5.29 53 0.58 73 0.58 89 0.58 100 1.00 101 0.00 HCl lation 12 Formu- 24 0.00 46 0.00 64 0.58 81 1.53 99 2.00 102 0.00 lation 13 Formu- 31 0.58 57 1.00 77 1.00 92 0.00 101 0.58 102 0.58 lation 14 Formu- 25 1.00 47 0.58 65 0.58 82 0.58 101 1.00 104 0.58 lation 15 pH 6.8 Formu- 28 1.00 50 1.15 61 1.73 44 12.66 11 3.79 5 0.58 lation 12 Formu- 22 0.58 43 1.53 58 3.61 70 1.00 82 1.15 83 1.53 lation 13 Formu- 24 0.58 46 0.58 61 1.00 69 1.53 76 0.58 75 2.31 lation 14 Formu- 23 0.58 43 1.73 58 1.00 70 1.15 79 1.00 79 1.15 lation 15

[0191] The above data shows that after the hydroxypropyl--cyclodextrin inclusion complex solution of vilazodone hydrochloride is granulated and compressed, the dissolution stability of the active ingredient in the pH 6.8 medium was reduced. The dissolution stability of the prepared plain tablets in the pH 6.8 medium is lower than that of the inclusion complex solutions; however, after adding 0.77%-5.49% (w/w) of the water-soluble polymer to the formulation, the dissolution stability of the prepared plain tablets in the pH 6.8 medium has been significantly improved, and the dissolution platform at 45 minutes did not appear to be significantly reduced. According to the mass concentration meter (w/v, g/ml), when the water-soluble polymer in the tablets is completely dissolved in the dissolution medium, its concentration is about 0.4%-3.0% (w/v, g/ml), it shows that as long as there is a small amount of stabilizing agent in the composition, the dissolution stability of vilazodone can be greatly improved.

Example 15

[0192] According to the formulations in Table 29, the dry granules were prepared according to the process of Example 14, and then the prescribed amounts of hypromellose, organic acid and sodium stearyl fumarate were added, mixed evenly, and compressed into tablets. According to the dissolution method in Comparative Example 1, the dissolution of 40 mg strength tablet samples in pH 6.8 medium was measured, and the pH value of the medium at the end of dissolution was tested. The specific results are shown in Table 30.

TABLE-US-00029 TABLE 29 Formulations of tablets with different organic acids (unit: g) Formu- Formu- Formu- Formu- Formu- lation lation lation lation lation Component 16 17 18 19 20 Vilazodone 40.00 40.00 40.00 40.00 40.00 hydrochloride HP--CD 400.00 400.00 400.00 400.00 400.00 Purified Water.sup.1 400.00 400.00 400.00 400.00 400.00 Microcrystalline 104.50 104.50 104.50 104.50 104.50 cellulose Colloidal silicon 2.75 2.75 2.75 2.75 2.75 dioxide Hypromellose E5 5.75 5.75 5.75 5.75 5.75 Citric acid 19.50 monohydrate Fumaric acid 19.50 Succinic acid 19.50 L-tartaric acid 19.50 Sodium Stearyl 2.50 2.50 2.50 2.50 2.50 Fumarate Total 555.5 575 575 575 575 Remarks: The purified water in 1 is removed during fluidized bed granulation and drying.

TABLE-US-00030 TABLE 30 Dissolution data of tablet samples with different organic acids 5 min 10 min 15 min 20 min 30 min 45 min 60 min 90 min Formulation 16 32 2.83 58 1.41 75 0.71 83 1.41 82 8.49 84 0.00 79 0.00 74 0.71 pH = 6.80 Formulation 17 34 0.58 61 1.73 79 1.00 86 1.53 87 1.00 89 2.52 86 2.08 87 2.08 pH = 6.81 Formulation 18 32 1.00 58 1.00 75 1.73 83 2.52 84 2.31 84 0.58 84 0.58 85 5.03 pH = 6.78 Formulation 19 34 1.15 60 1.73 77 2.31 85 2.52 85 0.71 85 1.41 87 2.12 87 0.75 pH = 6.82 Formulation 20 32 1.53 59 0.00 77 2.00 85 2.08 84 2.08 84 1.53 81 0.58 82 0.71 pH = 6.78

[0193] The above data shows that adding an organic acid in the case that a water-soluble polymer is already contained in the formulation can further increase the dissolution stability of the active ingredient in the pH 6.8 medium. The dissolution platform of the prepared plain tablets did not significantly decrease at 90 minutes. By measuring the pH value of the medium at the end of the dissolution, it was found that the addition of a small amount of organic acid did not significantly change the pH value of the medium system, indicating that the addition of the organic acid did not increase the dissolution stability of the tablets by changing the pH value of the medium (it is speculated that the possible reason is that the inclusion complex forms a more stable triple complex with water-soluble polymers and organic acids, which ultimately leads to a more stable dissolution platform of vilazodone hydrochloride in a pH 6.8 medium). The results of this experiment suggest that the composition containing a stabilizing agent and an organic acid has higher oral bioavailability in vivo.

Example 16

[0194] According to the formulations in Table 31, the dry granules were prepared according to the process of Example 14, and then the prescribed amounts of hypromellose, citric acid monohydrate and sodium stearyl fumarate were added, mixed evenly, and compressed into tablets. According to the dissolution method in Comparative Example 1, the dissolution of 40 mg strength samples in pH 6.8 medium was measured, and the pH value of the dissolution medium at the end of the dissolution was detected. The specific results are shown in Table 32.

TABLE-US-00031 TABLE 31 Formulations of tablets with different amounts of citric acid monohydrate (unit: g) Formu- Formu- Formu- Formu- Formu- lation lation lation lation lation Component 21 22 23 24 25 Vilazodone 40.00 40.00 40.00 40.00 40.00 hydrochloride HP--CD 400.00 400.00 400.00 400.00 400.00 Purified Water.sup.1 400.00 400.00 400.00 400.00 400.00 Microcrystalline 104.50 104.50 104.50 104.50 104.50 cellulose Colloidal silicon 2.75 2.75 2.75 2.75 2.75 dioxide Hypromellose E5 5.60 5.67 5.73 5.79 5.85 Citric acid 5.60 17.19 23.16 29.25 61.80 monohydrate Sodium Stearyl 2.80 2.87 2.90 2.93 3.09 Fumarate Total 561 573 579 585 618 Remarks: The purified water in 1 is removed during fluidized bed granulation and drying.

TABLE-US-00032 TABLE 32 Dissolution data of tablet samples with different amounts of citric acid monohydrate 5 min 10 min 15 min 20 min 30 min 45 min 60 min Formulation 21 30 2.31 55 2.52 76 1.73 87 1.53 87 2.52 85 5.03 81 3.21 pH = 6.79 Formulation 22 33 1.15 60 1.53 80 1.53 91 1.15 94 0.58 91 1.15 91 1.53 pH = 6.78 Formulation 23 31 1.73 59 0.58 79 1.00 91 0.58 94 0.58 92 1.00 91 1.53 pH = 6.81 Formulation 24 31 2.31 60 2.65 80 1.53 91 0.58 92 1.15 90 1.53 86 2.08 pH = 6.80 Formulation 25 31 2.52 60 2.89 78 4.04 91 2.52 95 1.53 94 0.00 92 0.00 pH = 6.82

[0195] The above data shows that when different amounts of organic acids (1%-10%, w/w) are added to the formulations, the dissolution of prepared plain tablets in the pH 6.8 medium is relatively stable, and no obvious downward trend appears.

Example 17

[0196] According to the formulations in Table 33, the dry granules were prepared according to the process of Example 14, then the prescribed amounts of hypromellose, citric acid monohydrate and sodium stearyl fumarate were added, mixed uniformly, and compressed into tablets. According to the dissolution method in Comparative Example 1, the dissolution of 40 mg strength samples in pH 6.8 medium was measured. The specific results are shown in Table 34.

TABLE-US-00033 TABLE 33 Formulations of tablets with different amounts of hypromellose and citric acid monohydrate (Unit: g) Formu- Formu- Formu- Component lation 26 lation 27 lation 28 Vilazodone hydrochloride 40.00 40.00 40.00 HP--CD 400.00 400.00 400.00 Purified water.sup.1 400.00 400.00 400.00 Microcrystalline cellulose 104.50 104.50 104.50 Colloidal silicon dioxide 2.75 2.75 2.75 Hypromellose E5 30.00 17.55 30.00 Microcrystalline cellulose 17.90 Citric acid monohydrate 17.55 17.90 Sodium stearyl fumarate 2.85 2.65 2.85 Total 598 585 598 The purified water in 1 is removed during fluidized bed granulation and drying.

TABLE-US-00034 TABLE 34 Dissolution data of tablet samples with different amounts of hypromellose and citric acid monohydrate 5 min 10 min 15 min 20 min 30 min 45 min 60 min Formulation 26 25 1.73 45 3.51 62 4.58 73 2.65 85 2.89 85 1.53 83 1.73 Formulation 27 30 0.58 55 1.00 73 1.53 85 1.53 89 1.53 88 1.15 85 1.00 Formulation 28 27 3.06 51 3.61 69 5.03 81 4.58 92 2.08 92 0.58 90 1.53

[0197] The above data shows that the tablets prepared by using different amounts of hypromellose and citric acid monohydrate have relatively stable dissolution in the pH 6.8 medium, and the dissolution platform does not drop significantly at 60 minutes.

Example 18

[0198] According to the formulations in Table 35, the prescribed amount of hydroxypropyl--cyclodextrin was added to purified water, stirred to dissolve, then vilazodone hydrochloride was added, heated to 85 C. and stirred until the solution was clear to obtain an inclusion complex solution. Then heat was stopped, hypromellose E5 and citric acid monohydrate were added and stirred to dissolve to obtain a mixture solution. The mixture solution was sprayed on the bottom material (microcrystalline cellulose and colloidal silicon dioxide) in a fluidized bed granulator, granulated to obtain dry granules; then sodium stearyl fumarate and/or hypromellose was added, mixed well, and compressed into tablets. According to the dissolution method in Comparative Example 1, the dissolution of 40 mg strength samples in pH 6.8 medium was measured. The specific results are shown in Table 36.

TABLE-US-00035 TABLE 35 Formulations of tablets with different amounts of hypromellose (Unit: g) Formu- Formu- Component lation 29 lation 30 Vilazodone hydrochloride 40.00 40.00 HP--CD 360.00 360.00 Hypromellose E5 5.50 5.50 Citric acid monohydrate 16.50 16.50 Purified water.sup.1 360.00 360.00 Microcrystalline cellulose 106.00 106.00 Colloidal silicon dioxide 2.75 2.75 Sodium stearyl fumarate 2.25 2.75 Hypromellose E5 16.50 Total 533 550 Remarks: The purified water in 1 is removed during fluidized bed granulation and drying.

TABLE-US-00036 TABLE 36 Dissolution data of tablet samples with different amounts of hypromellose 5 min 10 min 15 min 20 min 30 min 45 min 60 min 90 min 120 min Formulation 19 1.53 37 1.53 53 1.00 66 1.15 83 3.06 94 0.58 95 1.00 94 0.58 94 1.00 29 Formulation 19 0.58 36 0.58 51 0.58 63 0.58 81 0.58 94 0.58 96 1.15 95 1.15 94 0.58 30

[0199] The above data shows that when the stabilizing agent hypromellose and the acid reagent citric acid monohydrate are added to the inclusion complex solution for granulation, and then compressed, the resulting tablets have a relatively high and stable dissolution platform in the pH 6.8 medium, and no significant decrease occurs at 120 minutes. In addition, the process of adding the stabilizing agent and acid reagent to the inclusion complex solution for granulation is smoother, simpler and more feasible than the external process.

Example 19

(1) Tablets Preparation

[0200] According to the formulation in Table 37, the dry granules were prepared according to the process of Example 14, and then the prescribed amounts of hypromellose and sodium stearyl fumarate were added, mixed well, and compressed into tablets. According to the dissolution method in Comparative Example 1, the dissolution of 10 mg strength samples in various mediums was determined respectively. The specific results are shown in Table 38.

TABLE-US-00037 TABLE 37 Formulation of tablets (Unit: g) Component Formulation 31 Vilazodone hydrochloride 40.00 HP--CD 400.00 Purified Water.sup.1 400.00 Microcrystalline cellulose 104.50 Colloidal silicon dioxide 2.75 Hypromellose E5 5.55 Sodium stearyl fumarate 2.20 Total 555 Remarks: The purified water in 1 is removed during fluidized bed granulation and drying.

TABLE-US-00038 TABLE 38 Dissolution data of tablet samples (10 mg strength) in various mediums Medium 5 min 10 min 15 min 20 min 30 min 45 min 60 min 0.1N HCl 55 14.15 82 4.73 93 3.79 95 5.51 96 5.77 96 6.08 96 6.08 pH 4.5 47 15.31 81 16.20 98 2.65 97 4.36 98 4.36 98 4.04 98 4.36 pH 6.8 50 2.65 84 3.51 95 2.08 97 2.08 97 2.00 96 3.06 94 1.53
(2) Experiments with Animals

[0201] Ten beagle dogs were randomly divided into two groups in double crossover experiments under fasted and fed conditions. Each dog was given a tablet (10 mg strength) of Formulation 31 orally, and whole blood samples were taken at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours respectively. Plasma samples were prepared as follows: whole blood 200 L to 400 L was placed in a centrifuge tube, K.sub.2EDTA was added as an anticoagulant, and centrifuged for 60 minutes. The plasma samples were kept at 70 C. The concentration of vilazodone in the blood plasma was measured by a validated LC-MS/MS method and pharmacokinetic parameters were assessed with non-compartment model using WinNonlin 6.3 software. The results are shown in Table 39. The plasma concentration-time curve is shown in FIG. 1. Among them, C.sub.max represents the highest concentration of the active ingredient in plasma; T.sub.max represents the time when the active ingredient reaches the highest concentration in plasma; AUC.sub.last represents the area under the drug-time curve from the beginning of sampling to the last time point.

TABLE-US-00039 TABLE 39 Pharmacokinetic parameters in fasted and fed dogs Pharmacokinetic T.sub.max C.sub.max AUC.sub.last parameters (n = 5) (h) (ng/mL) (h * ng/mL) Fasted Mean 0.85 78.50 235.00 CV % 55.8 35.1 40.7 Fed Mean 2.10 50.20 218.00 CV % 69.00 50.4 50.4

[0202] As shown in Table 39, the AUC.sub.last and the C.sub.max of the tablets of Formulation 31 under fasted conditions are higher than that under fed conditions, achieving the purpose of improving the bioavailability under fasted conditions. And the AUC.sub.last under fasted conditions is basically equivalent to that under fed conditions, indicating that the compositions provided by the present invention can be taken under fasted and fed conditions, and have basically the same therapeutic effect. Referring to Example 10, the C.sub.max of RLD (Reference Listed Drug) under fasted conditions is only about 32.1% of the C.sub.max under fed conditions and the AUC.sub.last of RLD under fasted conditions is only about 41% of the AUC.sub.last under fed conditions, the RLD has a serious food effect. Therefore, the compositions or formulations provided by the present invention can significantly improve the oral bioavailability of vilazodone under fasted conditions and reduce the influence of food effects, thereby they can be taken under fasted and fed conditions, and have basically the same curative effect, which significantly improves the compliance of patients with medication.

[0203] The solutions and methods of the present invention have been described through the preferred embodiments. It is obvious that relevant persons can make appropriate alterations, changes or combinations of the solutions, methods and applications described herein within the content and scope of the present invention to realize and apply the technology of the present invention. Those skilled in the art can learn from the content of this article and appropriately improve relevant parameters. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.