Formulations of vilazodone

Abstract

A kind of pellet, the pellet includes blank core and drug layer, the drug layer is wrapped in the outer layer of blank core;Wherein, the drug layer includes: vilazodone or its pharmaceutically acceptable salt or ester, and carrier;The carrier includes at least one selected from povidone, copovidone, hypromellose, sucrose and mannitol.The pellet, whether in the environment of pH 6.8 medium, or in the environment of pH 6.8 medium after 0.1M HCl first, has higher solubility, especially can maintain the supersaturated state in the environment of pH 6.8 medium after 0.1M HCl first, therefore, whether with food, or fasting, has higher bioavailability.

Description

Vilazodone preparations Technical Field

[0001] The present invention belongs to the field of biopharmaceutical technology. Specifically, the present invention relates to a vilazodone preparation, and more specifically, the present invention relates to a vilazodone pellet and a preparation method thereof, and a vilazodone tablet. Background Art

[0002] Vilazodone is the first indolealkylamine antidepressant, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist. Vilazodone hydrochloride tablets were approved in the United States in 2011 for the treatment of major depressive disorder. These tablets have a severe food effect, with a bioavailability of approximately 72% when taken with food, and a 50-60% decrease when taken on an empty stomach, making it difficult to meet clinical treatment needs. Therefore, the drug must be taken with food. Because patients with depression often experience loss of appetite, this method of administration, which requires taking the drug with food, causes significant inconvenience for patients and leads to poor compliance, resulting in poor clinical treatment outcomes. Therefore, there is an urgent need to develop a vilazodone formulation that can be taken on an empty stomach.

[0003] Summary of the Invention

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. To this end, the present invention provides a vilazodone hydrochloride micropill, which has high bioavailability regardless of whether it is taken with food or on an empty stomach.

[0005] The present invention is accomplished based on the following findings of the inventors:

[0006] During the inventor's experiment, it was found that the main reason for the difference in bioavailability of vilazodone under fasting and feeding conditions was that there was a significant difference in the solubility of vilazodone under different physiological pH conditions. Vilazodone is mainly absorbed in the small intestine, where the physiological pH is about 6.8, but at such a pH, the solubility of vilazodone is very low. Therefore, the amount and rate of vilazodone dissolved in the stomach will affect its absorption in the small intestine. Since vilazodone dissolves well in a buffer with a pH value of 3.1 (simulating gastric feeding conditions). Therefore, when consumed with food, vilazodone shows good release and bioavailability. However, in 0.1M HCl solution (simulating gastric fasting conditions), the solubility of vilazodone is poor, resulting in a significant reduction in bioavailability. This is consistent with the content of the label of the currently available vilazodone hydrochloride tablets (reference preparation), that is, the vilazodone preparation should be used with food to achieve a bioavailability of 72% and ensure effectiveness. Under fasting conditions, bioavailability can be reduced by about 50% to 60%, failing to achieve clinical efficacy.

[0007] In the first aspect of the present invention, a micropill is proposed. According to an embodiment of the present invention, the micropill includes a blank core and a drug layer, and the drug layer is wrapped around the outer layer of the blank core; wherein the drug layer includes: vilazodone or a pharmaceutically acceptable salt or ester thereof, and a carrier; the carrier includes at least one selected from povidone, copovidone, hydroxypropyl methylcellulose, sucrose and mannitol. The micropill of the present invention has a high solubility in an environment of pH 6.8 or in an environment of 0.1M HCl followed by a pH 6.8 medium, and in particular, it can maintain a supersaturated state in an environment of 0.1M HCl followed by a pH 6.8 medium. Therefore, the micropill of the present invention has a high bioavailability whether taken with food or on an empty stomach.

[0008] According to an embodiment of the present invention, the above-mentioned micropills may further include at least one of the following technical features:

[0009] According to an embodiment of the present invention, the vilazodone or a pharmaceutically acceptable salt or ester thereof is vilazodone hydrochloride.

[0010] According to an embodiment of the present invention, the povidone includes at least one of PVP K25, PVP K29 / 32, PVP K30 and PVP K17.

[0011] According to an embodiment of the present invention, the carrier comprises: povidone and / or copovidone; and optionally at least one of hypromellose, sucrose and mannitol.

[0012] According to an embodiment of the present invention, the carrier includes: 1) povidone; 2) copovidone; or 3) povidone, and at least one of hypromellose, sucrose and mannitol.

[0013] According to an embodiment of the present invention, the carrier includes povidone, and at least one of hypromellose, sucrose and mannitol, and the weight ratio of the weight of the povidone to the total weight of at least one of the hypromellose, sucrose and mannitol is (1-11):(1-11), for example, 1:(0.09-11), 1:(0.09-0.2), 1:(0.5-11), 1:(0.5-10), 1:(0.5-5), 1:(0.5-4), 1:(0.5-3), 1:(0.5-2), 1:(1-10), 1:(1-5), 1:(1-4), 1:(1-3), 1:(1-2).

[0014] According to an embodiment of the present invention, the carrier includes: 1) PVPK25; 2) PVPK29 / 32; or 3) PVPK25 or PVPK29 / 32, and sucrose.

[0015] According to an embodiment of the present invention, the carrier includes PVPK25 or PVPK29 / 32, and sucrose, and the weight ratio of the PVPK25 or PVPK29 / 32 to sucrose is (1-11): (1-11), for example, 1: (0.09-11), 1: (0.09-0.2), 1: (0.5-11), 1: (0.5-10), 1: (0.5-5), 1: (0.5-4), 1: (0.5-3), 1: (0.5-2), 1: (1-10), 1: (1-5), 1: (1-4), 1: (1-3), 1: (1-2).

[0016] According to an embodiment of the present invention, the weight ratio of the vilazodone or a pharmaceutically acceptable salt or ester thereof to the carrier is 1:(4-9), for example, 1:(5-9), 1:(5-8), 1:(5-7), 1:(5-6), 1:(6-9), 1:(6-8), 1:(6-7), 1:6.

[0017] According to an embodiment of the present invention, the blank pellet core is selected from sucrose blank pellet core.

[0018] According to an embodiment of the present invention, the weight ratio of vilazodone or its pharmaceutically acceptable salt or ester to the blank pellet core is 1: (2-12), for example, 1: (4-11), 1: (4-10), 1: (4-9), 1: (4-8), 1: (4-7), 1: (4-6), 1:(4-5), 1:(5-12), 1:(5-11), 1:(5-10), 1:(5-9), 1:(5-8), 1:(5-7), 1:(5-6), 1:(6-12), 1:(6-11), 1:(6-10), 1:(7-12), 1:(7-11), 1:(7-10), 1:(8-12), 1:(8-11), 1:(8-10), 1:(9-12), 1:(9-11), 1:(9-10), 1:(2-6), 1:(2-5), 1:(4-10), or 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, etc.

[0019] According to an embodiment of the present invention, the drug layer further includes a pH adjuster.

[0020] According to an embodiment of the present invention, the pH adjuster is selected from citric acid and / or L-tartaric acid.

[0021] According to an embodiment of the present invention, the pH adjuster is citric acid.

[0022] According to an embodiment of the present invention, the pH adjuster is citric acid monohydrate.

[0023] According to an embodiment of the present invention, the weight ratio of the vilazodone or a pharmaceutically acceptable salt or ester thereof and the pH regulator is 1:(1-3), for example, 1:(1-3), 1:(1-2.5), 1:(1-2), 1:(1-1.5), 1:(1.5-3), 1:(1.5-2.5), 1:(1.5-2).

[0024] According to an embodiment of the present invention, the drug layer comprises 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, and 100 to 180 parts by weight of a carrier.

[0025] According to an embodiment of the present invention, the drug layer comprises 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, and 100 to 120 parts by weight of a carrier.

[0026] According to an embodiment of the present invention, the drug layer comprises 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, and 100 to 120 parts by weight of povidone.

[0027] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 60 parts by weight of a pH adjuster, and 100 to 180 parts by weight of a carrier.

[0028] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of a pH adjuster, and 100 to 180 parts by weight of a carrier.

[0029] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 60 parts by weight of a pH adjuster, and 100 to 120 parts by weight of a carrier.

[0030] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of a pH adjuster, and 100 to 120 parts by weight of a carrier.

[0031] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of L-tartaric acid, and 100 to 120 parts by weight of povidone.

[0032] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, and 100 to 120 parts by weight of hypromellose.

[0033] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, and 100 to 120 parts by weight of copovidone.

[0034] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 60 parts by weight of citric acid monohydrate, and 100 to 180 parts by weight of povidone.

[0035] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, 100 to 110 parts by weight of povidone, and 10 to 20 parts by weight of hypromellose.

[0036] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, 100 to 110 parts by weight of povidone, and 10 to 20 parts by weight of mannitol.

[0037] According to an embodiment of the present invention, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, 10 to 110 parts by weight of povidone, and 10 to 110 parts by weight of sucrose; wherein the weight ratio of the vilazodone or a pharmaceutically acceptable salt or ester thereof to the carrier is 1: (4 to 9).

[0038] According to an embodiment of the present invention, the micropills include 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 100 to 180 parts by weight of a carrier, and 180 to 200 parts by weight of a blank pellet core.

[0039] In some embodiments, the micropellets include 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 100-140 parts by weight of a carrier, and 60-100 parts by weight of a blank pellet core.

[0040] According to an embodiment of the present invention, the micropills include 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 100 to 120 parts by weight of a carrier, and 180 to 200 parts by weight of a blank pellet core.

[0041] According to an embodiment of the present invention, the micropellets include: 20 parts by weight of vilazodone hydrochloride, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 180-200 parts by weight of sucrose blank pellet cores.

[0042] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 60 parts by weight of a pH regulator, 100 to 140 parts by weight of a carrier, and 60 to 100 parts by weight of a blank pellet core.

[0043] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of a pH regulator, 100 to 180 parts by weight of a carrier, and 180 to 200 parts by weight of a blank pellet core.

[0044] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 60 parts by weight of a pH regulator, 100 to 120 parts by weight of a carrier, and 180 to 200 parts by weight of a blank pellet core.

[0045] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of a pH regulator, 100 to 120 parts by weight of a carrier, and 180 to 200 parts by weight of a blank pellet core.

[0046] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of L-tartaric acid, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 180-200 parts by weight of sucrose blank pellet cores.

[0047] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20-30 parts by weight of citric acid monohydrate, 100-120 parts by weight of hypromellose, and 180-200 parts by weight of sucrose blank pellet cores. According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid monohydrate, 100-120 parts by weight of copolyvidone, and 180-200 parts by weight of sucrose blank pellet cores.

[0048] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20 to 60 parts by weight of citric acid monohydrate, 100 to 180 parts by weight of PVP K29 / 32 or PVP K25, and 80 to 200 parts by weight of sucrose blank pellet cores.

[0049] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20-60 parts by weight of citric acid monohydrate, 100-120 parts by weight of PVP K25, and 180-200 parts by weight of sucrose blank pellet cores.

[0050] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid monohydrate, 100-120 parts by weight of PVP K25, and 180-200 parts by weight of sucrose blank pellet cores.

[0051] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 30 parts by weight of citric acid monohydrate, 100-120 parts by weight of PVP K25, and 180-200 parts by weight of sucrose blank pellet cores.

[0052] According to an embodiment of the present invention, the micropellets include: 20 parts by weight of vilazodone hydrochloride, 30 parts by weight of citric acid monohydrate, 100 parts by weight of PVP K25, and 200 parts by weight of sucrose blank pellet cores.

[0053] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20 to 60 parts by weight of citric acid monohydrate, 100 to 120 parts by weight of PVP K29 / 32, and 180 to 200 parts by weight of sucrose blank pellet cores.

[0054] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid monohydrate, 100-120 parts by weight of PVP K29 / 32, and 180-200 parts by weight of sucrose blank pellet cores.

[0055] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 30 parts by weight of citric acid monohydrate, 100-120 parts by weight of PVP K29 / 32, and 180-200 parts by weight of sucrose blank pellet cores.

[0056] According to an embodiment of the present invention, the micropellets include: 20 parts by weight of vilazodone hydrochloride, 30 parts by weight of citric acid monohydrate, 100 parts by weight of PVP K29 / 32, and 200 parts by weight of sucrose blank pellet cores.

[0057] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid monohydrate, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 50-100 parts by weight of sucrose blank pellet cores.

[0058] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid monohydrate, 100-110 parts by weight of PVP K29 / 32 or PVP K25, 10-20 parts by weight of hypromellose, and 180-200 parts by weight of sucrose blank pellet cores.

[0059] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid monohydrate, 100-110 parts by weight of PVP K29 / 32 or PVP K25, 10-20 parts by weight of mannitol, and 180-200 parts by weight of sucrose blank pellet cores.

[0060] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of citric acid monohydrate, 10 to 110 parts by weight of PVP K29 / 32 or PVP K25, 10 to 110 parts by weight of sucrose, and 180 to 200 parts by weight of sucrose blank pellet cores; wherein the weight ratio of the vilazodone hydrochloride to the carrier is 1: (4 to 9).

[0061] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid monohydrate, 50-60 parts by weight of PVP K29 / 32 or PVP K25, 50-60 parts by weight of sucrose, and 180-200 parts by weight of sucrose blank pellet cores.

[0062] According to an embodiment of the present invention, the micropellets include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid monohydrate, 10 parts by weight of PVP K29 / 32 or PVP K25, 110 parts by weight of sucrose, and 180-200 parts by weight of sucrose blank pellet cores.

[0063] According to an embodiment of the present invention, the micropills include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid monohydrate, 60 parts by weight of PVP K29 / 32 or PVP K25, 60 parts by weight of sucrose, and 180-200 parts by weight of sucrose blank pellet cores.

[0064] According to an embodiment of the present invention, the micropellets include: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid monohydrate, 110 parts by weight of PVP K29 / 32 or PVP K25, 10 parts by weight of sucrose, and 180-200 parts by weight of sucrose blank pellet cores.

[0065] In some embodiments, the micropellets include: 20 parts by weight of vilazodone hydrochloride, 20-40 parts by weight of citric acid monohydrate, 40-80 parts by weight of PVPK29 / 32 or PVPK25, 40-80 parts by weight of sucrose, and 50-100 parts by weight of sucrose blank pellet cores.

[0066] In some embodiments, the micropellets include: 20 parts by weight of vilazodone hydrochloride, 30 parts by weight of citric acid monohydrate, 60 parts by weight of PVPK29 / 32, 60 parts by weight of sucrose, and 80 parts by weight of sucrose blank pellet cores.

[0067] According to an embodiment of the present invention, the micropellets include: 20 parts by weight of vilazodone hydrochloride, 30 parts by weight of citric acid monohydrate, 10 parts by weight of PVP K29 / 32 or PVP K25, 110 parts by weight of sucrose, and 200 parts by weight of sucrose blank pellet cores.

[0068] According to an embodiment of the present invention, the micropellets include: 20 parts by weight of vilazodone hydrochloride, 30 parts by weight of citric acid monohydrate, 60 parts by weight of PVP K29 / 32 or PVP K25, 60 parts by weight of sucrose, and 200 parts by weight of sucrose blank pellet cores.

[0069] According to an embodiment of the present invention, the micropellets include: 20 parts by weight of vilazodone hydrochloride, 30 parts by weight of citric acid monohydrate, 110 parts by weight of PVP K29 / 32 or PVP K25, 10 parts by weight of sucrose, and 200 parts by weight of sucrose blank pellet cores.

[0070] In the second aspect of the present invention, the present invention proposes a method for preparing the micropills described in the first aspect. According to an embodiment of the present invention, the method comprises: mixing a carrier, an optional pH regulator, and vilazodone or a pharmaceutically acceptable salt or ester thereof with an acetone aqueous solution to obtain a drug solution, spraying the drug solution on the outer layer of the blank pill core to obtain the micropills. The preparation method of the present invention is simple, and the prepared micropills have a high solubility, especially they can maintain a supersaturated state in a medium environment of 0.1M HCl followed by pH 6.8. Therefore, the micropills of the present invention have a high bioavailability regardless of whether they are taken with food or on an empty stomach.

[0071] According to an embodiment of the present invention, the acetone aqueous solution is a 50-70% acetone aqueous solution (V / V, volume ratio), preferably a 55-65% acetone aqueous solution (V / V, volume ratio).

[0072] In some optional embodiments of the present invention, the acetone aqueous solution is a 60% acetone aqueous solution (V / V, volume ratio).

[0073] According to an embodiment of the present invention, the weight-to-volume ratio (g / ml) of the vilazodone or a pharmaceutically acceptable salt or ester thereof to the acetone aqueous solution is 1:(50-80), preferably 1:(50-75).

[0074] According to an embodiment of the present invention, the temperature of the medicine solution is 42°C to 50°C, for example, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C.

[0075] In its third aspect, the present invention provides a tablet. According to an embodiment of the present invention, the tablet comprises: the micropellets described in the first aspect of the present invention, or the micropellets prepared according to the method described in the second aspect; and additional excipients. The tablet of the present invention has the advantages of high solubility and strong stability. It can maintain a supersaturated state in a 0.1M HCl followed by a pH 6.8 medium. Furthermore, the tablet has high bioavailability whether taken with food or on an empty stomach.

[0076] According to an embodiment of the present invention, the added excipients include a filler and a disintegrant.

[0077] According to an embodiment of the present invention, the filler includes mannitol and / or sucrose.

[0078] According to an embodiment of the present invention, the filler is mannitol or sucrose, preferably sucrose.

[0079] According to an embodiment of the present invention, the disintegrant is selected from at least one of cross-linked polyvinylpyrrolidone, low-substituted cellulose, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

[0080] According to an embodiment of the present invention, the weight ratio of the filler to the disintegrant is 1:(0.04-0.08), preferably 1:(0.04-0.05).

[0081] According to an embodiment of the present invention, the additional auxiliary material further includes a lubricant.

[0082] According to an embodiment of the present invention, the lubricant includes polyethylene glycol 6000 and / or sodium stearyl fumarate, preferably polyethylene glycol 6000.

[0083] According to an embodiment of the present invention, the weight ratio of the filler to the lubricant is 1:(0.04-0.08), preferably 1:(0.04-0.05).

[0084] According to an embodiment of the present invention, the additional excipients include: 1 part by weight of mannitol and 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone.

[0085] According to an embodiment of the present invention, the additional excipients include: 1 part by weight of sucrose and 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone.

[0086] According to an embodiment of the present invention, the additional excipients include: 1 part by weight of sucrose, 0.04 to 0.06 parts by weight of cross-linked polyvinylpyrrolidone, and

[0087] 0.04-0.06 parts by weight of polyethylene glycol 6000.

[0088] According to an embodiment of the present invention, the additional excipients include: 1 part by weight of sucrose, 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone, and 0.04-0.05 parts by weight of sodium stearyl fumarate.

[0089] According to an embodiment of the present invention, the tablet comprises pellets and external excipients;

[0090] The micropills comprise: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 80-100 parts by weight of sucrose blank pellet cores;

[0091] The added auxiliary materials include: 1 part by weight of mannitol and 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone.

[0092] According to an embodiment of the present invention, the tablet comprises pellets and external excipients;

[0093] The micropills comprise: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 80-100 parts by weight of sucrose blank pellet cores;

[0094] The added auxiliary materials include: 1 part by weight of sucrose and 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone.

[0095] According to an embodiment of the present invention, the tablet comprises pellets and external excipients;

[0096] The micropills comprise: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 80-100 parts by weight of sucrose blank pellet cores;

[0097] The added auxiliary materials include: 1 part by weight of sucrose, 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone, and 0.04-0.05 parts by weight of polyethylene glycol 6000.

[0098] According to an embodiment of the present invention, the tablet comprises pellets and external excipients;

[0099] The micropills comprise: 20 parts by weight of vilazodone hydrochloride, 20-30 parts by weight of citric acid, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 80-100 parts by weight of sucrose blank pellet cores;

[0100] The added auxiliary materials include: 1 part by weight of sucrose, 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone, and 0.04-0.05 parts by weight of sodium stearyl fumarate.

[0101] In some embodiments, the tablet comprises pellets and a coating material;

[0102] The micropills comprise: 20 parts by weight of vilazodone hydrochloride, 20 to 40 parts by weight of citric acid, 40 to 80 parts by weight of PVPK29 / 32, 40 to 80 parts by weight of sucrose, and 60 to 100 parts by weight of sucrose blank pellet cores;

[0103] The coating material comprises: 1 part by weight of sucrose, 0.04-0.06 parts by weight of cross-linked polyvinylpyrrolidone, and 0.04-0.06 parts by weight of sodium stearyl fumarate.

[0104] In some embodiments, the tablet comprises pellets and a coating material;

[0105] The micropellets comprise: 20 parts by weight of vilazodone hydrochloride, about 30 parts by weight of citric acid, about 60 parts by weight of PVPK29 / 32, about 60 parts by weight of sucrose, and about 80 parts by weight of sucrose blank pellet cores;

[0106] The coating material comprises: 1 part by weight of sucrose, about 0.05 part by weight of cross-linked polyvinylpyrrolidone, and about 0.05 part by weight of sodium stearyl fumarate.

[0107] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0108] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0109] FIG1 is an XRD diffraction pattern of prescription 35 in Example 10 of the present invention. DETAILED DESCRIPTION

[0110] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0111] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0112] Detailed description of the invention

[0113] Definitions and General Terms

[0114] Before describing the present invention in more detail, it should be understood that the present invention is not limited to the specific embodiments described herein, as such embodiments may vary. It should also be understood that the terms used herein are only used to describe the purpose of specific embodiments, and the terms are not used to limit. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All publications and patents referenced herein are incorporated herein by reference in their entirety.

[0115] Where a numerical range is provided, it is understood that intervening values ​​between the upper and lower limits of the range and any other stated or intervening values ​​in the stated range are encompassed within the present invention, to the tenth of the unit of the lower limit, unless the context clearly indicates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller range and are also encompassed within the present invention, subject to any specifically excluded limitations within the stated range. Where the stated range includes one or both of the stated limits, ranges excluding either or both of those included limits are also encompassed within the present invention.

[0116] The terms "optionally," "optional," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, if the composition of the present invention includes an optional binder, it means that the composition may or may not include the binder.

[0117] The term "include" or "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0118] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith. Preferably, the "pharmaceutically acceptable" herein means approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0119] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compound vilazodone of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in Berge et al., describing pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 1997, 66, 1-19. In some embodiments, the pharmaceutically acceptable salts of the present invention include, but are not limited to, hydrochloride, benzenesulfonate, p-toluenesulfonate, sulfate, hydrobromide, and the like. Preferably, the pharmaceutically acceptable salt of the present invention is the hydrochloride.

[0120] For these and other pharmaceutically acceptable excipients or processes mentioned herein, reference is made to the extensive literature on the subject, in particular to Handbook of Pharmaceutical Excipients, 3rd edition, Arthur H. Kibbe, ed., American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, HP Fiedler, ed., 4th edition, edited by Cantor, Aulendorf and earlier editions.

[0121] The term "pharmaceutically acceptable ester" refers to a vilazodone compound of the present invention formed by reacting with a suitable alcohol or phenol, including but not limited to vilazodone methyl ester, vilazodone ethyl ester, vilazodone phenyl ester, vilazodone benzyl ester, etc. Preferably, the pharmaceutically acceptable ester of vilazodone is a vilazodone fatty alcohol ester, such as vilazodone methyl ester.

[0122] Micropill provided by the present invention or tablet can be given to the patient separately, also can be given or co-administered with other active agents.Term " give together " and " combine " are included in the situation that there is no specific time limit and give two or more therapeutic agents simultaneously or sequentially.In one embodiment, therapeutic agent is present in cell or in individual body simultaneously, or brings into play biological or therapeutic effect simultaneously.In certain embodiments, before giving the second therapeutic agent (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks ago), simultaneously or afterwards (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks later) give first reagent.

[0123] The term "parts by weight" refers to the mass fraction obtained by comparing the mass of a component of a composition with the mass of other components.

[0124] PVP refers to povidone, and PVP K25, PVP K29 / 32, PVP K30 and PVP K17 represent different types of povidone;

[0125] PVPP refers to cross-linked polyvinylpyrrolidone; HP-β-CD refers to hydroxypropyl-β-cyclodextrin;

[0126] HPMC refers to hypromellose; PEG refers to polyethylene glycol.

[0127] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0128] The dissolution rate in the pH 6.8 medium (phosphate buffer) alone in the comparative examples and examples of the present invention was determined by the following method: dissolution in the pH 6.8 medium was determined according to the United States Pharmacopoeia II method (USP II) using 900 mL of medium at 60 rpm. After the test began, 10 ml of the sample was taken at 5, 10, 15, 20, 30, and 45 minutes, and immediately supplemented with 10 ml of fresh dissolution medium. The test was continued. The sample was filtered through a 0.45 μm filter, and an appropriate amount of the filtrate was taken. The drug content in the sample was determined by HPLC, and the cumulative dissolution rate at each time point was calculated.

[0129] Acid-resistant conditions (i.e., dissolving the sample in 0.1 M HCl followed by dissolution in pH 6.8 medium (phosphate buffer)) were tested according to the United States Pharmacopoeia II (USP II) method. 500 mL of 0.1 M HCl was used as the medium at 60 rpm. 10 mL of sample was taken at 15 and 30 min, immediately replenished with 10 mL of fresh dissolution medium, and the dissolution rate in the medium was measured. After sampling in 0.1 M HCl, the medium was replenished to 900 mL without changing the speed. The pH was quickly adjusted to 6.8 with 10 M NaOH. 10 mL of sample was taken at 5, 10, 15, 20, 30, 45, 60, 90, and 120 min, immediately replenished with 10 mL of fresh dissolution medium, and the test continued. The sample was filtered through a 0.45 μm filter, and the filtrate was collected. The drug content in the sample was determined by HPLC, and the cumulative dissolution rate at each time point was calculated.

[0130] HPLC chromatographic conditions:

[0131] HPLC instrument model: Agilent 1260,

[0132] Chromatographic column: Kromasil 100-5C18 4.6x150mm, 5um,

[0133] Detector: UV detector,

[0134] Detection wavelength: 242nm,

[0135] Flow rate: 1.0 mL / min,

[0136] Column temperature: 30°C,

[0137] Injection volume: 10 μL,

[0138] Run time: 4.5 minutes,

[0139] Mobile phase: 0.02 M potassium hydrogen phosphate (pH 6.0) and acetonitrile (54:46, V / V).

[0140] Comparative Example 1

[0141] According to the formula ratio in Table 1, weigh povidone PVP K25 or citric acid monohydrate and vilazodone hydrochloride powder into a beaker. Add 60% acetone aqueous solution (v / v, volume ratio) and stir to dissolve. The solution is then spray-dried in a Buchi small spray dryer (inlet air temperature: 170°C, outlet air temperature: 90°C, rotation speed: 20 rpm) to obtain a spray-dried powder. The spray-dried powder is then mixed with microcrystalline cellulose in a 1:1 ratio. A 40 mg sample is tested for dissolution and acid resistance in a pH 6.8 medium. The results are shown in Tables 2-3.

[0142] Table 1: Preparation of Vilazodone Spray-dried Powder by Spray Drying

[0143] Table 2: Dissolution of 40 mg spray-dried powder in pH 6.8 medium (Mean ± SD)

[0144] Table 3: Comparative Example 1-2 Prescription 40 mg Sample First 0.1M HCl Then pH 6.8 Medium Continuous Multi-Media Dissolution (Mean ± SD)

[0145] The results in Table 2 above show that, keeping the drug-to-load ratio (i.e., the ratio of vilazodone hydrochloride to PVP K25) unchanged, the acidic agent was added to Comparative Example 1-2, and the dissolution of the spray-dried powder in a pH 6.8 medium was higher than that of the formulation without the addition of the acidic agent (Comparative Example 1-1).

[0146] The results in Table 3 above show that when the two batches of spray-dried powders of Comparative Examples 1-1 and 1-2 were first subjected to an acid resistance test and then to a pH 6.8 medium test, the dissolution of these two batches of spray-dried powders was unstable when they were first subjected to acid resistance and then to a pH 6.8 medium, and the platform gradually decreased. However, the acid resistance stability of the formulation with the addition of an acidic agent (Comparative Example 1-2) was higher than that of the formulation without an acidic agent (Comparative Example 1-1). Therefore, it can be shown that adding an acidic agent to a formulation can improve the acid resistance of the formulation.

[0147] Comparative Example 2

[0148] According to the prescription ratio in Table 4, povidone PVP K29 / 32, vilazodone hydrochloride powder, and optionally citric acid monohydrate were weighed and added to a beaker. 60% acetone aqueous solution (V / V, volume ratio) was added and stirred to dissolve until a yellow clear solution was obtained. The prescribed amount of microcrystalline cellulose and colloidal silicon dioxide, or mannitol and colloidal silicon dioxide, was used as a base material. The clear solution was sprayed on the base material in a top spraying manner and dried to obtain vilazodone hydrochloride fluidized bed granules. Dissolution and acid resistance were tested in a pH 6.8 medium according to a 40 mg specification sample. The results are shown in Tables 5-6.

[0149] Table 4: Preparation of Vilazodone Fluidized Bed Granules by Fluidized Bed Drying

[0150] Table 5: Dissolution of 40 mg fluidized bed granules in pH 6.8 medium (Mean ± SD)

[0151] Table 6: Continuous multi-media dissolution of 40 mg samples of Comparative Example 2-1, Comparative Example 2-2 and Comparative Example 2-3 in 0.1 M HCl followed by pH 6.8 (Mean ± SD)

[0152] The results in Table 5 above show that the solid dispersion particles were prepared by fluidized bed spray drying technology, the drug-loading ratio was kept unchanged, and the solid dispersion particles prepared by adding an acidic agent (Comparative Example 2-2) and the solid dispersion particles prepared by not adding an acidic agent (Comparative Example 2-1) in a pH 6.8 medium had the same dissolution platform (the dissolution platform is the time when the solubility does not increase with time).

[0153] The results in Table 6 above show that the acid-resistant stability of the solid dispersion formulations prepared with the addition of an acidic agent (Comparative Examples 2-2 and 2-3) is better than that of the solid dispersion formulation prepared without the addition of an acidic agent (Comparative Example 2-1), which verifies that the acidic agent has a certain stabilizing effect on the acid resistance of the solid dispersion particles.

[0154] However, through Comparative Examples 1 and 2, it was found that regardless of whether the vilazodone solid dispersion prepared by the spray drying process or the fluidized bed process was acid-resistant and then entered into a pH 6.8 medium, the stability time was short and precipitation was easy. Therefore, the stability of the vilazodone solid dispersions prepared in Comparative Examples 1 and 2 after acid resistance is somewhat challenging.

[0155] Comparative Example 3

[0156] 1. According to the prescription ratio in Table 7, copolyvidone, hypromellose, and vilazodone hydrochloride powders were weighed into a beaker. A 60% acetone aqueous solution (v / v, volume ratio) was added and stirred to dissolve. The above solution was spray-dried in a Buchi small spray dryer (inlet air temperature: 170°C, outlet air temperature: 90°C, rotation speed: 20 rpm) to obtain a spray-dried powder. The spray-dried powder was dry-granulated with microcrystalline cellulose, magnesium aluminum silicate, crospovidone, and micropowdered silica gel to obtain dry granules. The obtained dry granules were uniformly mixed with the additional excipients microcrystalline cellulose, crospovidone, and magnesium stearate. The total mixture was passed through a 40-mesh sieve and compressed into 10 mg tablets (based on vilazodone hydrochloride). The tablets were coated with the coating solution to produce vilazodone hydrochloride tablets. The dissolution of the 10 mg sample in pH 6.8 medium was tested. The results are shown in Table 8.

[0157] Table 7: Comparative Example 3 Solid Dispersion Tablet Formulation Composition

[0158] Table 8: Dissolution of Comparative Example 3 in pH 6.8 dissolution medium (Mean ± SD)

[0159] 2. The coated tablets prepared in Comparative Example 3 (specification 10 mg (based on vilazodone hydrochloride)) were subjected to a crossover study in 6 beagle dogs under fasting and fed conditions to verify their pharmacokinetic characteristics in beagle dogs. Whole blood was collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h, and plasma was prepared: 200-400 uL of whole blood was placed in a centrifuge tube, anticoagulated with K2EDTA, and centrifuged within 60 min. Plasma was collected and stored at -70°C. The vilazodone content in plasma was detected by LC-MS-MS, and the pharmacokinetic parameters were calculated using the non-compartmental model method using WinNonlin 6.3 software. The results are shown in Table 9.

[0160] Table 9: Comparative Example 3 Vilazodone Hydrochloride Tablets and Reference Preparations in Beagle Dogs under Fasting and Fed Conditions (10 mg) Pharmacokinetic data (Mean±SD, n=6)

[0161] The solid dispersion prepared in Comparative Example 3 had a significantly increased bioavailability under fasting conditions in animals, and C max The results show that the vilazodone hydrochloride solid dispersion tablets prepared in Comparative Example 3 eliminated the food effect in beagle dogs under fed conditions.

[0162] 3. In order to verify the pharmacokinetic characteristics of the vilazodone hydrochloride tablets obtained in Comparative Example 3 in humans, a clinical trial was conducted using the prescription of Comparative Example 3 to prepare another strength of vilazodone hydrochloride tablets (40 mg strength (calculated as vilazodone hydrochloride)). Bioequivalence of vilazodone hydrochloride tablets 40 mg under fed conditions.

[0163] This trial used a randomized, three-period crossover design and included 30 healthy male adult volunteers aged 18-45 years (inclusive) with a body mass index (BMI) between 18.5 and 24.9 kg / m 2 (inclusive) between.

[0164] Fasting study: fast for at least 10 hours overnight and take the drug with 240±2mL of water in the morning of the next day.

[0165] Intake study: Fast overnight for at least 10 hours, eat a high-fat, high-calorie breakfast the next morning, and take the medicine with 240±2mL of water 30 minutes later.

[0166] Plasma sampling: 25 blood samples (4.0 mL each) were collected from each subject. Plasma samples were collected 0.000 h before administration. After administration, blood samples were collected at 0.5000 h, 1.000 h, 2.000 h, 2.500 h, 3.000 h, 3.500 h, 4.000 h, 4.333 h, 4.667 h, 5.000 h, 5.500 h, 6.000 h, 6.500 h, 7.000 h, 8.000 h, 10.000 h, 12.000 h, 16.000 h, 24.000 h, 36.000 h, 48.000 h, 72.000 h, 96.000 h, and 120.000 h, respectively. K2EDTA was used as the anticoagulant.

[0167] Table 10: Comparative Example 3 Prescription 40 mg Tablet Specification pH 6.8 Medium Dissolution (Mean ± SD)

[0168] Table 11: Pharmacokinetic results of Comparative Example 3 in humans under fasting and feeding conditions

[0169] Note: T-Fed means the vilazodone hydrochloride tablets obtained in Comparative Example 3 were administered in a fed state, T-Fast means the vilazodone hydrochloride tablets obtained in Comparative Example 3 were administered in a fasting state, and R-Fed means the reference preparation. (40 mg) is administered in the fed state.

[0170] As shown in Tables 10 and 11, the dissolution platform of the vilazodone hydrochloride tablets obtained in Comparative Example 3 in a pH 6.8 medium was about 85%, but in the fed state, the dissolution platform of the vilazodone hydrochloride tablets was about 85%. max and AUC 0-inf The values ​​of C in the fasting state were about 2.2 times and 2.1 times of those in the fasting state of the vilazodone hydrochloride tablets obtained in Comparative Example 3. max and AUC 0-inf The bioequivalence of the vilazodone hydrochloride tablets obtained in Comparative Example 3 to the reference preparation in the fed state is about 44% and 48% respectively, indicating that the vilazodone hydrochloride tablets obtained in Comparative Example 3 have a serious food effect.

[0171] 4. Further, after the clinical trial, the acid dissolution resistance of the vilazodone hydrochloride tablets obtained in Comparative Example 3 was investigated. The results are as follows:

[0172] Table 12: Comparative Example 3 Prescription 40 mg Tablet Specifications First 0.1 M HCl Then pH 6.8 Medium Continuous Multi-Media Dissolution (%, Mean ± SD)

[0173] The results are shown in Table 12. The dissolution of the vilazodone hydrochloride tablets obtained in Comparative Example 3 in a pH 6.8 medium was very unstable after acid resistance testing, and the dissolution platform dropped rapidly, resulting in a significant reduction in in vivo absorption. It can be said that the results in humans are somewhat correlated with the results of the acid resistance dissolution test.

[0174] Comparative Example 4

[0175] According to the formulation shown in Table 13, the prescribed amount of hydroxypropyl-β-cyclodextrin was weighed and added to purified water, stirred to dissolve. Vilazodone hydrochloride was then added, heated to 85°C, and stirred until the solution became clear to obtain an inclusion complex solution. This inclusion complex solution was sprayed onto microcrystalline cellulose in a fluidized bed granulator to obtain dry granules. The prescribed amount of hypromellose and sodium stearyl fumarate was then added, mixed, and tableted. The dissolution of a 10 mg sample of the formulation in a pH 6.8 medium was measured. The results are shown in Table 14.

[0176] Table 13: Tablet prescription (unit: g)

[0177] Table 14: Dissolution of Comparative Example 4 Tablets (10 mg) in pH 6.8 Medium (Mean ± SD)

[0178] 2. The tablets prepared in Comparative Example 4 (specification 10 mg (vilazodone hydrochloride)) were subjected to a crossover study in 10 beagle dogs under fasting and fed conditions. Specifically, the 10 beagle dogs were randomly divided into two groups, and each dog was orally administered one tablet (10 mg) prepared according to the prescription of Comparative Example 4. Whole blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours to prepare plasma: 200-400 uL of whole blood was collected into a centrifuge tube, K2EDTA was added for anticoagulation, and the blood was centrifuged for 60 minutes. The plasma was collected and stored at -70°C. The content of vilazodone in the plasma was detected by LC-MS-MS, and the pharmacokinetic parameters were calculated using the non-compartmental model method using WinNonlin 6.3 software. The results are shown in Table 15.

[0179] Table 15: Pharmacokinetic parameters of Comparative Example 4 tablets in dogs under fasting and fed conditions

[0180] The data showed that the AUC of the comparative example 4 tablets under fasting conditions was last and C max Higher AUC than that under fed conditions last and Cmax , to achieve the purpose of improving bioavailability under fasting conditions.

[0181] 3. In order to verify the pharmacokinetic characteristics of the vilazodone hydrochloride tablets obtained in Comparative Example 4 in humans, a clinical trial was conducted using the prescription of Comparative Example 4 to prepare another strength of vilazodone hydrochloride tablets (40 mg strength (calculated as vilazodone hydrochloride)). Bioequivalence of vilazodone hydrochloride tablets 40 mg under fed conditions.

[0182] The trial adopted a randomized, three-period crossover design and included 30 healthy male adult volunteers aged between 18 and 45 years (inclusive) with a body mass index (BMI) between 18.5 and 24.9 kg / m 2 (inclusive) between.

[0183] Fasting study: fast for at least 10 hours overnight and take the drug with 240±2mL of water in the morning of the next day.

[0184] Intake study: Fast overnight for at least 10 hours, eat a high-fat, high-calorie breakfast the next morning, and take the medicine with 240±2mL of water 30 minutes later.

[0185] Plasma sampling: 6.0 mL per blood sample. 0.00 h plasma sample was collected 1 h before administration. After administration, blood samples were collected at 0.50 h, 1.00 h, 2.00 h, 2.500 h, 3.00 h, 4.00 h, 5.00 h, 6.00 h, 7.00 h, 8.00 h, 10.00 h, 14.00 h, 6.500 h, 24.00 h, 48.00 h, 72.00 h, and 96.00 h. K2EDTA was used as the anticoagulant.

[0186] Table 16: Comparative Example 4 Prescription 40 mg Tablet Specification pH 6.8 Medium Dissolution (%, Mean ± SD)

[0187] Table 17: Comparative Example 4 Prescription 40 mg Tablet Specifications First 0.1M HCl Then pH 6.8 Medium Continuous Multi-Media Dissolution (%, Mean ± SD)

[0188] Table 18: Pharmacokinetic results of Comparative Example 4 in humans under fasting and feeding conditions

[0189] Note: T-Fed means the vilazodone hydrochloride tablets obtained in Comparative Example 4 were administered in a fed state, T-Fast means the vilazodone hydrochloride tablets obtained in Comparative Example 4 were administered in a fasting state, and R-Fed means the reference preparation. (40 mg) is administered in the fed state.

[0190] Before the human clinical trial of Comparative Example 4, the vilazodone hydrochloride tablets prepared in Comparative Example 4 were subjected to dissolution tests in pH 6.8 medium and acid-resistant conditions. As shown in Tables 16 and 17, in the 6.8 medium and acid-resistant dissolution tests alone, the dissolution platforms of the vilazodone hydrochloride tablets obtained in Comparative Example 4 were close to 90%. The human results shown in Table 18 show that the vilazodone hydrochloride tablets prepared in Comparative Example 4 are bioequivalent in the fed state and the fasted state, that is, the food effect is eliminated. The AUC and C values ​​of the vilazodone hydrochloride tablets prepared in Comparative Example 4 in the fasted state are similar. max The results of Comparative Example 4 show that under in vitro acid-resistant conditions (simulating human fasting conditions), the solubilization results of the inclusion complex are not destroyed in an acidic environment, and after entering a pH 6.8 medium, it still maintains a high solubility, thereby achieving complete absorption of vilazodone hydrochloride in the body, especially in the small intestine, thereby improving the bioavailability in the fasting state.

[0191] From the results of Comparative Examples 3 and 4, it can be seen that the in vitro acid dissolution test has a certain correlation with the drug absorption results under fasting conditions in vivo. This is because vilazodone hydrochloride is a weak base salt and its solubility in an acidic environment is originally high. Therefore, when it is solubilized, the sample obtained is easily destroyed in an acidic environment, resulting in the separation of vilazodone hydrochloride alone, resulting in the failure of solubilization, and thus affecting the absorption in the body.

[0192] Example 1

[0193] 1. Commercially available preparations Dissolution assay

[0194] Pick Tablets (40mg) 6 tablets, testing 40mg specification The dissolution and acid resistance of tablet samples in pH 6.8 medium were investigated. The specific results are shown in Tables 19-20.

[0195] Table 19: 40mg Specifications Tablet dissolution in pH 6.8 medium (%, Mean ± SD)

[0196] Table 20: 40mg Specifications Tablet dissolution in 0.1M HCl followed by pH 6.8 continuous medium (%, Mean ± SD)

[0197] 2. Selection of carrier materials

[0198] According to the recipe in Table 21, the prescribed amount of each carrier material and vilazodone hydrochloride powder were placed in a beaker, 60% acetone aqueous solution (v / v) was added, and the mixture was stirred to dissolve, yielding a yellow clear solution. The prescribed amount of blank sucrose pellets was placed in a pellet coating fluidized bed, and the clear solution was sprayed onto the blank sucrose pellets using a bottom spray method. After drying, vilazodone hydrochloride pellets were obtained. The dissolution of a 40 mg sample in a pH 6.8 medium was tested, and the results are shown in Table 22.

[0199] Table 21: Prescriptions of different carrier materials

[0200] Table 22: Dissolution results of micropellets prepared with different carrier materials in pH 6.8 medium (%, Mean ± SD)

[0201] The above results show that the dissolution rate of vilazodone hydrochloride solid dispersion micropellets prepared with polyvidone such as PVP K25 in simulated intestinal fluid (pH 6.8 medium) is relatively high. Under high strength (40 mg) conditions, the dissolution platform is greater than 50%, which is much greater than that of the reference preparation. The dissolution rate can serve as the basis for subsequent formulation optimization.

[0202] Example 2: Investigation of different acid reagents

[0203] According to the recipe in Table 23, the prescribed amount of PVP material and different acid reagents were placed in a beaker, 60% acetone aqueous solution (V / V) was added, and after stirring to dissolve, vilazodone hydrochloride was added and stirred until a yellow clear solution was obtained. The prescribed amount of blank sucrose pellets were placed in a micropellet coating fluidized bed, and the above clear solution was sprayed on the blank sucrose pellets using a bottom spray method. After drying, vilazodone hydrochloride micropellets were obtained. The dissolution of the 40mg sample in a pH 6.8 medium and acid resistance were tested. The results are shown in Tables 24-25.

[0204] Table 23: Investigation of different acid reagents

[0205] Table 24: Dissolution results of micropellets with different acid reagents in pH 6.8 medium (%, Mean ± SD)

[0206] Table 25: Continuous dissolution results of 40 mg pellets in 0.1 M HCl followed by pH 6.8 medium (%, Mean ± SD)

[0207] The above results show that, keeping the amount of acidic reagent added unchanged, only the vilazodone hydrochloride pellets prepared with citric acid monohydrate and L-tartaric acid have a dissolution plateau exceeding 80% in simulated intestinal fluid (pH 6.8 medium), and the dissolution rate of the citric acid monohydrate formulation is even better. The results of this example thus demonstrate that acidic reagents can significantly increase the solubility of vilazodone hydrochloride in alkaline simulated intestinal fluid (pH 6.8 medium).

[0208] As shown in Comparative Examples 1-1 and 1-2, under the same preparation process, the addition of an acidic agent can increase the solubility of salt vilazodone in simulated intestinal fluid (pH 6.8 medium). Compared with Prescription 5 and Prescription 7, Comparative Example 1-2 has the same solid dispersion prescription ratio. In simulated intestinal fluid (pH 6.8 medium), the dissolution rate of the micropill drug application process is higher than that of the spray-dried powder, with no significance. However, in the continuous multi-media detection of pH 6.8 medium after 0.1M HCl, the stability of the micropills is significantly higher than that of the reference preparation and Comparative Example 1-2, which shows that the solid dispersion micropills prepared by the micropill coating process can improve the stability after acid resistance by adding an acidic agent to the vilazodone hydrochloride prescription, which has an unexpected effect.

[0209] Example 3: Investigation of the Acid Reagent Ratio

[0210] According to the recipe in Table 26, the prescribed amount of PVP material and citric acid monohydrate were placed in a beaker, 60% acetone aqueous solution (V / V) was added, and after stirring to dissolve, vilazodone hydrochloride was added and stirred until a yellow clear solution was obtained. The prescribed amount of blank sucrose pellets were placed in a micropellet coating fluidized bed, and the clear solution was sprayed onto the blank sucrose pellets using a bottom spray method. After drying, vilazodone hydrochloride micropellets were obtained. The dissolution of the 40mg sample in a pH 6.8 medium and acid resistance were tested. The results are shown in Tables 27-28.

[0211] Table 26: Acid-reagent ratio investigation

[0212] Table 27: Dissolution results of pellets with different acid reagent ratios in pH 6.8 medium (%, Mean ± SD)

[0213] Table 28: Dissolution results of pellets with different acid reagent ratios in 0.1M HCl followed by pH 6.8 medium (%, Mean ± SD)

[0214] The above results show that the solubility of vilazodone hydrochloride solid dispersion microcapsules in simulated intestinal fluid (pH 6.8 medium) is significantly improved by adding citric acid monohydrate to the formulation. As the amount of citric acid monohydrate added increases, the dissolution platform gradually stabilizes and the dissolution stability also gradually stabilizes. This indicates that the addition of acidic reagents has a significant positive effect on vilazodone hydrochloride. When the ratio of the raw material to citric acid monohydrate is 1: (1.5-3), the solubility and acid stability of the microcapsules in simulated intestinal fluid (pH 6.8 medium) are good.

[0215] Example 4: PVP K29 / 32 as a carrier

[0216] According to the prescription in Table 29, the prescribed amount of PVP material and citric acid monohydrate were added to a beaker, and a 60% acetone aqueous solution (V / V) was added. After stirring to dissolve, the prescribed amount of vilazodone hydrochloride was added and continued to stir until a yellow clear solution was obtained. The prescribed amount of blank sucrose pellets were placed in a micropellet coating fluidized bed. The clear solution was sprayed on the blank sucrose pellets using a bottom spray method. After drying, vilazodone hydrochloride pellets were obtained. The dissolution of the 40 mg sample in a pH 6.8 medium and acid resistance were tested. The results are shown in Tables 30-31.

[0217] Table 29: PVP K29 / 32 as a carrier formulation study

[0218] Table 30: Dissolution results of 40 mg PVP K29 / 32 as carrier pellets in pH 6.8 medium (%, Mean ± SD)

[0219] Table 31: Continuous dissolution results of 40 mg PVP K29 / 32 pellets as carrier in 0.1 M HCl followed by pH 6.8 medium (%, Mean ± SD)

[0220] The dissolution results above show that, when used as a carrier, PVP K29 / 32, without the acidity regulator monohydrate citric acid, achieved a significantly lower plateau than the formulation containing an acidity regulator, both in pH 6.8 dissolution alone and in acid-resistant dissolution. PVP K25 and PVP K29 / 32, when used as carriers, also exhibited high dissolution rates in both pH 6.8 and acid-resistant media.

[0221] Using the same liquid formulation, the dissolution of the particles prepared by the fluidized bed in Comparative Example 2-1 in a single pH 6.8 medium was significantly lower than the dissolution of the pellets prepared by pellet coating in Formulation 12. Similarly, using the same liquid formulation, the dissolution of the particles prepared by the fluidized bed in Comparative Examples 2-2 and 2-3 in a single pH 6.8 medium was significantly lower than the dissolution of the pellets prepared by pellet coating in Formulation 13. Comparative Example 2-3, which had relatively good dissolution in a single pH 6.8 medium, had a significantly lower dissolution platform in the acid resistance test than the pellets prepared by pellet coating in Formulations 12 and 13. Therefore, it can be further demonstrated that the use of pellet coating in solid dispersion formulations has an unexpected effect.

[0222] Example 5: Investigation of carrier ratio

[0223] According to the recipe in Table 32, the prescribed amount of PVP material and citric acid monohydrate were placed in a beaker, 60% acetone aqueous solution (V / V) was added, and after stirring to dissolve, vilazodone hydrochloride was added and stirred until a yellow clear solution was obtained. The prescribed amount of blank sucrose pellets were placed in a micropellet coating fluidized bed, and the clear solution was sprayed on the blank sucrose pellets using a bottom spray method. After drying, vilazodone hydrochloride micropellets were obtained. The dissolution of the 40 mg sample in a pH 6.8 medium and acid resistance were tested. The results are shown in Tables 33-34.

[0224] Table 32: Investigation of different ratios of PVP K29 / 32 carriers

[0225] Table 33: Dissolution results of PVP K29 / 32 carrier pellets at different ratios in pH 6.8 medium (%, Mean ± SD)

[0226] Table 34: Continuous multi-media dissolution results of PVP K29 / 32 micropellets with different carrier ratios in 0.1M HCl followed by pH 6.8 medium (%, Mean ± SD)

[0227] The above results show that in simulated intestinal fluid (pH 6.8 medium), when the weight ratio of vilazodone hydrochloride to carrier is 1: (5-9), the dissolution platform of vilazodone hydrochloride solid dispersion microcapsules in simulated intestinal fluid (pH 6.8 medium) and the dissolution platform in the acid resistance test are relatively stable. The continued increase of the carrier cannot further improve the dissolution platform of the microcapsules.

[0228] Example 6: Investigation of other or mixed carrier acid formulations

[0229] According to the recipe in Table 35, the prescribed amount of carrier and citric acid monohydrate were placed in a beaker, 60% acetone aqueous solution (V / V) was added, and after stirring to dissolve, vilazodone hydrochloride was added and stirred continuously until a yellow clear solution was obtained. The prescribed amount of blank sucrose pellets were placed in a micropellet coating fluidized bed, and the clear solution was sprayed onto the blank sucrose pellets using a bottom spray method. After drying, vilazodone hydrochloride micropellets were obtained. The dissolution of a 40 mg sample in a pH 6.8 medium was tested, and the results are shown in Tables 36-37.

[0230] Table 35: Mixed carrier investigation

[0231] Table 36: Dissolution of micropellets prepared with mixed carriers in pH 6.8 medium (%, Mean ± SD)

[0232] Table 37 Mixed carrier prepared pellets first 0.1M HCl then pH 6.8 medium continuous multi-media dissolution results (%, Mean ± SD)

[0233] The above results show that compared with the single carrier, the dissolution of the micropellets prepared with the mixed carrier in the pH 6.8 medium has no significant difference from the dissolution of the single PVP K29 / 32 carrier. However, in the acid resistance test, compared with the formulation with the single carrier of hypromellose, the other formulations have better dissolution platforms, especially the single carrier PVP K29 / 32 and the mixed carrier PVP K29 / 32 and sucrose.

[0234] Example 7: Investigation of preparation process parameters

[0235] According to the prescription in Table 38, the prescribed amount of PVP material and citric acid monohydrate were placed in a beaker, 60% acetone aqueous solution (V / V) was added, and after stirring to dissolve, vilazodone hydrochloride was added and continued to stir until a yellow clear solution was obtained. Other process parameters remained unchanged, and different material temperatures were set according to the prescription. The prescribed amount of blank sucrose pellets were placed in the micropellet coating fluidized bed, and the above-mentioned clear solution was sprayed on the blank sucrose pellets in the form of bottom spraying. After drying, vilazodone hydrochloride pellets were obtained. According to the method under the above-mentioned "Dissolution Determination of Commercially Available Preparations", the solubility of 40 mg sample in pH 6.8 medium and acid resistance was tested. The results are shown in Tables 39-40.

[0236] Table 38: Preparation of micropellets at different material temperatures

[0237] Table 39: Dissolution results of pellets at different material temperatures in pH 6.8 medium (%, Mean ± SD)

[0238] Table 40 Dissolution results of pellets in continuous medium at different material temperatures (0.1M HCl followed by pH 6.8) (Mean ± SD)

[0239] The above results show that when the material temperature is too low, the dissolution platform and stability of the micropellets are affected. When the material temperature is greater than or equal to 42°C, the dissolution platform of the micropellets prepared by micropellet coating is significantly increased in the pH 6.8 medium, and the dissolution platform and stability of the micropellets are significantly increased in the acid resistance test.

[0240] Example 8: Investigation of drug solution concentration

[0241] According to the prescription in Table 41, a prescribed amount of 60% acetone aqueous solution (V / V) was prepared. Under stirring, the prescribed amount of PVP K29 / 32 and citric acid monohydrate were added to the 60% acetone aqueous solution (V / V). After stirring and dissolving, vilazodone hydrochloride was added and stirred continuously until a yellow clear solution was obtained. Drug solutions of different concentrations were obtained. The prescribed amount of blank sucrose pellets were placed in a micropellet coating fluidized bed. The clear solution was sprayed onto the blank sucrose pellets using a bottom spray method. After drying, vilazodone hydrochloride micropellets were obtained. The dissolution of a 40 mg sample in a pH 6.8 medium was tested. The results are shown in Tables 42-43.

[0242] Table 41: Investigation of prescriptions for drug solutions at different concentrations

[0243] Table 42: Dissolution results of pellets prepared with different concentrations of drug solution in pH 6.8 medium (%, Mean ± SD)

[0244] Table 43: Dissolution results of pellets prepared with different drug concentrations in 0.1M HCl followed by pH 6.8 continuous medium (%, Mean ± SD)

[0245] The drug density was increased and different drug concentrations were tested. The results showed that the dissolution of micropellets prepared with different drug concentrations in a single pH 6.8 medium was not affected, and the acid resistance test was also unaffected, with a high and stable dissolution platform.

[0246] Example 9: Preparation of Vilazodone Hydrochloride Tablets

[0247] The above-mentioned pellets were prepared according to the formulations shown in Table 44. Formulations 32-36 were prepared according to Example 8. Spray-dried powder was prepared according to Comparative Example 1 for Formulation 37. Fluidized bed granules were prepared according to Comparative Example 2 for Formulation 38. Excipients were added to the resulting samples as shown in Table 43, mixed, and tableted. The dissolution of 40 mg tablets in a pH 6.8 medium and acid resistance were tested according to the method described above under "Dissolution Determination of Commercially Available Formulations." The results are shown in Tables 45-46.

[0248] Table 44: Tablet preparation formula

[0249] Table 45: Dissolution results of tablets prepared from solid dispersion micropellets in pH 6.8 medium (%, Mean ± SD)

[0250] Table 46: Dissolution results of solid dispersion pellets in tablets prepared in 0.1 M HCl followed by pH 6.8 continuous medium (%, Mean ± SD)

[0251] Comparative Example 3 is a tablet prepared from a solid dispersion, and a solid dispersion micropellet tablet prepared using PVP K29 / 32 as the sole carrier. The above results show that the dissolution of the tablet prepared from the solid dispersion micropellet in a pH 6.8 medium is much higher than that of the tablet prepared from the solid dispersion, and is consistent with the tablet prepared from the inclusion compound in Comparative Example 4. The inventors also surprisingly discovered that when sucrose is selected as the carrier and the additional filler, the dissolution platform and stability of the vilazodone tablet can be further improved.

[0252] The tablets prepared from the solid dispersion micropellets are acid-resistant and still maintain high solubility in a pH 6.8 medium, which is a huge difference from the solid dispersion tablets prepared in Comparative Example 3, and this result is consistent with the result of Comparative Example 4. Therefore, the vilazodone hydrochloride preparation provided by the present invention can significantly improve the oral bioavailability of vilazodone hydrochloride under fasting conditions, thereby achieving the same therapeutic effect under both fasting and fed conditions, and significantly improving the patient's compliance with medication.

[0253] Example 10: Accelerated stability study

[0254] According to prescription 35, vilazodone hydrochloride tablets were prepared and placed in 60 mL oral solid pharmaceutical high-density polyethylene bottles. One bag of silica gel desiccant (3 g) was placed in each bottle and sealed with an oral solid pharmaceutical polypropylene bottle cap (Φ33 mm). The bottles were stored at 40° C. and 75% RH (humidity) for 6 months. After the time point was reached, samples were taken to test the tablets for dissolution in a pH 6.8 medium alone, acid resistance dissolution, content, related substances, and XRD. The dissolution results are shown in Tables 47-49, and the XRD diffraction pattern is shown in Figure 1.

[0255] Table 47: Dissolution results of Vilazodone Hydrochloride Tablets in pH 6.8 Medium during Stability Process (%, Mean ± SD)

[0256] Table 48: Acid dissolution results of Vilazodone Hydrochloride Tablets during stability (%, Mean ± SD)

[0257] Table 49: Related substances and content results of Vilazodone Hydrochloride Tablets during stability

[0258] The above data show that the dissolution, content and related substance stability of the vilazodone hydrochloride solid dispersion pellets prepared by the fluidized bed pellet coating process are good. The XRD test data show that after 6 months of acceleration, there is no characteristic peak of the crystalline API near the 2Theta angle of 10°, indicating that the crystal form is stable.

[0259] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0260] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A micro-pellet, characterized in that: It comprises a blank pill core and a drug layer, wherein the drug layer is wrapped around the outer layer of the blank pill core; Wherein, the drug layer comprises: vilazodone or a pharmaceutically acceptable salt or ester thereof, and a carrier; The carrier comprises at least one selected from the group consisting of povidone, copovidone, hypromellose, sucrose and mannitol.

2. The micropellet according to claim 1, characterized in that The vilazodone or a pharmaceutically acceptable salt or ester thereof is vilazodone hydrochloride; Optionally, the povidone comprises at least one of PVP K25, PVP K29 / 32, PVP K30 and PVP K17; Optionally, the carrier comprises povidone and / or copovidone, and optionally at least one of hypromellose, sucrose and mannitol; Optionally, the carrier comprises: 1) Povidone; or 2) copolyvidone; or 3) povidone, and at least one of hypromellose, sucrose and mannitol; Optionally, the carrier comprises povidone and at least one of hypromellose, sucrose and mannitol, and the weight ratio of the weight of the povidone to the total weight of at least one of the hypromellose, sucrose and mannitol is (1-11): (1-11); Optionally, the carrier comprises: 1) PVP K25; or 2) PVP K29 / 32; or 3) PVP K25 or PVP K29 / 32, and sucrose; Optionally, the carrier comprises PVP K25 or PVP K29 / 32, and sucrose, and the weight ratio of PVP K25 or PVP K29 / 32 to sucrose is (1-11):(1-11), preferably 1:(0.5-11); Optionally, the weight ratio of the vilazodone or its pharmaceutically acceptable salt or ester to the carrier is 1:(4-9), preferably 1:(5-9); Optionally, the blank pellet core is selected from sucrose blank pellet core; Optionally, the weight ratio of the vilazodone or a pharmaceutically acceptable salt or ester thereof to the blank pellet core is 1:(2-12).

3. The micropellet according to claim 1, characterized in that The drug layer further comprises a pH adjuster; Optionally, the pH adjuster is selected from citric acid and / or L-tartaric acid, preferably citric acid; Optionally, the pH adjuster is citric acid monohydrate; Optionally, the weight ratio of the vilazodone or its pharmaceutically acceptable salt or ester to the pH regulator is 1:(1-3), The preferred ratio is 1: (1.5-3).

4. The micropellet according to any one of claims 1 to 3, characterized in that: The drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, and 100 to 180 parts by weight of a carrier; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, and 100 to 120 parts by weight of a carrier; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 60 parts by weight of a pH adjuster, and 100 to 180 parts by weight of a carrier; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of a pH adjuster, and 100 to 180 parts by weight of a carrier; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 60 parts by weight of a pH adjuster, and 100 to 120 parts by weight of a carrier; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of a pH adjuster, and 100 to 120 parts by weight of a carrier.

5. The micropellet according to claim 4, characterized in that The drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, and 100-120 parts by weight of povidone; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of L-tartaric acid, and 100-120 parts by weight of povidone; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, and 100-120 parts by weight of hypromellose; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, and 100-120 parts by weight of copolyvidone; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 60 parts by weight of citric acid monohydrate, and 100-180 parts by weight of povidone; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, 100 to 110 parts by weight of povidone, and 10 to 20 parts by weight of hypromellose; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, 100 to 110 parts by weight of povidone, and 10 to 20 parts by weight of mannitol; Optionally, the drug layer comprises: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, 10 to 110 parts by weight of povidone, and 10 to 110 parts by weight of sucrose; Wherein, the weight ratio of the vilazodone or its pharmaceutically acceptable salt or ester to the carrier is 1:(4-9).

6. The micropellet according to any one of claims 1 to 3, characterized in that: The micropellets include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 100 to 180 parts by weight of a carrier, and 180-200 parts by weight of blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 100 to 140 parts by weight of a carrier, and 60 to 100 parts by weight of blank pellet cores; Optionally, the pellets include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 100 to 120 parts by weight of a carrier, and 180-200 parts by weight of blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 60 parts by weight of a pH adjuster, 100 to 140 parts by weight of a carrier, and 60 to 100 parts by weight of blank pellet cores; Optionally, the pellets include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of a pH adjuster, 100 to 180 parts by weight of a carrier, and 180-200 parts by weight of blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 60 parts by weight of a pH adjuster, 100 to 120 parts by weight of a carrier, and 180-200 parts by weight of blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of a pH adjuster, 100 to 120 parts by weight of a carrier, and 180 to 200 parts by weight of blank pellet cores.

7. The micropellet according to claim 6, characterized in that The micropellets include: 20 parts by weight of vilazodone hydrochloride, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 180-200 parts by weight of sucrose blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of L-tartaric acid, 100-120 parts by weight of PVPK29 / 32 or PVPK25, and 180-200 parts by weight of sucrose blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone or a pharmaceutically acceptable salt or ester thereof, 20 to 30 parts by weight of citric acid monohydrate, 100 to 120 parts by weight of hypromellose, and 180-200 parts by weight of sucrose blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of citric acid monohydrate, 100 to 120 parts by weight of copolyvidone, and 180-200 parts by weight of sucrose blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone hydrochloride, 20 to 60 parts by weight of citric acid monohydrate, 100-180 parts by weight of PVP K29 / 32 or PVP K25, and 80 to 200 parts by weight of sucrose blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of citric acid monohydrate, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 50 to 100 parts by weight of sucrose blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of citric acid monohydrate, 100-110 parts by weight of PVP K29 / 32 or PVP K25, 10 to 20 parts by weight of hypromellose, and 180-200 parts by weight of sucrose blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of citric acid monohydrate, 100-110 parts by weight of PVP K29 / 32 or PVP K25, 10 to 20 parts by weight of mannitol, and 180-200 parts by weight of sucrose blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of citric acid monohydrate, 10 to 110 parts by weight of PVP K29 / 32 or PVP K25, 10 to 110 parts by weight of sucrose, and 180-200 parts by weight of sucrose blank pellet core; Optionally, the pellets include: 20 parts by weight of vilazodone hydrochloride, 20 to 40 parts by weight of citric acid monohydrate, 40-80 parts by weight of PVP K29 / 32 or PVP K25, 40 to 80 parts by weight of sucrose, and 50 to 100 parts by weight of sucrose blank pellet cores; wherein the weight ratio of vilazodone hydrochloride to the carrier is 1:(4 to 9).

8. A method for preparing the micropellets according to any one of claims 1 to 7, characterized in that: include: The carrier, the optional pH adjuster, and vilazodone or a pharmaceutically acceptable salt or ester thereof are mixed with the acetone aqueous solution to obtain a drug solution. Spraying the drug solution onto the outer layer of the blank pellet core to obtain the pellets; Optionally, the acetone aqueous solution is a 50-70% acetone aqueous solution (V / V), preferably a 55-65% acetone aqueous solution (V / V); Optionally, the weight-to-volume ratio (g / ml) of the vilazodone or a pharmaceutically acceptable salt or ester thereof to the acetone aqueous solution is 1:(50-80), preferably 1:(50-75); Optionally, the temperature of the drug solution is 42°C to 50°C.

9. A tablet, characterized in that include: The micropellets according to any one of claims 1 to 7 or the micropellets prepared according to the method of claim 8; as well as Additional auxiliary materials.

10. The tablet according to claim 9, characterized in that The added excipients include fillers and disintegrants; Optionally, the filler comprises mannitol and / or sucrose; Optionally, the filler is mannitol or sucrose, preferably sucrose; Optionally, the disintegrant is selected from at least one of crospovidone, low-substituted cellulose, croscarmellose sodium and sodium carboxymethyl starch; Optionally, the weight ratio of the filler to the disintegrant is 1:(0.04-0.05); Optionally, the additional auxiliary materials further include a lubricant; Optionally, the lubricant comprises polyethylene glycol 6000 and / or sodium stearyl fumarate, preferably polyethylene glycol 6000; Optionally, the weight ratio of the filler to the lubricant is 1:(0.04-0.05).

11. The tablet according to claim 9, characterized in that The additional auxiliary materials include: 1 part by weight of mannitol, and 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone; Optionally, the additional auxiliary materials include: 1 part by weight of sucrose, and 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone; Optionally, the additional auxiliary materials include: 1 part by weight of sucrose, 0.04-0.06 parts by weight of cross-linked polyvinylpyrrolidone, and 0.04-0.06 parts by weight of polyethylene glycol 6000; Optionally, the additional auxiliary materials include: 1 part by weight of sucrose, 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone, and 0.04-0.05 parts by weight of sodium stearyl fumarate.

12. The tablet according to any one of claims 9 to 11, characterized in that The tablet comprises pellets and additional excipients; Wherein, the micropill comprises: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of citric acid monohydrate, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 80 to 100 parts by weight of sucrose blank pellet core; The additional auxiliary materials include: 1 part by weight of mannitol, and 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone; Optionally, the tablet comprises pellets and additional excipients; Wherein, the micropill comprises: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of citric acid monohydrate, 100-120 parts by weight of PVPK 29 / 32 or PVP K25, and 80 to 100 parts by weight of sucrose blank pellet core; The additional auxiliary materials include: 1 part by weight of sucrose, and 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone; Optionally, the tablet comprises pellets and additional excipients; Wherein, the micropill comprises: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of citric acid monohydrate, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 80 to 100 parts by weight of sucrose blank pellet core; The additional auxiliary materials include: 1 part by weight of sucrose, 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone, and 0.04-0.05 parts by weight of polyethylene glycol 6000; Optionally, the tablet comprises pellets and additional excipients; Wherein, the micropill comprises: 20 parts by weight of vilazodone hydrochloride, 20 to 30 parts by weight of citric acid, 100-120 parts by weight of PVP K29 / 32 or PVP K25, and 80 to 100 parts by weight of sucrose blank pellet core; The additional auxiliary materials include: 1 part by weight of sucrose, 0.04-0.05 parts by weight of cross-linked polyvinylpyrrolidone, and 0.04-0.05 parts by weight of sodium stearyl fumarate; Optionally, the tablet comprises pellets and additional excipients; Wherein, the micropill comprises: 20 parts by weight of vilazodone hydrochloride, 20 to 40 parts by weight of citric acid, 40-80 parts by weight of PVP K29 / 32, 40 to 80 parts by weight of sucrose, and 60 to 100 parts by weight of sucrose blank pellet core; The additional auxiliary materials include: 1 part by weight of sucrose, 0.04-0.06 parts by weight of cross-linked polyvinylpyrrolidone, and 0.04-0.06 parts by weight of sodium stearyl fumarate.

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