Lurasidone hydrochloride formulation

Abstract

A lurasidone hydrochloride formulation, comprising lurasidone hydrochloride and a carrier, wherein the carrier comprises: Soluplus, and at least one of HPMCAS HG and HPMCAS HF. The formulation can increase the dissolution rate and solubility of lurasidone hydrochloride and ensure increased dissolution of lurasidone hydrochloride in the small intestine, such that the bioavailability and in-vivo absorption of lurasidone hydrochloride is improved, reducing excessive medication restrictions, avoiding reduced or even ineffective therapeutic effects caused by improper medication, and thus ensuring normal exertion of the efficacy of the drug. Moreover, the lurasidone hydrochloride formulation can also weaken or eliminate the food effect, thereby facilitating greater flexibility and compliance in patient medication.

Description

Lurasidone hydrochloride preparations Technical Field

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

[0002] Lurasidone hydrochloride is an atypical antipsychotic. Lurasidone hydrochloride tablets were approved for marketing in the United States in 2010 in strengths of 20mg, 40mg, 60mg, 80mg, and 120mg per tablet for the treatment of schizophrenia. In 2013, lurasidone received approval for two new indications: monotherapy and adjunctive therapy with lithium or sodium valproate for major depressive episodes associated with bipolar I disorder in adults. Compared to similar medications, lurasidone hydrochloride offers advantages such as superior efficacy, safety, and good tolerability, and has been established as a first-line antipsychotic.

[0003] Currently available lurasidone tablets have low bioavailability and must be taken with food containing at least 350 calories. Otherwise, the average peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of lurasidone decrease by 3-fold and 2-fold, respectively. Schizophrenia patients are prone to mistaking or missing doses, leading to treatment discontinuation and worsening of their condition.

[0004] The solubility of lurasidone hydrochloride is highly pH-dependent. Its solubility in 0.1 mol / L hydrochloric acid, pH 6.8 phosphate buffer and water is 5.24×10 -2 mg / mL, <3.00×10 -2 mg / mL and 0.224 mg / mL. According to the Biopharmaceutics Classification System, lurasidone hydrochloride is a BCS Class II drug characterized by low solubility and high permeability. When the active pharmaceutical ingredient (API) has poor water solubility, lurasidone hydrochloride dissolved or partially dissolved in the stomach may precipitate in large quantities upon entering the neutral environment of the intestine, leaving only a very small portion of the drug dissolved and absorbed. This can affect drug dissolution in specific areas and is a key factor leading to differences in clinical efficacy. Furthermore, the small amount of dissolved and absorbed drug may amplify the increase in gastrointestinal surfactant caused by food, resulting in an excessive food effect. Therefore, if lurasidone hydrochloride can be solubilized to a significant extent, increasing the drug's dissolution rate and solubility in multiple media, while simultaneously inhibiting drug precipitation in partially neutral media and improving dissolution stability, drug absorption can be significantly improved.

[0005] Summary of the Invention

[0006] The present invention aims to at least partially address the technical problems existing in the prior art. To this end, the present invention provides a lurasidone hydrochloride formulation that can increase the dissolution rate and solubility of lurasidone hydrochloride, thereby improving the in vivo absorption and bioavailability of lurasidone hydrochloride.

[0007] In a first aspect, the present invention provides a composition. According to an embodiment of the present invention, the composition comprises lurasidone hydrochloride and a carrier, wherein the carrier comprises Soluplus and at least one of HPMCAS HG and HPMCAS HF.

[0008] The composition of the present invention can increase the dissolution rate and solubility of lurasidone hydrochloride, ensuring increased dissolution of lurasidone hydrochloride in the small intestine, improving its bioavailability and absorption in the body, reducing excessive medication restrictions, avoiding reduced or even ineffective efficacy due to improper medication, and ensuring the normal functioning of the drug. Furthermore, the lurasidone hydrochloride composition of the present invention can also reduce or eliminate the food effect, thereby improving patient flexibility and compliance with medication.

[0009] According to an embodiment of the present invention, the above composition may further include at least one of the following technical features:

[0010] According to an embodiment of the present invention, the mass ratio of lurasidone hydrochloride to the carrier is 1:(4-24), for example, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, or a range value between two ratios thereof, such as 1:(5-24), 1:(5-12), 1:(5-10), 1:(5-9), 1:(5-8), 1:(5-7), 1:(5-6), 1:(6-24), 1:(6-12), 1:(6-10), 1:(6-9), 1:(6-8), 1:(6-7). Thus, the dissolution rate and solubility of lurasidone hydrochloride can be further improved, the dissolution of lurasidone hydrochloride in the small intestine can be increased, the bioavailability of lurasidone hydrochloride can be increased, and the absorption in the body can be improved.

[0011] In this article, the term "drug-to-carrier ratio" refers to the weight ratio of the active ingredient to the carrier, that is, the weight ratio of lurasidone hydrochloride to the carrier. When there are multiple carriers, the weight of the carrier is the combined weight of the multiple carriers.

[0012] According to an embodiment of the present invention, the carrier includes Soluplus and HPMCAS HG.

[0013] According to an embodiment of the present invention, the carrier includes Soluplus and HPMCAS HF.

[0014] According to an embodiment of the present invention, the mass ratio of Soluplus to HPMCAS HF is 1:(0.5-5), for example, 1:0.5, 1:1, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, or a range between these two ratios, such as 1:(0.5-1) or 1:(0.5-2). This can further improve the dissolution rate and solubility of lurasidone hydrochloride, ensure increased dissolution of lurasidone hydrochloride in the small intestine, and enhance the bioavailability and in vivo absorption of lurasidone hydrochloride.

[0015] According to an embodiment of the present invention, the composition further includes a surfactant.

[0016] According to an embodiment of the present invention, the surfactant includes at least one of TPGS, Kolliphor RH40, Tween 80 and SDS.

[0017] According to an embodiment of the present invention, the surfactant is Kolliphor RH40.

[0018] According to an embodiment of the present invention, based on the total mass of the composition, the mass percentage of the surfactant is 5% to 15%, for example, 5%, 5.06%, 5.08%, 6%, 7%, 8%, 9%, 9.92%, 10%, 11%, 12%, 13%, 14%, 14.75%, 15% or a range value between two point values, such as 5.06% to 14.75%, 5.08% to 14.75%.

[0019] According to an embodiment of the present invention, the composition further includes an inorganic salt.

[0020] According to an embodiment of the present invention, the inorganic salt comprises K ions and / or Na ions.

[0021] According to an embodiment of the present invention, the inorganic salt includes at least one of KCl, K2SO4 and KH2PO4.

[0022] According to an embodiment of the present invention, the weight ratio of lurasidone hydrochloride to the inorganic salt is 1:(0.1-2), for example, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.05 or a range value between two ratios thereof, such as 1:(0.5-1.5), 1:(0.5-1).

[0023] According to an embodiment of the present invention, the composition is an oral solid preparation.

[0024] According to an embodiment of the present invention, the oral solid preparation is a micropill, a capsule or a tablet.

[0025] It should be noted that when the composition is a different oral solid preparation, depending on the type of dosage form, it may further include other pharmaceutically acceptable ingredients contained in the dosage form. Such ingredients are not specifically limited and are within the scope of protection of the present invention. For example, when the composition is a micropill, it may further include a blank pellet core, such as a sucrose pellet core; when the composition is a capsule, it may further include a capsule layer; when the composition is a tablet, it may further include a coating material.

[0026] In this article, "micropills" are spherical or quasi-spherical solid dosage forms with a diameter within a certain range, which can be taken alone, put into capsules, compressed into tablets, or made into other preparations.

[0027] According to an embodiment of the present invention, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 40 to 260 parts by weight of Soluplus, and 80 to 200 parts by weight of HPMCAS HF or HPMCAS HG; wherein the mass ratio of lurasidone hydrochloride to the carrier is 1:(5 to 12).

[0028] According to an embodiment of the present invention, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 40 to 260 parts by weight of Soluplus, 80 to 200 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of a surfactant; wherein the mass ratio of lurasidone hydrochloride to the carrier is 1:(5 to 12).

[0029] According to an embodiment of the present invention, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 40 to 260 parts by weight of Soluplus, 80 to 200 parts by weight of HPMCAS HF or HPMCAS HG, 10 to 20 parts by weight of a surfactant, and 30 to 40 parts by weight of an inorganic salt; wherein the mass ratio of lurasidone hydrochloride to the carrier is 1:(5 to 12).

[0030] According to an embodiment of the present invention, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 120 to 240 parts by weight of Soluplus, and 80 to 160 parts by weight of HPMCAS HF.

[0031] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 140-170 parts by weight of Soluplus, and 70-100 parts by weight of HPMCAS HF or HPMCAS HG.

[0032] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 90 to 140 parts by weight of Soluplus, and 100 to 150 parts by weight of HPMCAS HF or HPMCAS HG.

[0033] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 60 to 90 parts by weight of Soluplus, and 150 to 180 parts by weight of HPMCAS HF or HPMCAS HG.

[0034] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 30 to 60 parts by weight of Soluplus, and 180 to 210 parts by weight of HPMCAS HF or HPMCAS HG.

[0035] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 220-240 parts by weight of Soluplus, and 220-240 parts by weight of HPMCAS HF or HPMCAS HG.

[0036] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 100-140 parts by weight of Soluplus, and 100-140 parts by weight of HPMCAS HF or HPMCAS HG.

[0037] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, and 120 parts by weight of HPMCAS HF or HPMCAS HG.

[0038] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 220-260 parts by weight of Soluplus, and 100-140 parts by weight of HPMCAS HF or HPMCAS HG.

[0039] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 240 parts by weight of Soluplus, and 120 parts by weight of HPMCAS HF or HPMCAS HG.

[0040] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 140-170 parts by weight of Soluplus, 70-100 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Kolliphor RH40.

[0041] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 160 parts by weight of Soluplus, 80 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.

[0042] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 90-140 parts by weight of Soluplus, 100-150 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Kolliphor RH40.

[0043] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 80-140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Kolliphor RH40.

[0044] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.

[0045] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 100 parts by weight of Soluplus, 100 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.

[0046] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 80 parts by weight of Soluplus, 80 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.

[0047] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 60-100 parts by weight of Soluplus, 140-180 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Kolliphor RH40.

[0048] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 80 parts by weight of Soluplus, 160 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.

[0049] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 30-60 parts by weight of Soluplus, 180-210 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Kolliphor RH40.

[0050] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 40 parts by weight of Soluplus, 200 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Kolliphor RH40.

[0051] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 80-140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of TPGS.

[0052] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 100-140 parts by weight of Soluplus, 100-140 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of TPGS.

[0053] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of TPGS.

[0054] According to an embodiment of the present invention, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80-140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Tween 80.

[0055] According to an embodiment of the present invention, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 100-140 parts by weight of Soluplus, 100-140 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Tween 80.

[0056] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of Tween 80.

[0057] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 80-140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of SDS.

[0058] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 100-140 parts by weight of Soluplus, 100-140 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of SDS.

[0059] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, and 15 parts by weight of SDS.

[0060] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 80-140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, 10-20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of KCl.

[0061] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 100-140 parts by weight of Soluplus, 100-140 parts by weight of HPMCAS HF or HPMCAS HG, 10-20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of KCl.

[0062] In some embodiments, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF, and optionally, 15 parts by weight of Kolliphor RH40.

[0063] In some embodiments, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 240 parts by weight of Soluplus, and 120 parts by weight of HPMCAS HF.

[0064] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, 10-20 parts by weight of Kolliphor RH40, and 33 parts by weight of KCl.

[0065] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 80-140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, 10-20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of K2SO4.

[0066] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, 15 parts by weight of Kolliphor RH40, and 33 parts by weight of K2SO4.

[0067] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 80-140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, 10-20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of KH2PO4.

[0068] According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 120 parts by weight of Soluplus, 120 parts by weight of HPMCAS HF or HPMCAS HG, 10-20 parts by weight of Kolliphor RH40, and 33 parts by weight of KH2PO4.

[0069] In a second aspect, the present invention provides a method for preparing the composition described in the first aspect. According to an embodiment of the present invention, the method comprises: mixing a carrier and lurasidone hydrochloride to obtain the composition. The preparation method of the present invention is simple, and the resulting composition has high solubility, which can increase the dissolution rate and solubility of lurasidone hydrochloride, thereby improving the in vivo absorption and bioavailability of lurasidone hydrochloride. Therefore, the lurasidone hydrochloride composition of the present invention can also reduce or eliminate the food effect, thereby facilitating improved patient flexibility and compliance.

[0070] According to an embodiment of the present invention, the above method may further include at least one of the following technical features:

[0071] According to an embodiment of the present invention, the composition may be in the form of particles or micropellets (or micropills).

[0072] According to an embodiment of the present invention, the composition is granules, and the method further comprises: mixing a surfactant and / or an inorganic salt with lurasidone hydrochloride and a carrier.

[0073] According to an embodiment of the present invention, the method further comprises: subjecting the mixed treatment product to a solvent volatilization treatment and / or a fluidized bed layer drug application treatment.

[0074] According to an embodiment of the present invention, the method further comprises: subjecting the mixed treatment product to a solvent volatilization treatment.

[0075] According to an embodiment of the present invention, the method further comprises: subjecting the mixed treatment product to a fluidized bed-level drug-coating treatment.

[0076] According to an embodiment of the present invention, the composition is a micropill, and the method further comprises: spraying the mixed treatment product onto the outer layer of a blank pellet core.

[0077] According to an embodiment of the present invention, the spraying is performed by fluidized bed layer-by-layer drug application.

[0078] According to an embodiment of the present invention, the atomization pressure of the fluidized bed layer for drug loading is 2.0 bar to 3.0 bar.

[0079] According to an embodiment of the present invention, the temperature of the fluidized bed layer for applying the drug is 30°C-50°C.

[0080] According to an embodiment of the present invention, before the spraying and before the mixing, the mixed product is dissolved using an organic solvent.

[0081] According to an embodiment of the present invention, the organic solvent includes dichloromethane and / or methanol.

[0082] According to an embodiment of the present invention, the organic solvent includes dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is (1-3):1, preferably 2:1.

[0083] According to an embodiment of the present invention, the composition is a micropill, and the composition further includes a blank pellet core.

[0084] According to an embodiment of the present invention, the blank pill core is selected from at least one of a sucrose blank pill core and a microcrystalline cellulose blank pill core.

[0085] 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

[0086] 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:

[0087] FIG1 is an XRD pattern of the lurasidone hydrochloride bulk drug in Example 14 of the present invention;

[0088] FIG2 is an XRD pattern of prescription F1 in Example 14 of the present invention;

[0089] FIG3 is an XRD pattern of prescription F4 in Example 14 of the present invention;

[0090] FIG4 is an XRD pattern of prescription F10 in Example 14 of the present invention;

[0091] FIG5 is an XRD pattern of prescription F11 in Example 14 of the present invention;

[0092] FIG6 is an XRD pattern of prescription F12 in Example 14 of the present invention;

[0093] FIG7 is an XRD pattern of prescription F15 in Example 14 of the present invention;

[0094] FIG8 is an XRD pattern of prescription F20 in Example 14 of the present invention;

[0095] FIG9 is an XRD pattern of prescription F30 in Example 14 of the present invention;

[0096] FIG10 is an XRD pattern of prescription F31 in Example 14 of the present invention;

[0097] FIG11 is an XRD pattern of prescription F32 in Example 14 of the present invention;

[0098] FIG12 is an XRD pattern of prescription F37 in Example 14 of the present invention;

[0099] FIG13 is an XRD pattern of prescription F38 in Example 14 of the present invention;

[0100] FIG14 is an XRD pattern of prescription F40 in Example 14 of the present invention;

[0101] FIG15 is an XRD pattern of prescription F52 in Example 14 of the present invention;

[0102] FIG16 is an XRD pattern of prescription F54 in Example 14 of the present invention;

[0103] FIG17 is an XRD pattern of prescription F55 in Example 14 of the present invention;

[0104] FIG18 is an XRD pattern of prescription F60 in Example 14 of the present invention;

[0105] FIG19 is an XRD pattern of prescription F76 in Example 14 of the present invention;

[0106] FIG20 shows the pharmacokinetic results of the formulations F78, F79 and the reference preparation (trade name: Latuda) in beagle dogs in Example 16 of the present invention. DETAILED DESCRIPTION

[0107] 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.

[0108] 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.

[0109] Detailed description of the invention

[0110] Definitions and General Terms

[0111] 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.

[0112] In the present invention, HPMCAS refers to hydropropyl methylcellulose acetate succinate, and HPMCAS HF, HPMCAS HG, HPMCAS LF, and HPMCAS MF are different types of hydropropyl methylcellulose acetate succinate;

[0113] Soluplus refers to polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

[0114] HPMC refers to hypromellose; HPC refers to hydroxypropyl cellulose; PVP refers to povidone;

[0115] KCl refers to potassium chloride; K2SO4 refers to potassium sulfate; KH2PO4 refers to potassium dihydrogen phosphate;

[0116] TPGS refers to vitamin E polyethylene glycol succinate;

[0117] HP50 refers to Hydroxypropyl Methylcellulose Phthalate 50, or Hydroxypropyl Methylcellulose Phthalate 50;

[0118] Kolliphor RH40 refers to polyoxyl 40 hydrogenated castor oil;

[0119] 44 / 14 refers to macrogol glycerides of laurate;

[0120] SDS refers to sodium dodecyl sulfate.

[0121] 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.

[0122] 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.

[0123] The term "include" or "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0124] The compositions or formulations provided herein can be administered to a patient alone or in combination with other active agents. The terms "co-administered" and "in combination" include administering two or more therapeutic agents simultaneously or sequentially without specific time limits. In one embodiment, the therapeutic agents are present in a cell or individual simultaneously or exert a biological or therapeutic effect simultaneously. In one embodiment, each therapeutic agent is in the same composition or unit dosage form. In other embodiments, each therapeutic agent is in a different composition or unit dosage form. In certain embodiments, the first agent is administered prior to (e.g., 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 before), concurrently with, or after (e.g., 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 after) the administration of the second therapeutic agent.

[0125] 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.

[0126] 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.

[0127] The detection method for dissolution under the pH 6.8 condition alone in the comparative examples and examples of the present invention is as follows: according to the United States Pharmacopoeia II method (USP II), with 900 mL ± 9 ml of medium, a rotation speed of 50 rpm / min, a medium temperature of 37.0 ± 0.5 ° C, and a slurry method, the dissolution in the pH 6.8 medium (phosphate buffer) is respectively measured. After the start of the test, 10 ml of samples are taken at 5 min, 30 min, 45 min, 60 min, 90 min and 120 min time points, and 10 ml of fresh dissolution medium is immediately added to continue the test. The sample is filtered through a 0.45 μm membrane, and an appropriate amount of filtrate is taken. The drug content in the sample is determined by HPLC method, and the cumulative dissolution rate at each time point is calculated.

[0128] Acid resistance test (i.e., dissolving the sample in 0.1M HCl first and then in pH 6.8 phosphate buffer) according to the United States Pharmacopoeia II method (USP II): first use 500mL of 0.1M HCl as the medium, 50rpm / min as the rotation speed, and the medium temperature of 37.0±0.5℃. At the 30-min time point, sample 10ml and immediately add 10ml of fresh dissolution medium. The dissolution in the medium is measured. After the 0.1M HCl medium sampling is completed, the rotation speed is unchanged, and pH 6.8 phosphate buffer is added to 900mL, and the pH is quickly adjusted to 6.8 with 10M NaOH. Samples of 10ml are taken at 15min, 30min, 45min, 60min, 90min, and 120min, and immediately supplemented with 10ml of fresh dissolution medium, and the test is continued. The sample was filtered through a 0.45 μm filter membrane, 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] HPLC chromatographic conditions:

[0130] Chromatographic column: Kromasil 100-5 C18 4.6x150mm, 5um,

[0131] Detector: UV detector,

[0132] Detection wavelength: 230nm,

[0133] Flow rate: 1.0 mL / min,

[0134] Column temperature: 30°C,

[0135] Injection volume: 5 μL,

[0136] Run time: 4.5 minutes,

[0137] Mobile phase: pH 3.0 phosphate buffer solution: acetonitrile = 40:60 (V / V).

[0138] Comparative Example 1:

[0139] 1. Prepare a lurasidone hydrochloride-polyethylene glycol 4000 solid dispersion. The specific preparation method is as follows: add lurasidone hydrochloride to molten polyethylene glycol 4000, control the temperature at 40-50°C, add methanol dropwise while stirring until the solid is completely dissolved, keep the temperature and stir for 15 minutes, evaporate the methanol under reduced pressure at 50-60°C, solidify the solid at below -15°C for 2 hours, crush, and pass through a 100-mesh sieve to obtain a lurasidone hydrochloride solid dispersion.

[0140] 2. Prepare lurasidone hydrochloride tablets according to the prescription in the table below.

[0141] Preparation method of lurasidone hydrochloride tablets:

[0142] ① Pass the lurasidone hydrochloride-polyethylene glycol 4000 solid dispersion, mannitol, partially pregelatinized starch, hydroxypropyl methylcellulose, and cross-linked sodium carboxymethylcellulose through a 100-mesh sieve;

[0143] ② Weigh the prescribed amount of lurasidone hydrochloride-polyethylene glycol 4000 solid dispersion, add the prescribed amount of mannitol, partially pregelatinized starch, hydroxypropyl methylcellulose, cross-linked sodium carboxymethylcellulose and magnesium stearate in sequence, and mix well;

[0144] ③ Press into tablets;

[0145] ④The tablets are film-coated.

[0146] Comparative Example 2:

[0147] Lurasidone hydrochloride tablets were prepared according to the following formula.

[0148] Preparation method: Potassium citrate and sorbitol are heated and melted in a hot melt extruder, and then lurasidone hydrochloride is added and melted, the melt is extruded and granulated, and then directly compressed with calcium hydrogen phosphate, micropowder silica gel, and magnesium stearate to form tablets.

[0149] Comparative Example 3:

[0150] Lurasidone hydrochloride capsules were prepared according to the following prescription.

[0151] Preparation method: Weigh lurasidone hydrochloride and copovidone according to the prescribed amount, dissolve them in a mixed solvent of methanol and dichloromethane in a volume ratio of 1:1 (total 200 mL) to fully dissolve the drug and carrier, and then spray dry at 60-65°C. Add magnesium stearate to the obtained spray-dried powder, mix, and fill capsules.

[0152] Comparative Example 4:

[0153] Lurasidone hydrochloride capsules were prepared according to the following prescription.

[0154] Preparation method:

[0155] 1) Weigh 15.00 g of purified water, and weigh HPMC and citric acid according to the prescribed amount, dissolve them in purified water, and use as the granulation solution;

[0156] 2) Weigh the additional ingredients according to the above recipe and mix for 10 minutes to prepare the granulation base. Add the granulation liquid and wet granulate manually. Pass the granules through a 40-mesh sieve for wet granulation. Then, dry them in an oven at 50°C for 60 minutes. Pass the granules through a 40-mesh sieve for dry granulation.

[0157] 3) Add magnesium stearate, mix, and fill into capsules.

[0158] Comparative Example 5:

[0159] Lurasidone hydrochloride capsules were prepared according to the following prescription.

[0160] Preparation method: Weigh the hot melt added components according to the prescription, mix them thoroughly and add them to the powder feeder of the hot melt extruder, set the temperatures of the feeding port to the extrusion die barrel to 110°C, 130°C, 165°C, 165°C, 165°C, 165°C, 165°C, and 160°C respectively, set the screw speed to 50rpm, and hot melt extrusion is carried out. After the extrudate is cooled, it is crushed and the crushed material is passed through a 60-mesh sieve. The obtained spray-dried powder is added with microcrystalline cellulose, mixed, and filled into capsules.

[0161] Comparative Example 6:

[0162] Lurasidone hydrochloride capsules were prepared according to the following prescription.

[0163] Preparation method: Weigh the hot melt internal components according to the prescription, mix them thoroughly and add them to the powder feeder of the hot melt extruder, set the temperatures of the feeding port to the extrusion die barrel to 110°C, 130°C, 165°C, 165°C, 165°C, 165°C, 165°C, and 160°C respectively, set the screw speed to 50rpm, hot melt extrusion, crush the extrudate after cooling, pass the crushed material through a 60-mesh sieve, add external components according to the components, mix, and press into tablets.

[0164] Then, the in vitro dissolution characteristics of Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4, Comparative Example 5, Comparative Example 6 and the reference preparation in pH 6.8 medium and acid resistance were measured. The results are shown in Table 1-1 and Table 1-2.

[0165] Table 1-1: Drug release results of comparative examples 1-6 and reference preparations (%)

[0166] Table 1-2: Drug release results of comparative examples 1-6 and reference preparations (%)

[0167] As shown in Tables 1-1 and 1-2, when using a single pH 6.8 medium to simulate human absorption after eating, the dissolution amounts of Comparative Examples 1, 2, 3, 4, 5, and 6 were only 1%-49%. Furthermore, when the solution was transferred to a pH 6.8 medium after half an hour of acid resistance, Comparative Examples 1, 2, 3, and 4 showed a significant precipitation effect, which failed to reduce the risk of precipitation of the drug dissolved in the stomach in the small intestine, and the final dissolution amount was extremely low, only 1%-15%. The final dissolution amounts of Comparative Examples 5 and 6 were only 18%-48%.

[0168] It can be seen that the dissolution amount of the above-mentioned drug preparation in the small intestine is very low, which may affect the absorption of the drug in the small intestine and cannot eliminate the food effect of lurasidone hydrochloride.

[0169] Example 1: Study on Lurasidone Hydrochloride Solid Dispersions with Different Formulas

[0170] The components and their dosages in solid dispersions of different formulations are as follows:

[0171] The solid dispersion was prepared by solvent evaporation method:

[0172] Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask. Add a predetermined amount of dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1). Stir and dissolve at room temperature until clear and transparent. Then, remove the dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1) by rotary evaporation at 70-80°C and a vacuum of -0.03-0.1 MPa. Remove the contents and dry them completely in an oven at 40°C. Sieve to obtain a lurasidone hydrochloride solid dispersion. Prepare capsules. Labeled weight per capsule: 40 mg.

[0173] The in vitro dissolution characteristics of Formulations F1, F2, F3, F4, F5, and F6 were measured using a paddle method at 50 rpm using a medium volume of 900 ± 9 ml, a medium temperature of 37.0 ± 0.5°C, and a medium volume of 900 ± 9 ml. The results are shown in Tables 2-1 and 2-2.

[0174] Table 2-1: Drug release results of formulations F1 to F6 and reference preparations (%)

[0175] Table 2-2: Drug release results of formulations F1 to F6 and reference preparations (%)

[0176] The results in Tables 2-1 and 2-2 indicate that when a pH 6.8 medium alone is used to simulate human absorption after a meal, the dissolution amounts of Formulas F1, F2, F3, F4, and F5 are extremely low, only approximately 1%-8%. Therefore, the small intestinal dissolution amounts of Formulas F1, F2, F3, F4, and F5 after a meal are very low, and small intestinal absorption is limited. When a pH 6.8 medium alone is used to simulate human absorption after a meal, the dissolution amount of Example F6 is relatively high, approximately 38%-67%. When an acid-resistant medium is transferred to a pH 6.8 medium after half an hour to simulate human absorption after fasting, the dissolution amounts of Formulas F1, F2, F3, F4, F5, and F6 are all relatively low. Therefore, after fasting administration, the small intestinal dissolution amounts of Formulas F1-F6 are very low, which may affect drug absorption in the small intestine.

[0177] In summary, prescriptions F1, F2, F3, F4, F5, and F6 failed to eliminate the pH dependence of lurasidone hydrochloride and could not improve the drug's absorption in vivo.

[0178] Example 2: Study on Lurasidone Hydrochloride Solid Dispersions with Different Formulas

[0179] The components and their dosages in solid dispersions of different formulations are as follows:

[0180] The solid dispersion was prepared by solvent evaporation method:

[0181] Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask. Add a predetermined amount of dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1). Stir and dissolve at room temperature until clear and transparent. Then, remove the dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1) by rotary evaporation at 70-80°C and a vacuum of -0.03-0.1 MPa. Remove the contents and dry them completely in an oven at 40°C. Sieve to obtain a lurasidone hydrochloride solid dispersion. Prepare capsules. Labeled weight per capsule: 40 mg.

[0182] The in vitro dissolution characteristics of formulations F7, F8, F9, F10, F11, and F12 in a pH 6.8 medium and in acid resistance were determined. The results are shown in Tables 3-1 and 3-2.

[0183] Table 3-1: Drug release results of prescriptions F7 to F12 and reference preparations (%)

[0184] Table 3-2: Drug release results of formulations F7 to F12 and reference preparations (%)

[0185] The results in Tables 3-1 and 3-2 show that when using a single pH 6.8 medium to simulate human absorption after a meal, the dissolution of formulations F7, F8, F10, F11, and F12 did not significantly improve; however, formulation F9 exhibited a higher dissolution rate of approximately 64%-75%. However, when transferring the medium to a pH 6.8 medium after a half-hour acid resistance to simulate human absorption after fasting, formulations F7, F8, F9, F10, F11, and F12 exhibited a more pronounced precipitation effect.

[0186] In summary, prescriptions F7, F8, F9, F10, F11, and F12 did not eliminate the pH dependence of lurasidone hydrochloride and could not improve the drug's absorption in vivo.

[0187] Example 3: Study on Lurasidone Hydrochloride Solid Dispersions with Different Formulas

[0188] The components and their dosages in solid dispersions of different formulations are as follows:

[0189] The solid dispersion was prepared by solvent evaporation method:

[0190] Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask. Add a predetermined amount of dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1). Stir and dissolve at room temperature until clear and transparent. Then, remove the dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1) by rotary evaporation at 70-80°C and a vacuum of -0.03-0.1 MPa. Remove the contents and dry them completely in an oven at 40°C. Sieve to obtain a lurasidone hydrochloride solid dispersion. Prepare capsules. Labeled weight per capsule: 40 mg.

[0191] The in vitro dissolution characteristics of Examples F13, F14, F15, F16, and F17 in a pH 6.8 medium and acid resistance were determined. The results are shown in Tables 4-1 and 4-2.

[0192] Table 4-1: Drug release results of prescriptions F13-17 and reference preparations (%)

[0193] Table 4-2: Drug release results of prescriptions F13-17 and reference preparations (%)

[0194] The results in Tables 4-1 and 4-2 show that when using a single pH 6.8 medium to simulate human absorption after eating, the dissolution of formulations F13, F14, F15, F16, and F17 did not improve significantly. However, when using a pH 6.8 medium after acid resistance for half an hour to simulate human absorption after fasting, formulations F13, F14, F15, F16, and F17 showed a more significant precipitation effect.

[0195] In summary, prescriptions F13, F14, F15, F16, and F17 did not eliminate the pH dependence of lurasidone hydrochloride and could not improve the drug's absorption in vivo.

[0196] Example 4: Study on Lurasidone Hydrochloride Solid Dispersions with Different Formulas

[0197] The components and their dosages in solid dispersions of different formulations are as follows:

[0198] The solid dispersion was prepared by solvent evaporation method:

[0199] Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask. Add a predetermined amount of dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1). Stir and dissolve at room temperature until clear and transparent. Then, remove the dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1) by rotary evaporation at 70-80°C and a vacuum of -0.03-0.1 MPa. Remove the contents and dry them completely in an oven at 40°C. Sieve to obtain a lurasidone hydrochloride solid dispersion. Prepare capsules. Labeled weight per capsule: 40 mg.

[0200] The in vitro dissolution characteristics of formulations F18, F19, F20, F21, F22, F23, F24, F25, and F26 in pH 6.8 medium and acid resistance were determined. The results are shown in Tables 5-1 and 5-2.

[0201] Table 5-1: Drug release results of prescriptions F18 to F26 and reference preparations (%)

[0202] Table 5-2: Drug release results of formulations F18 to F26 and reference preparations (%)

[0203] The results in Tables 5-1 and 5-2 show that when a pH 6.8 medium alone was used to simulate human absorption after eating, the dissolution of formulations F18, F19, F20, F21, F22, F23, F24, F25, and F26 did not show significant improvement. When a pH 6.8 medium was transferred after half an hour of acid resistance to simulate human absorption after fasting, formulations F18, F19, F20, F21, F23, F25, and F26 showed significant improvement compared to the formulations in Examples 1, 2, and 3 (none of which had a precipitation effect).

[0204] In summary, although Formulations F18, F19, F20, F21, F22, F23, F24, F25, and F26 did not eliminate the pH dependence of lurasidone hydrochloride and could not improve drug absorption in vivo, the inventors unexpectedly discovered that, compared with Examples 1-4, the use of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) as a carrier in the formulations can reduce the risk of lurasidone hydrochloride dissolved in the stomach from precipitating in the small intestine, thereby improving drug absorption in the small intestine after fasting.

[0205] Example 5: Study on Lurasidone Hydrochloride Solid Dispersions with Different Formulas

[0206] The components and their dosages in solid dispersions of different formulations are as follows:

[0207] The solid dispersion was prepared by solvent evaporation method:

[0208] Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask. Add a predetermined amount of dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1). Stir and dissolve at room temperature until clear and transparent. Then, remove the dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1) by rotary evaporation at 70-80°C and a vacuum of -0.03-0.1 MPa. Remove the contents and dry them completely in an oven at 40°C. Sieve to obtain a lurasidone hydrochloride solid dispersion. Prepare capsules. Labeled weight per capsule: 40 mg.

[0209] The in vitro dissolution characteristics of Examples F27, F28, F29, F30, F31, and F32 in a pH 6.8 medium and acid resistance were determined. The results are shown in Tables 6-1 and 6-2.

[0210] Table 6-1: Drug release results of formulations F19, F21, F27 to F32 and reference preparations (%)

[0211] Table 6-2: Drug release results of formulations F19, F21, F27 to F32 and reference preparations (%)

[0212] The results in Tables 6-1 and 6-2 indicate that, using a single pH 6.8 medium to simulate human absorption after a meal, Formulation F32 exhibited the highest dissolution rate, demonstrating a significant improvement over Formulation F19. Polymer screening revealed that HPMCAS HF, when used as a mixed carrier, exhibited a surprising effect, significantly improving limited small intestinal absorption after a meal. Simulating human absorption after fasting by transferring to a pH 6.8 medium after a half-hour acid-resistant reaction, data showed that the addition of HPMCAS HF slowed dissolution in acid, but did not affect the dissolution plateau after transferring to a pH 6.8 medium. In summary, Example F32 can eliminate the pH dependence of lurasidone hydrochloride and improve drug absorption in vivo.

[0213] Example 6: Study on Lurasidone Hydrochloride Solid Dispersions with Different Formulas

[0214] The components and their dosages in solid dispersions of different formulations are as follows:

[0215] The solid dispersion was prepared by solvent evaporation method:

[0216] Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask. Add a predetermined amount of dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1). Stir and dissolve at room temperature until clear and transparent. Then, remove the dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1) by rotary evaporation at 70-80°C and a vacuum of -0.03-0.1 MPa. Remove the contents and dry them completely in an oven at 40°C. Sieve to obtain a lurasidone hydrochloride solid dispersion. Prepare capsules. Labeled weight per capsule: 40 mg.

[0217] The in vitro dissolution characteristics of Examples F33, F34, F35, F36, and F37 in a pH 6.8 medium and acid resistance were determined. The results are shown in Tables 7-1 and 7-2.

[0218] Table 7-1: Drug release results of prescriptions F32 to F37 and reference preparations (%)

[0219] Table 7-2: Drug release results of prescriptions F32 to F37 and reference preparations (%)

[0220] The results in Tables 7-1 and 7-2 show that, when using a single pH 6.8 medium to simulate human absorption after a meal, formulations F34, F35, F36, and F37 exhibited lower dissolution compared to formulations F32 and F33. When using an acid-resistant medium shifted to a pH 6.8 medium after half an hour to simulate human absorption after fasting, only formulations F34 and F35 exhibited dissolution comparable to that of formulation F32. In summary, formulations F33–F37 do not eliminate the pH dependence of lurasidone hydrochloride, but rather improve its absorption.

[0221] Example 7: Study on Lurasidone Hydrochloride Solid Dispersions with Different Formulas

[0222] The components and their dosages in solid dispersions of different formulations are as follows:

[0223] The solid dispersion was prepared by solvent evaporation method:

[0224] Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask. Add a predetermined amount of dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1). Stir and dissolve at room temperature until clear and transparent. Then, remove the dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1) by rotary evaporation at 70-80°C and a vacuum of -0.03-0.1 MPa. Remove the contents and dry them completely in an oven at 40°C. Sieve to obtain a lurasidone hydrochloride solid dispersion. Prepare capsules. Labeled weight per capsule: 40 mg.

[0225] The in vitro dissolution characteristics of formulations F38, F39, F40, F41, F42, F43, F44, F45, and F46 in pH 6.8 and acid resistance were determined. The results are shown in Tables 8-1 and 8-2.

[0226] Table 8-1: Drug release results of prescriptions F32, F38~F46 and reference preparations (%)

[0227] Table 8-2: Drug release results of prescriptions F32, F38~F46 and reference preparations (%)

[0228] The results in Tables 8-1 and 8-2 show that when using a single pH 6.8 medium to simulate human absorption after eating, the dissolution rates of formulations F38, F40, F41, and F42 were significantly improved compared to formulation F32. When using a pH 6.8 medium after half an hour of acid resistance to simulate human absorption after fasting, only formulation F40 (with Kolliphor RH40 added) showed a significant improvement in dissolution rate compared to formulation F32.

[0229] In summary, prescription F40 can further significantly improve absorption in the body.

[0230] Example 8: Study on Lurasidone Hydrochloride Solid Dispersions with Different Formulas

[0231] The components and their dosages in solid dispersions of different formulations are as follows:

[0232] The solid dispersion was prepared by solvent evaporation method:

[0233] Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask. Add a predetermined amount of dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1). Stir and dissolve at room temperature until clear and transparent. Then, remove the dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1) by rotary evaporation at 70-80°C and a vacuum of -0.03-0.1 MPa. Remove the contents and dry them completely in an oven at 40°C. Sieve to obtain a lurasidone hydrochloride solid dispersion. Prepare capsules. Labeled weight per capsule: 40 mg.

[0234] The in vitro dissolution characteristics of formulations F47, F48, F49, and F50 in a pH 6.8 medium and in acid resistance were determined. The results are shown in Tables 9-1 and 9-2.

[0235] Table 9-1: Drug release results of prescriptions F32, F40, F47~F50 and reference preparations (%)

[0236] Table 9-2: Drug release results of prescriptions F32, F40, F47~F50 and reference preparations (%)

[0237] The results in Tables 9-1 and 9-2 indicate that the dissolution rates of Formulations F40 and F47 were comparable, whether using a pH 6.8 medium alone to simulate human absorption after a meal or transferring to a pH 6.8 medium after a half-hour acid-resistant period to simulate human absorption after fasting. Therefore, the results of this example demonstrate that the dissolution rates of HPMC succinate HF and HPMC HG differ significantly depending on their particle size, and that they can be substituted in equal amounts.

[0238] Moreover, compared with the reference preparation, the dissolution of prescriptions F47-50 was significantly improved, whether the pH 6.8 medium alone was used to simulate human absorption after eating, or the pH 6.8 medium was transferred to simulate human absorption after fasting after half an hour of acid resistance.

[0239] When a single pH 6.8 medium was used to simulate human absorption after eating, the dissolution of prescriptions F47, F48, F49 and F50 was lower than that of prescriptions F32 and F40. When an acid-resistant medium was transferred to a pH 6.8 medium after half an hour to simulate human absorption after fasting, the dissolution of prescriptions F47, F48, F49 and F50 was equivalent.

[0240] Example 9: Study on Lurasidone Hydrochloride Solid Dispersion Using Soluplus and HPMCAS HF as Carriers

[0241] The components and their dosages in solid dispersions of different formulations are as follows:

[0242] The solid dispersion was prepared by solvent evaporation method:

[0243] Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask. Add a predetermined amount of dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1). Stir and dissolve at room temperature until clear and transparent. Then, remove the dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1) by rotary evaporation at 70-80°C and a vacuum of -0.03-0.1 MPa. Remove the contents and dry them completely in an oven at 40°C. Sieve to obtain a lurasidone hydrochloride solid dispersion. Prepare capsules. Labeled weight per capsule: 40 mg.

[0244] The in vitro dissolution characteristics of formulations F51, F52, F53, F54, F55, F56, F57, F58, F59, and F60 in pH 6.8 medium and acid resistance were determined. The results are shown in Tables 10-1 and 10-2.

[0245] Table 10-1: Drug release results of prescriptions F32, F40, F51 to F60 and reference preparations (%)

[0246] Table 10-2: Drug release results of prescriptions F32, F40, F51 to F60 and reference preparations (%)

[0247] The results in Tables 10-1 and 10-2 show that compared to formulations F51 and F58-F60, formulations F52-F57 showed significantly improved dissolution, both when using a pH 6.8 medium alone to simulate human absorption after a meal, and when transferring to a pH 6.8 medium after a half-hour acid-resistant period to simulate human absorption after fasting. Therefore, a mass ratio of lurasidone hydrochloride to carrier of 1:4-1:24 and a Soluplus:HPMCAS HF mass ratio of 1:(0.5-5) significantly improved in vivo absorption.

[0248] Example 10: Study on Lurasidone Hydrochloride Solid Dispersion Using Soluplus and HPMCAS HF as Carriers

[0249] The components and their dosage (mg) in the solid dispersions of different formulations are as follows:

[0250] The solid dispersion was prepared by solvent evaporation method:

[0251] Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask. Add a predetermined amount of dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1). Stir and dissolve at room temperature until clear and transparent. Then, remove the dichloromethane-methanol (methylene chloride:methanol mass ratio = 2:1) by rotary evaporation at 70-80°C and a vacuum of -0.03-0.1 MPa. Remove the contents and dry them completely in an oven at 40°C. Sieve to obtain a lurasidone hydrochloride solid dispersion. Prepare capsules. Labeled weight per capsule: 40 mg.

[0252] The in vitro dissolution characteristics of formulations F61, F62, F63, F64, F65, F66, F67, F68, F69, F70, F71, F72, F73, F74, and F75 were determined in pH 6.8 and acid-resistant medium. The results are shown in Tables 11-1 and 11-2.

[0253] Table 11-1: Drug release results of prescriptions F61 to F75 and reference preparations (%)

[0254] Table 11-2: Drug release results of prescriptions F61 to F75 and reference preparations (%)

[0255] The results in Tables 11-1 and 11-2 show that, regardless of whether the pH 6.8 medium alone was used to simulate absorption after a meal, or the pH 6.8 medium was shifted to simulate absorption after fasting after a half-hour acid-resistant period, the dissolution of formulations F61, F62, F63, F67, F69, F70, F72, and F75 was significantly improved. Therefore, Kolliphor RH40 significantly improves in vivo absorption when its weight percentage in the formulation is approximately 5.08%-14.75%.

[0256] Example 11: Study on Lurasidone Free Base Solid Dispersion

[0257] The components and their dosages in solid dispersions of different formulations are as follows:

[0258] Preparation method: Weigh the hot melt added components according to the prescription, mix them thoroughly and add them to the powder feeder of the hot melt extruder, set the temperatures of the feeding port to the extrusion die barrel to 110°C, 130°C, 165°C, 165°C, 165°C, 165°C, 165°C, and 160°C respectively, set the screw speed to 50rpm, and hot melt extrusion is carried out. After the extrudate is cooled, it is crushed and the crushed material is passed through a 60-mesh sieve. The obtained spray-dried powder is added with microcrystalline cellulose, mixed, and filled into capsules.

[0259] The in vitro dissolution characteristics of Example F75 and Example F76 in a pH 6.8 medium and acid resistance were determined. The results are shown in Tables 12-1 and 12-2.

[0260] Table 12-1: Drug release results of formulations F40, F76, F77 and reference preparations (%)

[0261] Table 12-2: Drug release results of formulations F40, F76, F77 and reference preparations (%)

[0262] The results in Tables 12-1 and 12-2 indicate that, when using a pH 6.8 medium alone to simulate human absorption after a meal, the dissolution amounts of Examples F76 and F77 were lower than those of Example F40, at only 19% to 52%. Furthermore, when transferring the medium to a pH 6.8 medium after a half-hour acid-resistant period to simulate human absorption after fasting, the dissolution amounts of Examples F76 and F77 were lower than those of Example F40, at 61% to 89%.

[0263] In summary, different from Comparative Examples 5 and 6, the inventors found that the use of lurasidone hydrochloride can better improve absorption in the body.

[0264] Example 12: Study on Lurasidone Hydrochloride Solid Dispersion Micropellets

[0265] Preparation Example F78: Preparation of Lurasidone Hydrochloride Solid Dispersion by Layered Drug Delivery: 1) Weigh the lurasidone hydrochloride and carrier in the amount prescribed in F32 into a beaker, add a certain amount of dichloromethane-methanol (dichloromethane:methanol = 2:1, mass ratio), and stir at room temperature to dissolve until clear and transparent; 2) Add the prescribed amount of pellet cores (sucrose pellet cores) into a fluidized bed as a filler; 3) Evenly spray the mixed solution onto the sucrose pellet cores. The fluidized bed spray rate is 6.0 g / ml, the atomization pressure is 2.0-3.0 bar, the inlet air temperature is 30-50°C, and the air flow rate is controlled at 50-80 m 3 / h, and after drying, sieve through a 35-mesh sieve; 4) The obtained lurasidone hydrochloride solid dispersion micropellets are encapsulated. The labeled weight of each pellet is 40 mg.

[0266] Preparation Example F79 or Example F80: Preparation of a lurasidone hydrochloride solid dispersion using layered drug delivery: 1) Weigh the lurasidone hydrochloride and carrier in the amount prescribed in F40 into a beaker, add a certain amount of dichloromethane-methanol (dichloromethane:methanol = 2:1, mass ratio), and stir at room temperature to dissolve until clear and transparent; 2) Add the prescribed amount of pellet cores (sucrose pellet cores or microcrystalline cellulose pellet cores) into a fluidized bed as a filler; 3) Evenly spray the mixed solution onto the sucrose pellet cores. The fluidized bed spray rate is 6.0 g / ml, the atomization pressure is 2.0-3.0 bar, the inlet air temperature is 30-50°C, and the air flow rate is controlled at 50-80 m 3 / h, and after drying, sieve through a 35-mesh sieve; 4) The obtained lurasidone hydrochloride solid dispersion micropellets are encapsulated. The labeled weight of each pellet is 40 mg.

[0267] Preparation Example F81, Example F82, or Example F83: Prepare a solid dispersion using fluidized bed granulation: 1) Weigh the lurasidone hydrochloride and carrier in the amount prescribed in F40 into a beaker, add a certain amount of dichloromethane-methanol (dichloromethane:methanol = 2:1, mass ratio), and stir at room temperature to dissolve until clear and transparent; 2) Add the prescribed amount of granulation substrate (microcrystalline cellulose, calcium phosphate, or mannitol) into the fluidized bed as a filler; 3) Evenly spray the mixed solution onto the filler at a fluidized bed spray rate of 8.0 g / ml, an atomization pressure of 1.5 bar, an inlet air temperature of 30-50°C, and an air flow rate controlled at 20-50 m 3 / h, and after drying, the granules are sieved through a 40-mesh sieve; 4) the obtained fluidized bed solid dispersion granules are mixed evenly with an appropriate amount of magnesium stearate and then filled into capsules. The labeled weight per capsule is 40 mg.

[0268] Preparation Example F84: Preparation of a solid dispersion using a spray drying method: 1) Weigh the lurasidone hydrochloride and carrier in the amount prescribed in F40 into a beaker, add a predetermined amount of dichloromethane-methanol (dichloromethane:methanol = 2:1, mass ratio), and dissolve with stirring at room temperature until clear and transparent; 2) The mixed solution is spray-dried and solidified using the following spray-drying parameters: inlet air temperature 170°C, outlet air temperature 60°C, fan frequency 50 Hz, atomizer frequency 45 Hz, pump speed 35 rpm, and solids content 15%; 3) The resulting lurasidone hydrochloride spray-dried solid dispersion particles are sieved through a 40-mesh sieve, mixed uniformly with an appropriate amount of magnesium stearate, and then filled into capsules. Labeled weight per capsule: 40 mg.

[0269] The in vitro dissolution characteristics of Examples F78, F79, F80, F81, F82, F83, and F84 in a pH 6.8 medium and acid resistance were determined. The results are shown in Tables 13-1 and 13-2.

[0270] Table 13-1: Drug release results of F32, F40, F78~F84 and reference preparations (%)

[0271] Table 13-2: Drug release results of F32, F40, F78~F84 and reference preparations (%)

[0272] The results in Tables 13-1 and 13-2 show that, using a single pH 6.8 medium to simulate human absorption after a meal, the dissolution of Formulation F78 showed little change compared to Formulation F32; while the dissolution of Formulations F79 and F80 improved compared to Formulation F40. When evaluating the pH 6.8 medium after a half-hour acid-resistant period, the dissolution of Formulations F78, F79, and F80 showed little change, and they were significantly better than Formulations F81, F82, F83, and F84. In summary, the dissolution of Examples F78, F79, and F80 was minimally affected, and subsequent curing using a fluidized bed layered drug application process may be considered.

[0273] When solidified using a fluidized bed multi-stage drug application process, Example F79 achieved an 18% higher final dissolution rate in a pH 6.8 medium alone than Example F78. After a half-hour acid-resistant treatment, the final dissolution rate in a pH 6.8 medium was comparable. In summary, the addition of the surfactant Kolliphor RH40 can improve drug absorption in vivo under specific conditions.

[0274] Example 13: Study on the Preparation Process of Lurasidone Hydrochloride Solid Dispersion Micropellets

[0275] Preparation Example F84, Example F85, Example F86 or Example F87: Preparation of Lurasidone Hydrochloride Solid Dispersion Using Layered Drug Delivery:

[0276] 1) Weigh the amount of lurasidone hydrochloride and carrier in the F40 recipe into a beaker, add a certain amount of dichloromethane-methanol (dichloromethane:methanol = 2:1, mass ratio), and stir at room temperature to dissolve until clear and transparent;

[0277] 2) adding the prescribed amount of pellets (sucrose pellets or microcrystalline cellulose pellets) into the fluidized bed as a filler;

[0278] 3) Spray the mixed solution evenly on the sucrose pellets. The fluidized bed spray rate is 6.0 g / ml, the atomization pressure is 2.0-3.0 bar, the inlet air temperature is 30-50 ° C, and the air flow rate is controlled at 50-80 m 3 / h, after drying, pass through a 35-mesh sieve;

[0279] 4) The prepared lurasidone hydrochloride solid dispersion pellets are encapsulated. The labeled weight per pellet is 40 mg.

[0280] The in vitro dissolution characteristics of Examples F85, F86, F87, and F88 in pH 6.8 medium and acid resistance were determined. The results are shown in Tables 14-1 and 14-2.

[0281] Table 14-1: Drug release results of F79, F85-F88 and reference preparations (%)

[0282] Table 14-2: Drug release results of F79, F85-F88 and reference preparations (%)

[0283] The results in Tables 14-1 and 14-2 show that when using a single pH 6.8 medium to simulate human absorption after a meal, the dissolution of formulations F85, F86, F87, and F88 showed little change compared to formulation F79. When evaluating the dissolution of formulations F85, F86, F87, and F88 by transferring the medium to pH 6.8 after a half-hour acid resistance test, the dissolution of formulations F85, F86, F87, and F88 showed little change compared to formulation F79.

[0284] In summary, when the lurasidone hydrochloride composition is prepared by the fluidized bed layered drug loading process, the atomization pressure is set to: 2.0 bar-3.0 bar; the material temperature is set to 30°C-50°C.

[0285] Example 14: Solid-state analysis XRD data

[0286] XRD: X-ray powder diffraction.

[0287] The forms of lurasidone hydrochloride were investigated. The specific steps were as follows: appropriate amounts of lurasidone hydrochloride API, formulations F1, F4, F10, F11, F12, F15, F20, F30, F31, F32, F37, F38, F40, F52, F54, F55, F60, and F76 were taken for investigation. The solid-state analysis XRD patterns are shown in Figure 1-19.

[0288] The XRD pattern results in Figure 1-19 show that the lurasidone hydrochloride raw material is crystalline, and formulations F1, F4, F10, F11, F12, F15, F20, F30, F31, F32, F37, F38, F40, F52, F54, F55, F60, and F76 are all amorphous.

[0289] Example 15: Stability Study

[0290] Take five tablets of each of prescriptions F40 and F58 and place them in a 200mL volumetric flask. Add 6mL of pH 6.8 buffer and shake for 20 minutes (amplitude 8). Add 15mL of 0.1M HCl and shake for 1.5 hours (amplitude 8). Add 90mL of acetonitrile and shake for 30 minutes (amplitude 4). Dilute to the mark with acetonitrile, shake well, and centrifuge (10,000 rpm, 10 minutes). Accurately transfer 5mL of the supernatant to a 10mL volumetric flask, dilute to the mark with 0.1M HCl, shake well, and centrifuge (10,000 rpm, 10 minutes). The supernatant is obtained. Prepare two replicates in parallel. The first aliquot was used for testing related substances. The results are shown in Table 15-1.

[0291] The in vitro dissolution characteristics of formulations F40 and F58 in pH 6.8 medium and acid resistance were determined. The results are shown in Tables 15-2 and 15-3.

[0292] Table 15-1: Results of related substances in the accelerated stability process of formulations F40 and F58

[0293] Table 15-2: Drug release results (%) of the accelerated stability process for formulations F40 and F58

[0294] Table 15-3: Drug release results (%) of the accelerated stability process for formulations F40 and F58

[0295] The results in Table 15-1, Table 15-2 and Table 15-3 show that the related substances of the lurasidone hydrochloride preparation F40 prepared by the present invention are stable from 0 day to 6 months of accelerated treatment, with no increase; the dissolution stability of F40 in a single pH 6.8 medium and a medium that is acid-resistant for half an hour and then converted to pH 6.8 medium is good, while the dissolution stability of F58 in a single pH 6.8 medium and a medium that is acid-resistant for half an hour and then converted to pH 6.8 medium is poor.

[0296] Example 16: Pharmacokinetic Study in Beagle Dogs

[0297] Beagle Dog PK Study: Formulas F78 and F79, along with a reference formulation (trade name: Latuda), were subjected to a three-formulation crossover pharmacokinetic study in beagle dogs. Eighteen healthy beagle dogs, half male and half female, were divided into three groups of six, with dosing administered once daily on a fed or fasted diet. The effects of food on their pharmacokinetic properties were investigated. Pentagastrin (used to promote gastric acid secretion; gastric pH in fasted beagles is 4-6, compared to 1.3 in humans) was used for pretreatment under fasting conditions. Lurasidone levels in beagle plasma were determined by LC-MS-MS, and pharmacokinetic parameters were calculated using a non-compartmental model using WinNonlin 6.3 software. The results are shown in Table 16 and Figure 20.

[0298] Table 16: Pharmacokinetics of Formulations F78, F79, and the Reference Formulation in Beagle Dogs

[0299] The review report reports that food can significantly increase the bioavailability of lurasidone hydrochloride. As shown in the table above, the exposure and Cmax of the reference formulation in beagle dogs when fasting differed significantly from those when fed. The exposure after feeding was 2.50 times that of the fasting formulation, and the Cmax after feeding was 3.25 times that of the fasting formulation, indicating a significant food effect. The exposure after feeding for formulation F79 was 1.02 times that of the fasting formulation, and the Cmax after feeding was 1.07 times that of the fasting formulation, and the bioavailability was improved compared to the reference formulation. The exposure after feeding for formulation F78 was 1.07 times that of the fasting formulation, and the Cmax after feeding was 1.21 times that of the fasting formulation, and the bioavailability was improved compared to the reference formulation.

[0300] Further comparison of the dissolution data of formulations F78 and F79 in pH 6.8 medium alone and in acid-resistant medium transferred to pH 6.8 medium for half an hour indicated that the use of fluidized bed process for solidification and the addition of surfactant polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH40) could improve in vivo absorption and reduce the food effect.

[0301] 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.

[0302] 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 composition, characterized in that including lurasidone hydrochloride and a carrier; Wherein, the carrier comprises: Soluplus, and At least one of HPMCAS HG and HPMCAS HF.

2. The composition according to claim 1, characterized in that The mass ratio of lurasidone hydrochloride to the carrier is 1:(4-24), preferably 1:(5-12); Optionally, the carrier comprises Soluplus and HPMCAS HG; or The carriers include Soluplus and HPMCAS HF; Optionally, the mass ratio of Soluplus to HPMCAS HF is 1:(0.5-5), preferably 1:(0.5-1).

3. The composition according to claim 1, characterized in that The composition further comprises a surfactant; Optionally, the surfactant comprises at least one of TPGS, Kolliphor RH40, Tween 80 and SDS; Optionally, the surfactant is Kolliphor RH40; Optionally, based on the total mass of the composition, the mass percentage of the surfactant is 5% to 15%.

4. The composition according to claim 1, characterized in that The composition further comprises an inorganic salt; Optionally, the inorganic salt comprises K ions and / or Na ions; Optionally, the inorganic salt includes at least one of KCl, K2SO4 and KH2PO4; Optionally, the weight ratio of lurasidone hydrochloride to the inorganic salt is 1:(0.1-2), preferably 1:(0.5-1).

5. The composition according to claim 1, characterized in that The composition is an oral solid preparation; Optionally, the oral solid preparation is a micropill, a capsule or a tablet.

6. The composition according to any one of claims 1 to 5, characterized in that The composition comprises: 40 parts by weight of lurasidone hydrochloride, 40 to 260 parts by weight of Soluplus, and 80-200 parts by weight of HPMCAS HF or HPMCAS HG; Wherein, the mass ratio of lurasidone hydrochloride to the carrier is 1:(5-12); Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 40 to 260 parts by weight of Soluplus, 80 to 200 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of a surfactant; Wherein, the mass ratio of lurasidone hydrochloride to the carrier is 1:(5-12); Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 40 to 260 parts by weight of Soluplus, and 80 to 200 parts by weight of HPMCAS HF or HPMCAS HG, 10 to 20 parts by weight of a surfactant, and 30 to 40 parts by weight of an inorganic salt; Wherein, the mass ratio of lurasidone hydrochloride to the carrier is 1:(5-12).

7. The composition according to any one of claims 1 to 5, characterized in that The composition comprises: 40 parts by weight of lurasidone hydrochloride, 120 to 240 parts by weight of Soluplus, and 80-160 parts by weight of HPMCAS HF; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 140-170 parts by weight of Soluplus, and 70-100 parts by weight of HPMCAS HF or HPMCAS HG; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 90 to 140 parts by weight of Soluplus, and 100-150 parts by weight of HPMCAS HF or HPMCAS HG; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 60 to 90 parts by weight of Soluplus, and 150-180 parts by weight of HPMCAS HF or HPMCAS HG; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 30 to 60 parts by weight of Soluplus, and 180-210 parts by weight of HPMCAS HF or HPMCAS HG; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 220-240 parts by weight of Soluplus, and 220-240 parts by weight of HPMCAS HF or HPMCAS HG; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 220-260 parts by weight of Soluplus, and 100-140 parts by weight of HPMCAS HF or HPMCAS HG.

8. The composition according to any one of claims 1 to 5, characterized in that The composition comprises: 40 parts by weight of lurasidone hydrochloride, 140-170 parts by weight of Soluplus, 70-100 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Kolliphor RH40; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Kolliphor RH40; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 60 to 100 parts by weight of Soluplus, 140-180 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Kolliphor RH40; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 30 to 60 parts by weight of Soluplus, 180-210 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Kolliphor RH40; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of TPGS; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of Tween 80; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10-20 parts by weight of SDS; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, 10 to 20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of KCl; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, 10 to 20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of K2SO4; Optionally, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 80 to 140 parts by weight of Soluplus, 80-140 parts by weight of HPMCAS HF or HPMCAS HG, 10 to 20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of KH2PO4.

9. A method for preparing the composition according to any one of claims 1 to 8, characterized in that: include: The carrier and lurasidone hydrochloride are mixed to obtain the composition.

10. The method according to claim 9, characterized in that Further including: Mixing a surfactant and / or an inorganic salt with lurasidone hydrochloride and a carrier; Optionally, the method further comprises: subjecting the mixed treatment product to solvent evaporation treatment and / or fluidized bed layer drug application treatment; Optionally, the composition is a micropellet, and the method further comprises: Spraying the mixed treatment product onto the outer layer of the blank pellet core; Optionally, the spraying is carried out by fluidized bed layer coating; Optionally, the atomization pressure of the fluidized bed layer is 2.0 bar-3.0 bar; Optionally, the temperature of the fluidized bed layer is 30°C-50°C; Optionally, before the spraying and before the mixing, the mixed product is dissolved by an organic solvent; Optionally, the organic solvent comprises dichloromethane and / or methanol; Optionally, the organic solvent includes dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is (1-3):1; Optionally, the composition is a micropellet, and the composition further comprises a blank pellet core; Optionally, the blank pellet core is selected from at least one of a sucrose blank pellet core and a microcrystalline cellulose blank pellet core.

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