WO2025087351A1

WO2025087351A1 - Lurasidone hydrochloride formulation

Info

Publication number: WO2025087351A1
Application number: PCT/CN2024/127194
Authority: WO
Inventors: 汪志辉; 冯双艳; 黄心; 游劲松; 黄芳芳
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2023-10-26
Filing date: 2024-10-25
Publication date: 2025-05-01
Anticipated expiration: 2026-04-26

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

本发明属于生物制药技术领域，具体地，本发明涉及一种盐酸鲁拉西酮制剂，更具体地，本发明涉及一种盐酸鲁拉西酮组合物及其制备方法。The present invention belongs to the technical field of biopharmaceuticals. 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

盐酸鲁拉西酮是一种非典型抗精神病药物，2010年盐酸鲁拉西酮片剂在美国获批上市，其规格分别有20mg、40mg、60mg、80mg、120mg/片，用于治疗精神分裂症。2013年，鲁拉西酮获批了两个新适应症，一是作为单药治疗，二是作为锂或丙戊酸钠的辅助药物治疗，用于成人患者中I型双相情感障碍相关的重性抑郁发作。与同类药物相比，盐酸鲁拉西酮具有疗效佳、安全性高、耐受性好等优点，已作为抗精神病药的一线药物。Lurasidone hydrochloride is an atypical antipsychotic drug. In 2010, lurasidone hydrochloride tablets were approved for marketing in the United States. The specifications are 20mg, 40mg, 60mg, 80mg, and 120mg per tablet, respectively, for the treatment of schizophrenia. In 2013, lurasidone was approved for two new indications, one as a monotherapy and the other as an adjunct to lithium or sodium valproate for major depressive episodes associated with type I bipolar disorder in adult patients. Compared with similar drugs, lurasidone hydrochloride has the advantages of good efficacy, high safety, and good tolerability, and has been used as a first-line antipsychotic drug.

目前上市的鲁拉西酮片剂生物利用度较低，必须与食物同时服用，且食物的热量必须大于350卡路里，否则会使鲁拉西酮的平均血药峰浓度(Cmax)和药-时曲线下面积(AUC)分别下降3倍和2倍。对于精神分裂症患者而言容易出现错服、漏服的现象，导致治疗中止，病情恶化。The currently available lurasidone tablets have low bioavailability and must be taken with food, and the calorie content of the food must be greater than 350 calories, otherwise the average peak blood concentration (Cmax) and area under the drug-time curve (AUC) of lurasidone will decrease by 3 times and 2 times, respectively. Schizophrenia patients are prone to taking the wrong dose or missing a dose, which may lead to treatment discontinuation and worsening of the condition.

盐酸鲁拉西酮溶解度具有较强的pH依赖性，在0.1mol/L盐酸、pH6.8磷酸盐缓冲液和水中的溶解度分别为5.24×10^-2mg/mL、<3.00×10^-2mg/mL和0.224mg/mL。根据生物药剂学分类系统，盐酸鲁拉西酮属于BCS II类药物，具有低溶解度、高渗透性的特点。当药物活性成分(API)的水溶性较差时，溶解或部分溶解于胃中的盐酸鲁拉西酮可能在进入肠道的中性环境后大量析出，而仅有极少部分药物溶解吸收，会对特定部位的药物溶出造成影响，是导致临床疗效差异的关键因素。同时，由于溶解和吸收的药物的量较少，可能放大食物引起的胃肠道表面活性剂增加，造成食物效应过大。因此，如果能对盐酸鲁拉西酮进行较大程度的增溶，提高药物在多介质中的溶出速度与溶解度，同时抑制药物在偏中性介质中的析出情况，改善溶出稳定性，就可以使药物的吸收得到较大程度的改善。The solubility of lurasidone hydrochloride is highly pH-dependent, with solubilities of 5.24× ^10-2 mg/mL, <3.00× ^10-2 mg/mL, and 0.224 mg/mL in 0.1 mol/L hydrochloric acid, pH 6.8 phosphate buffer, and water, respectively. According to the biopharmaceutics classification system, lurasidone hydrochloride belongs to BCS Class II drugs, which have the characteristics of low solubility and high permeability. When the water solubility of the active pharmaceutical ingredient (API) is poor, lurasidone hydrochloride dissolved or partially dissolved in the stomach may precipitate in large quantities after entering the neutral environment of the intestine, while only a very small part of the drug is dissolved and absorbed, which will affect the dissolution of the drug in specific parts and is a key factor leading to differences in clinical efficacy. At the same time, due to the small amount of dissolved and absorbed drug, the increase in gastrointestinal surfactant caused by food may be magnified, resulting in an excessive food effect. Therefore, if lurasidone hydrochloride can be solubilized to a greater extent, the dissolution rate and solubility of the drug in multiple media can be increased, while the precipitation of the drug in a neutral medium can be inhibited and the dissolution stability can be improved, the absorption of the drug can be improved to a greater extent.

发明内容Summary of the invention

本发明旨在至少在一定程度上解决现有技术中存在的技术问题。为此，本发明提供了一种盐酸鲁拉西酮制剂，该制剂可提高盐酸鲁拉西酮的溶出速度与溶解度，从而改善盐酸鲁拉西酮的体内吸收和生物利用度。The present invention aims to solve the technical problems existing in the prior art to at least a certain extent. To this end, the present invention provides a lurasidone hydrochloride preparation, which can increase the dissolution rate and solubility of lurasidone hydrochloride, thereby improving the in vivo absorption and bioavailability of lurasidone hydrochloride.

在本发明的第一方面，本发明提出了一种组合物。根据本发明的实施例，所述组合物包括盐酸鲁拉西酮和载体；其中，所述载体包括：Soluplus，以及HPMCAS HG和HPMCAS HF中的至少之一。In a first aspect of the present invention, 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.

本发明的组合物可提高盐酸鲁拉西酮的溶出速度与溶解度，可保证盐酸鲁拉西酮在小肠的溶出增加，提高盐酸鲁拉西酮的生物利用度和改善体内吸收，降低过多的服药限制，避免因服药不当导致的疗效降低甚至无效，保证药效的正常发挥。并且，本发明的盐酸鲁拉西酮组合物还可减弱或消除食物效应，从而有利于提高患者用药的的灵活性和顺应性。The composition of the present invention can improve the dissolution rate and solubility of lurasidone hydrochloride, ensure the increased dissolution of lurasidone hydrochloride in the small intestine, improve the bioavailability of lurasidone hydrochloride and improve the in vivo absorption, reduce excessive medication restrictions, avoid the reduction of efficacy or even ineffectiveness caused by improper medication, and ensure the normal performance of the drug effect. In addition, the lurasidone hydrochloride composition of the present invention can also weaken or eliminate the food effect, thereby facilitating the improvement of the flexibility and compliance of patients in medication.

根据本发明的实施例，上述组合物还可以进一步包括如下技术特征中的至少之一：According to an embodiment of the present invention, the above composition may further include at least one of the following technical features:

根据本发明的实施例，所述盐酸鲁拉西酮和载体的质量比为1：(4～24)，例如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或者它们两个比值之间的范围值，如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)。由此，可进一步提高盐酸鲁拉西酮的溶出速度与溶解度，可保证盐酸鲁拉西酮在小肠的溶出增加，提高盐酸鲁拉西酮的生物利用度和改善体内吸收。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 the range value between two ratios, 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). Thereby, 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.

在本文中，术语“药载比”是指活性成分和载体的重量比，即盐酸鲁拉西酮和载体的重量比。当载体为多种时，载体的重量为多种载体的综合。Herein, the term "drug-carrying 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.

根据本发明的实施例，所述载体包括Soluplus和HPMCAS HG。According to an embodiment of the present invention, the carrier includes Soluplus and HPMCAS HG.

根据本发明的实施例，所述载体包括Soluplus和HPMCAS HF。According to an embodiment of the present invention, the carrier includes Soluplus and HPMCAS HF.

根据本发明的实施例，所述Soluplus和HPMCAS HF的质量比为1：(0.5～5)，例如1：0.5、1：1、、1：2、1：2.5、1：3、1：3.5、1：4、1：4.5、1：5或者它们两个比值之间的范围值，如1：(0.5～1)、1：(0.5～2)。由此，可进一步提高盐酸鲁拉西酮的溶出速度与溶解度，可保证盐酸鲁拉西酮在小肠的溶出增加，提高盐酸鲁拉西酮的生物利用度和改善体内吸收。According to an embodiment of the present invention, the mass ratio of Soluplus to HPMCAS HF is 1:(0.5-5), such as 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 the two ratios, such as 1:(0.5-1), 1:(0.5-2). 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.

根据本发明的实施例，所述组合物进一步包括表面活性剂。According to an embodiment of the present invention, the composition further comprises a surfactant.

根据本发明的实施例，所述表面活性剂包括TPGS、Kolliphor RH40、吐温80和SDS中的至少之一。According to an embodiment of the present invention, the surfactant includes at least one of TPGS, Kolliphor RH40, Tween 80 and SDS.

根据本发明的实施例，所述表面活性剂为Kolliphor RH40。According to an embodiment of the present invention, the surfactant is Kolliphor RH40.

根据本发明的实施例，以所述组合物总质量计，所述表面活性剂的质量百分比为5％～15％，例如5％、5.06％、5.08％、6％、7％、8％、9％、9.92％、10％、11％、12％、13％、14％、14.75％、15％或者它们两个点值之间的范围值，如5.06％～14.75％、5.08％～14.75％。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 thereof, such as 5.06% to 14.75%, 5.08% to 14.75%.

根据本发明的实施例，所述组合物进一步包括无机盐。According to an embodiment of the present invention, the composition further comprises an inorganic salt.

根据本发明的实施例，所述无机盐包含K离子和/或Na离子。According to an embodiment of the present invention, the inorganic salt comprises K ions and/or Na ions.

根据本发明的实施例，所述无机盐包括KCl、K₂SO₄和KH₂PO₄中的至少之一。According to an embodiment of the present invention, the inorganic salt includes at least one of KCl, K ₂ SO ₄ and KH ₂ PO ₄ .

根据本发明的实施例，所述盐酸鲁拉西酮和无机盐的重量比为1：(0.1～2)，例如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或者它们两个比值之间的范围值，如1：(0.5～1.5)、1：(0.5～1)。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).

根据本发明的实施例，所述组合物为口服固体制剂。According to an embodiment of the present invention, the composition is an oral solid preparation.

根据本发明的实施例，所述口服固体制剂为微丸剂、胶囊剂或片剂。According to an embodiment of the present invention, the oral solid preparation is a micropill, a capsule or a tablet.

需要说明的是，当组合物为不同的口服固体制剂，根据该剂型的种类，还可以进一步包括该剂型所含有的其它药学上可接受的成分，该成分不受具体限制，均在本发明的保护范围内。例如，当组合物为微丸剂，还可以进一步包括空白丸芯，例如蔗糖丸芯等；当组合物为胶囊剂，还可以进一步包括胶囊层；当组合物为片剂，还可以进一步包括包衣材料。It should be noted that when the composition is a different oral solid preparation, according to the type of the dosage form, it may further include other pharmaceutically acceptable ingredients contained in the dosage form, which 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, etc.; 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.

在本文中，“微丸剂”是直径在一定范围内的球形或类球形固体剂型，其可以单独服用，也可装入胶囊、压制成片剂、或制成其他制剂。In this article, "micropellets" 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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，40～260重量份的Soluplus，以及80～200重量份的HPMCAS HF或HPMCAS HG；其中，所述盐酸鲁拉西酮和载体的质量比为1：(5～12)。 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).

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，40～260重量份的Soluplus，80～200重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的表面活性剂；其中，所述盐酸鲁拉西酮和载体的质量比为1：(5～12)。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).

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，40～260重量份的Soluplus，以及80～200重量份的HPMCAS HF或HPMCAS HG，10～20重量份的表面活性剂，以及30～40重量份的无机盐；其中，所述盐酸鲁拉西酮和载体的质量比为1：(5～12)。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).

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，120～240重量份的Soluplus，以及80～160重量份的HPMCAS HF。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，140～170重量份的Soluplus，以及70～100重量份的HPMCAS HF或HPMCAS HG。According to an embodiment of the present invention, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 140 to 170 parts by weight of Soluplus, and 70 to 100 parts by weight of HPMCAS HF or HPMCAS HG.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，90～140重量份的Soluplus，以及100～150重量份的HPMCAS HF或HPMCAS HG。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，60～90重量份的Soluplus，以及150～180重量份的HPMCAS HF或HPMCAS HG。According to an embodiment of the present invention, the composition comprises: 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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，30～60重量份的Soluplus，以及180～210重量份的HPMCAS HF或HPMCAS HG。According to an embodiment of the present invention, the composition comprises: 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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，220～240重量份的Soluplus，以及220～240重量份的HPMCAS HF或HPMCAS HG。According to an embodiment of the present invention, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 220 to 240 parts by weight of Soluplus, and 220 to 240 parts by weight of HPMCAS HF or HPMCAS HG.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，100～140重量份的Soluplus，以及100～140重量份的HPMCAS HF或HPMCAS HG。According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 100 to 140 parts by weight of Soluplus, and 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，120重量份的Soluplus，以及120重量份的HPMCAS HF或HPMCAS HG。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，220～260重量份的Soluplus，以及100～140重量份的HPMCAS HF或HPMCAS HG。According to an embodiment of the present invention, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 220 to 260 parts by weight of Soluplus, and 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，240重量份的Soluplus，以及120重量份的HPMCAS HF或HPMCAS HG。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，140～170重量份的Soluplus，70～100重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的Kolliphor RH40。According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 140 to 170 parts by weight of Soluplus, 70 to 100 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Kolliphor RH40.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，160重量份的Soluplus，80重量份的HPMCAS HF或HPMCAS HG，以及15重量份的Kolliphor RH40。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，90～140重量份的Soluplus，100～150重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的Kolliphor RH40。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, 100 to 150 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Kolliphor RH40.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，80～140重量份的Soluplus，80～140重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的Kolliphor RH40。According to an embodiment of the present invention, the composition includes: 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 Kolliphor RH40.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，120重量份的Soluplus，120重量份的HPMCAS HF或HPMCAS HG，以及15重量份的Kolliphor RH40。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，100重量份的 Soluplus，100重量份的HPMCAS HF或HPMCAS HG，以及15重量份的Kolliphor RH40。According to an embodiment of the present invention, the composition comprises: 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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，80重量份的Soluplus，80重量份的HPMCAS HF或HPMCAS HG，以及15重量份的Kolliphor RH40。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，60～100重量份的Soluplus，140～180重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的Kolliphor RH40。According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 60 to 100 parts by weight of Soluplus, 140 to 180 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Kolliphor RH40.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，80重量份的Soluplus，160重量份的HPMCAS HF或HPMCAS HG，以及15重量份的Kolliphor RH40。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，30～60重量份的Soluplus，180～210重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的Kolliphor RH40。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, 180 to 210 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Kolliphor RH40.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，40重量份的Soluplus，200重量份的HPMCAS HF或HPMCAS HG，以及15重量份的Kolliphor RH40。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，80～140重量份的Soluplus，80～140重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的TPGS。According to an embodiment of the present invention, the composition includes: 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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，100～140重量份的Soluplus，100～140重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的TPGS。According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 100 to 140 parts by weight of Soluplus, 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of TPGS.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，120重量份的Soluplus，120重量份的HPMCAS HF或HPMCAS HG，以及15重量份的TPGS。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，80～140重量份的Soluplus，80～140重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的吐温80。According to an embodiment of the present invention, 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 Tween 80.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，100～140重量份的Soluplus，100～140重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的吐温80。According to an embodiment of the present invention, the composition comprises: 40 parts by weight of lurasidone hydrochloride, 100 to 140 parts by weight of Soluplus, 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of Tween 80.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，120重量份的Soluplus，120重量份的HPMCAS HF或HPMCAS HG，以及15重量份的吐温80。According to an embodiment of the present invention, the composition comprises: 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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，80～140重量份的Soluplus，80～140重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的SDS。According to an embodiment of the present invention, the composition includes: 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 SDS.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，100～140重量份的Soluplus，100～140重量份的HPMCAS HF或HPMCAS HG，以及10～20重量份的SDS。According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 100 to 140 parts by weight of Soluplus, 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG, and 10 to 20 parts by weight of SDS.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，120重量份的Soluplus，120重量份的HPMCAS HF或HPMCAS HG，以及15重量份的SDS。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，80～140重量份的Soluplus，80～140重量份的HPMCAS HF或HPMCAS HG，10～20重量份的Kolliphor RH40，以及30～40重量份的KCl。According to an embodiment of the present invention, the composition includes: 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, 10 to 20 parts by weight of Kolliphor RH40, and 30 to 40 parts by weight of KCl.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，100～140重量份的Soluplus，100～140重量份的HPMCAS HF或HPMCAS HG，10～20重量份的Kolliphor RH40，以及30～40重量份的KCl。According to an embodiment of the present invention, the composition includes: 40 parts by weight of lurasidone hydrochloride, 100 to 140 parts by weight of Soluplus, 100 to 140 parts by weight of HPMCAS HF or HPMCAS HG, 10 to 20 parts by weight of Kolliphor RH40, and 30 to 40 parts by weight of KCl.

在一些实施例中，所述组合物包括：40重量份的盐酸鲁拉西酮，120重量份的Soluplus，120重量份的HPMCAS HF，任选地，15重量份的Kolliphor RH40。 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.

在一些实施例中，所述组合物包括：40重量份的盐酸鲁拉西酮，240重量份的Soluplus，120重量份的HPMCAS HF。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.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，120重量份的Soluplus，120重量份的HPMCAS HF或HPMCAS HG，10～20重量份的Kolliphor RH40，以及33重量份的KCl。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 to 20 parts by weight of Kolliphor RH40, and 33 parts by weight of KCl.

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，80～140重量份的Soluplus，80～140重量份的HPMCAS HF或HPMCAS HG，10～20重量份的Kolliphor RH40，以及30～40重量份的K₂SO₄。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, 10-20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of K ₂ SO ₄ .

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，120重量份的Soluplus，120重量份的HPMCAS HF或HPMCAS HG，15重量份的Kolliphor RH40，以及33重量份的K₂SO₄。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 K ₂ SO ₄ .

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，80～140重量份的Soluplus，80～140重量份的HPMCAS HF或HPMCAS HG，10～20重量份的Kolliphor RH40，以及30～40重量份的KH₂PO₄。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, 10-20 parts by weight of Kolliphor RH40, and 30-40 parts by weight of KH ₂ PO ₄ .

根据本发明的实施例，所述组合物包括：40重量份的盐酸鲁拉西酮，120重量份的Soluplus，120重量份的HPMCAS HF或HPMCAS HG，10～20重量份的Kolliphor RH40，以及33重量份的KH₂PO₄。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 KH ₂ PO ₄ .

在本发明的第二方面，本发明提出了一种制备第一方面所述组合物的方法。根据本发明的实施例，所述方法包括：将载体以及盐酸鲁拉西酮进行混合处理，得到所述组合物。本发明的制备方法工艺简单，且制备得到的组合物均具有较高的溶解度，可提高盐酸鲁拉西酮的溶出速度与溶解度，从而改善盐酸鲁拉西酮的体内吸收和生物利用度。因此，本发明的盐酸鲁拉西酮组合物还可减弱或消除了食物效应，从而有利于提高患者的的灵活性和顺应性。In the second aspect of the present invention, the present invention proposes 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 prepared compositions have 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 weaken or eliminate the food effect, thereby helping to improve the flexibility and compliance of patients.

根据本发明的实施例，上述方法还可以进一步包括如下技术特征中的至少之一：According to an embodiment of the present invention, the above method may further include at least one of the following technical features:

根据本发明的实施例，所述组合物可以为颗粒、还可以为微丸(或称微丸剂)。According to an embodiment of the present invention, the composition may be in the form of particles or micropellets (or micropellets).

根据本发明的实施例，所述组合物为颗粒，所述方法进一步包括：将表面活性剂和/或无机盐与盐酸鲁拉西酮和载体进行混合处理。According to an embodiment of the present invention, the composition is a granule, and the method further comprises: mixing a surfactant and/or an inorganic salt with lurasidone hydrochloride and a carrier.

根据本发明的实施例，所述方法进一步包括：将混合处理产物进行溶剂挥干处理和/或流化床层级上药处理。According to an embodiment of the present invention, the method further comprises: subjecting the mixed treatment product to solvent evaporation treatment and/or fluidized bed layer drug application treatment.

根据本发明的实施例，所述方法进一步包括：将混合处理产物进行溶剂挥干处理。According to an embodiment of the present invention, the method further comprises: subjecting the mixed treatment product to solvent evaporation treatment.

根据本发明的实施例，所述方法进一步包括：将混合处理产物进行流化床层级上药处理。According to an embodiment of the present invention, the method further comprises: subjecting the mixed treatment product to fluidized bed-level drug treatment.

根据本发明的实施例，所述组合物为微丸剂，所述方法进一步包括：将所述混合处理产物喷涂于空白丸芯的外层。According to an embodiment of the present invention, the composition is a micropill, and the method further comprises: spraying the mixed treatment product on the outer layer of a blank pellet core.

根据本发明的实施例，所述喷涂是采用流化床层级上药进行的。According to an embodiment of the present invention, the spraying is performed by fluidized bed layer coating.

根据本发明的实施例，所述流化床层级上药的雾化压力为2.0bar-3.0bar。According to an embodiment of the present invention, the atomization pressure of the fluidized bed layer loading is 2.0 bar-3.0 bar.

根据本发明的实施例，所述流化床层级上药的温度为30℃-50℃。According to an embodiment of the present invention, the temperature of the fluidized bed layer for applying medicine is 30°C-50°C.

根据本发明的实施例，在所述喷涂之前、所述混合处理之前，采用有机溶剂对所述混合处理产物进行溶解处理。According to an embodiment of the present invention, before the spraying and before the mixing, an organic solvent is used to dissolve the mixed product.

根据本发明的实施例，所述有机溶剂包括二氯甲烷和/或甲醇。 According to an embodiment of the present invention, the organic solvent includes dichloromethane and/or methanol.

根据本发明的实施例，所述有机溶剂包括二氯甲烷和甲醇，所述二氯甲烷和甲醇的体积比为(1～3)：1，优选为2：1。According to an embodiment of the present invention, the organic solvent includes dichloromethane and methanol, and the volume ratio of the dichloromethane to methanol is (1-3):1, preferably 2:1.

根据本发明的实施例，所述组合物为微丸剂，所述组合物进一步包括空白丸芯。According to an embodiment of the present invention, the composition is a micropellet, and the composition further includes a blank pellet core.

根据本发明的实施例，所述空白丸芯选自蔗糖空白丸芯、微晶纤维素空白丸芯中的至少之一。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.

本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：The above and/or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

图1为本发明实施例14中盐酸鲁拉西酮原料药的XRD图谱；FIG1 is an XRD pattern of the lurasidone hydrochloride bulk drug in Example 14 of the present invention;

图2为本发明实施例14中处方F1的XRD图谱；FIG2 is an XRD pattern of prescription F1 in Example 14 of the present invention;

图3为本发明实施例14中处方F4的XRD图谱；FIG3 is an XRD pattern of prescription F4 in Example 14 of the present invention;

图4为本发明实施例14中处方F10的XRD图谱；FIG4 is an XRD pattern of prescription F10 in Example 14 of the present invention;

图5为本发明实施例14中处方F11的XRD图谱；FIG5 is an XRD pattern of prescription F11 in Example 14 of the present invention;

图6为本发明实施例14中处方F12的XRD图谱；FIG6 is an XRD pattern of prescription F12 in Example 14 of the present invention;

图7为本发明实施例14中处方F15的XRD图谱；FIG7 is an XRD pattern of prescription F15 in Example 14 of the present invention;

图8为本发明实施例14中处方F20的XRD图谱；FIG8 is an XRD pattern of prescription F20 in Example 14 of the present invention;

图9为本发明实施例14中处方F30的XRD图谱；FIG9 is an XRD pattern of prescription F30 in Example 14 of the present invention;

图10为本发明实施例14中处方F31的XRD图谱；FIG10 is an XRD pattern of prescription F31 in Example 14 of the present invention;

图11为本发明实施例14中处方F32的XRD图谱；FIG11 is an XRD pattern of prescription F32 in Example 14 of the present invention;

图12为本发明实施例14中处方F37的XRD图谱；FIG12 is an XRD pattern of prescription F37 in Example 14 of the present invention;

图13为本发明实施例14中处方F38的XRD图谱；FIG13 is an XRD pattern of prescription F38 in Example 14 of the present invention;

图14为本发明实施例14中处方F40的XRD图谱；FIG14 is an XRD pattern of prescription F40 in Example 14 of the present invention;

图15为本发明实施例14中处方F52的XRD图谱；FIG15 is an XRD pattern of prescription F52 in Example 14 of the present invention;

图16为本发明实施例14中处方F54的XRD图谱；FIG16 is an XRD pattern of prescription F54 in Example 14 of the present invention;

图17为本发明实施例14中处方F55的XRD图谱；FIG17 is an XRD pattern of prescription F55 in Example 14 of the present invention;

图18为本发明实施例14中处方F60的XRD图谱；FIG18 is an XRD pattern of prescription F60 in Example 14 of the present invention;

图19为本发明实施例14中处方F76的XRD图谱；FIG19 is an XRD pattern of prescription F76 in Example 14 of the present invention;

图20为本发明实施例16中处方F78、F79和参比制剂(商品名：Latuda)在比格犬体内的药代动力学结果。FIG. 20 shows the pharmacokinetic results of the prescriptions F78, F79 and the reference preparation (trade name: Latuda) in Example 16 of the present invention in beagle dogs.

DETAILED DESCRIPTION

下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。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.

需要说明的是，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。进一步地，在本发明的描述中，除非另有说明，“多个”的含义是两个或两个以上。It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Therefore, features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise stated, It is noted that “plurality” means two or more.

本发明详细说明Detailed description of the invention

定义及一般术语Definitions and general terms

在更详细地描述本发明之前，应理解，本发明不限于本文中描述的特定实施方式，因为这样的实施方式可以变化。还应理解，本文中使用的术语仅用于描述特定实施方式的目的，并且术语不用于限制。除非另有规定，本文使用的所有技术和科学术语具有本领域技术人员普遍理解的相同含义。本文参照的所有出版物和专利均通过引用将其全部内容并入本文。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, because such embodiments may vary. It should also be understood that the terms used herein are only used for the purpose of describing specific embodiments, and the terms are not used for limitation. Unless otherwise specified, all technical and scientific terms used herein have the same meanings generally understood by those skilled in the art. All publications and patents referenced herein are incorporated herein by reference in their entirety.

本发明中，HPMCAS指醋酸羟丙甲纤维素琥珀酸酯，HPMCAS HF、HPMCAS HG、HPMCAS LF、HPMCAS MF是醋酸羟丙甲纤维素琥珀酸酯的不同型号；In the present invention, HPMCAS refers to hydroxypropyl methylcellulose acetate succinate, and HPMCAS HF, HPMCAS HG, HPMCAS LF, and HPMCAS MF are different types of hydroxypropyl methylcellulose acetate succinate;

Soluplus指聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物；Soluplus refers to polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

HPMC指羟丙甲纤维素；HPC指羟丙基纤维素；PVP指聚维酮；HPMC refers to Hydroxypropyl Methylcellulose; HPC refers to Hydroxypropyl Cellulose; PVP refers to Povidone;

KCl指氯化钾；K₂SO₄指硫酸钾；KH₂PO₄磷酸二氢钾；KCl refers to potassium chloride; K ₂ SO ₄ refers to potassium sulfate; KH ₂ PO ₄ refers to potassium dihydrogen phosphate;

TPGS指维生素E聚乙二醇琥珀酸酯；TPGS refers to vitamin E polyethylene glycol succinate;

HP50指邻苯二甲酸羟丙甲纤维素酯50，或者羟丙甲纤维素邻苯二甲酸酯50；HP50 refers to Hydroxypropyl Methylcellulose Phthalate 50, or Hydroxypropyl Methylcellulose Phthalate 50;

Kolliphor RH40指聚氧乙烯40氢化蓖麻油；Kolliphor RH40 refers to polyoxyl 40 hydrogenated castor oil;

44/14指月桂酸聚乙二醇甘油酯； 44/14 refers to laurate macrogol glyceride;

SDS指十二烷基硫酸钠。SDS refers to sodium dodecyl sulfate.

在提供数值范围的情况下，应理解，除非上下文另有明确指出，至下限单位的十分之一，该范围上下限之间的插入值和在所述范围中的任何其他陈述或插入的值被涵盖在本发明内。这些较小范围的上下限可以独立地包括在该较小范围内并且也涵盖在本发明中，经过在所述范围内的任何具体地排除限制。在所述范围包括所述界限之一或两个的情况下，排除那些包括界限的任一个或二者的范围也包括在本发明中。Where a numerical range is provided, it is understood that, unless the context clearly indicates otherwise, to one tenth of the unit of the lower limit, intervening values between the upper and lower limits of the range and any other stated or intervening values in the range are encompassed within the present invention. These smaller range limits may be independently included within the smaller range and are also encompassed within the present invention, subject to any specific exclusion of limitation within the range. Where the range includes one or both of the limits, the range excluding either or both of those including the limits is also encompassed within the present invention.

术语“任选地”，“任选的”或“任选”是指随后所述的事件或状况可以但未必发生，并且该描述包括其中发生该事件或状况的情况，以及其中未发生该事件或状况的情况。例如，本发明所述组合物包含任选的粘合剂，代表所述组合物可以包含粘合剂，也可以不包含粘合剂。The term "optionally", "optional" or "optionally" means that the subsequently described event or situation may but need not occur, and the description includes situations where the event or situation occurs, and situations where the event or situation does not occur. For example, the composition of the present invention includes an optional binder, which means that the composition may include the binder or may not include the binder.

术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term “comprise” or “include” is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

本发明所提供的组合物或制剂可单独给予患者，也可与其他活性制剂共同给予或联合给药。术语“共同给予”和“联合”包括在没有具体时限的情况下同时或顺序给予两种或多种治疗剂。在一个实施方案中，治疗剂同时存在于细胞中或个体体内，或者同时发挥生物或治疗效果。在一个实施方案中，各治疗剂在同一组合物或单位剂型中。在其他实施方案中，各治疗剂在不同的组合物或单位剂型中。在某些实施方案中，在给予第二治疗剂之前(例如，5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周前)、同时或之后(例如，5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6 周、8周或12周后)给予第一种试剂。The compositions or preparations provided by the present invention can be administered to the patient alone, or can be administered together or in combination with other active agents. The terms "administered together" and "combined" include administering two or more therapeutic agents simultaneously or sequentially without a specific time limit. In one embodiment, the therapeutic agents are present in cells or in the individual body at the same time, or exert biological or therapeutic effects simultaneously. In one embodiment, each therapeutic agent is in the same composition or unit dosage form. In other embodiments, each therapeutic agent is in different compositions or unit dosage forms. In certain embodiments, the second therapeutic 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 before). The first agent is administered after 1 week, 8 weeks or 12 weeks.

术语“重量份”是指组合物某一成分质量与其他成分质量对比后获得的质量份数。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.

下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

本发明对比例和实施例中的单独pH6.8条件溶出的检测方法为：按照美国药典Ⅱ法(USPⅡ)，以900mL±9ml介质，50rpm/min转速为条件，介质温度37.0±0.5℃，浆法，分别测定其在pH6.8介质(磷酸盐缓冲液)中的溶出。试验开始后，于5min、30min、45min、60min、90min和120min时间点取样10ml，立即补以10ml新鲜溶出介质，继续试验。将所取样品过0.45μm滤膜，取适量续滤液，用HPLC方法测定样品中药物含量，计算每个时间点的累积溶出率。The detection method of dissolution under the condition of pH 6.8 in the comparative examples and embodiments of the present invention is as follows: according to the United States Pharmacopoeia II method (USP II), with 900mL±9ml medium, 50rpm/min rotation speed as the conditions, medium temperature 37.0±0.5℃, slurry method, respectively determine its dissolution in pH 6.8 medium (phosphate buffer). After the test starts, 10ml of samples are taken at 5min, 30min, 45min, 60min, 90min and 120min time points, and 10ml of fresh dissolution medium is immediately added to continue the test. The sample is filtered through a 0.45μm filter 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.

耐酸条件(即为将样品先置于0.1M HCl条件下溶出，然后再置于pH6.8磷酸盐缓冲液介质条件下溶出)检测：按照美国药典Ⅱ法(USPⅡ)，先以500mL 0.1M HCl为介质，50rpm/min转速为条件，介质温度37.0±0.5℃，于30min时间点取样10ml，立即补以10ml新鲜溶出介质，分别测定其在介质中的溶出，在0.1M HCl介质取样结束后，转速不变，补充pH6.8磷酸盐缓冲液至900mL，并用10M NaOH快速调节pH至6.8，于15min、30min、45min、60min、90min和120min时间点取样10ml，立即补以10ml新鲜溶出介质，继续试验。将所取样品过0.45μm滤膜，取适量续滤液，用HPLC方法测定样品中药物含量，计算每个时间点的累积溶出率。Acid-resistant conditions (i.e., the sample is first dissolved under 0.1M HCl conditions, and then dissolved under pH 6.8 phosphate buffer medium conditions) test: According to the United States Pharmacopoeia II method (USP II), first use 500mL 0.1M HCl as the medium, 50rpm/min as the rotation speed, and the medium temperature of 37.0±0.5℃. At 30min, sample 10ml and immediately add 10ml of fresh dissolution medium to measure its dissolution in the medium. After the 0.1M HCl medium sampling is completed, the rotation speed remains unchanged, and pH 6.8 phosphate buffer is added to 900mL, and 10M NaOH is used to quickly adjust the pH to 6.8. Sample 10ml at 15min, 30min, 45min, 60min, 90min and 120min, and immediately add 10ml of fresh dissolution medium to continue the test. 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.

HPLC法色谱条件：HPLC chromatographic conditions:

色谱柱:Kromasil 100-5 C18 4.6x150mm，5um，Column: Kromasil 100-5 C18 4.6x150mm, 5um,

检测器：UV检测器，Detector: UV detector,

检测波长：230nm，Detection wavelength: 230nm,

流速：1.0mL/min，Flow rate: 1.0 mL/min,

柱温：30℃，Column temperature: 30°C,

进样量：5μL，Injection volume: 5 μL,

运行时间：4.5min，Running time: 4.5min,

流动相:pH3.0磷酸盐缓冲溶液:乙腈＝40:60(V/V)。Mobile phase: pH 3.0 phosphate buffer solution: acetonitrile = 40:60 (V/V).

对比例1：Comparative Example 1:

1、制备盐酸鲁拉西酮－聚乙二醇4000固体分散体，制备方法具体为：向熔融的聚乙二醇4000中加入盐酸鲁拉西酮，控温40～50℃，边搅拌边滴加甲醇至固体完全溶解，保温搅拌15min，50～60℃减压蒸除甲醇，固体于－15℃以下固化2h，粉碎，过100目筛，即得盐酸鲁拉西酮固体分散体。1. Prepare lurasidone hydrochloride-polyethylene glycol 4000 solid dispersion. The specific preparation method is: 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 lurasidone hydrochloride solid dispersion.

2、按照下表的处方制备盐酸鲁拉西酮片剂。

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

盐酸鲁拉西酮片剂的制备方法：Preparation method of lurasidone hydrochloride tablets:

①将盐酸鲁拉西酮－聚乙二醇4000固体分散体、甘露醇、部分预胶化淀粉、羟丙甲基纤维素、交联羧甲基纤维素钠过100目筛；① Pass lurasidone hydrochloride-polyethylene glycol 4000 solid dispersion, mannitol, partially pregelatinized starch, hydroxypropyl methylcellulose, and cross-linked sodium carboxymethyl cellulose through a 100-mesh sieve;

②称取处方量的盐酸鲁拉西酮－聚乙二醇4000固体分散体，依次加入处方量的甘露醇、部分预胶化淀粉、羟丙基甲基纤维素、交联羧甲基纤维素钠及硬脂酸镁，混合均匀；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 carboxymethyl cellulose and magnesium stearate in sequence, and mix evenly;

③压制成片；③ Press into tablets;

④片剂包薄膜衣。④The tablets are film-coated.

对比例2：Comparative Example 2:

按照下表的处方制备盐酸鲁拉西酮片剂。
Lurasidone hydrochloride tablets were prepared according to the following prescription.

制备方法：将枸橼酸钾和山梨醇在热熔挤出机中加热熔融，然后加入盐酸鲁拉西酮熔融，将熔融液挤出制粒，与磷酸氢钙、微粉硅胶、硬脂酸镁直接压片而成。Preparation method: Potassium citrate and sorbitol are heated and melted in a hot melt extruder, and then lurasidone hydrochloride is added and melted, the molten liquid is extruded and granulated, and then directly tableted with calcium hydrogen phosphate, micro-powder silica gel and magnesium stearate.

对比例3：Comparative Example 3:

按照下表的处方制备盐酸鲁拉西酮胶囊剂。
Lurasidone hydrochloride capsules were prepared according to the following prescription.

制备方法：按处方量称取盐酸鲁拉西酮和共聚维酮，溶解于甲醇和二氯甲烷体积比1：1的混合溶剂(共200mL)中，使药物和载体充分溶解，而后60-65℃下喷雾干燥，得到的喷干粉末外加硬脂酸镁，混合，灌装胶囊。 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 (200 mL in total) to fully dissolve the drug and the carrier, and then spray dry at 60-65°C, add magnesium stearate to the obtained spray-dried powder, mix, and fill capsules.

对比例4：Comparative Example 4:

制备方法：Preparation method:

1)称取纯化水15.00g，并按处方量称取HPMC和柠檬酸，溶解在纯化水中，作为制粒液备用；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 them as granulation liquid for later use;

2)按上述处方称取外加组分，混合10min，作为制粒底物。加制粒液，手工湿法制粒，过40目筛网进行湿整粒，之后在烘箱进行干燥，50℃干燥60min。过40目筛网进行干整粒；2) Weigh the additional components according to the above prescription, mix for 10 minutes, and use them as the granulation base. Add the granulation liquid, wet granulate manually, pass through a 40-mesh sieve for wet granulation, and then dry in an oven at 50°C for 60 minutes. Pass through a 40-mesh sieve for dry granulation;

3)外加硬脂酸镁，混合，灌胶囊。3) Add magnesium stearate, mix, and fill into capsules.

对比例5：Comparative Example 5:

制备方法：按处方称取热熔内加组分，充分混合后加入到热熔挤出机的饲粉器中，加料口到挤出口模机筒温度分别设定为110℃、130℃、165℃、165℃、165℃、165℃、165℃、160℃，螺杆转速设置为50rpm，热熔挤出，挤出物冷却后进行粉碎，粉碎后的物料过60目筛网，得到的喷干粉末外加微晶纤维素，混合，灌装胶囊。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, hot melt extrusion, crush the extrudate after cooling, pass the crushed material through a 60-mesh sieve, add microcrystalline cellulose to the obtained spray-dried powder, mix, and fill capsules.

对比例6：Comparative Example 6:

制备方法：按处方称取热熔内加组分，充分混合后加入到热熔挤出机的饲粉器中，加料口到挤出口模机筒温度分别设定为110℃、130℃、165℃、165℃、165℃、165℃、165℃、160℃，螺杆转速设置为50rpm，热熔挤出，挤出物冷却后进行粉碎，粉碎后的物料过60目筛网，按组分加入外加组分，混合，压片。Preparation method: Weigh the hot-melt added components according to the prescription, add them to the powder feeder of the hot-melt extruder after thorough mixing, 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.

然后，测定对比例1、对比例2、对比例3对比例4、对比例5、对比例6和参比制剂在pH6.8介质及耐酸的体外溶出特性，结果参见表1-1和表1-2。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.

表1-1：对比例1-6和参比制剂药物释放结果(％)
Table 1-1: Drug release results of comparative examples 1-6 and reference preparations (%)

表1-2：对比例1-6和参比制剂药物释放结果(％)

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

由表1-1和表1-2可知，采用单独pH6.8介质模拟进食后的人体吸收，对比例1、对比例2、对比例3、对比例4、对比例5和对比例6溶出量仅为1％-49％。进一步采用耐酸半小时后转移pH6.8介质中，对比例1、对比例2、对比例3和对比例4呈现明显的析出效应，不能降低已在胃中溶解的药物在小肠析出的风险，且最终溶出量极低，仅为1％-15％；对比例5和对比例6最终溶出量仅为18％-48％。As shown in Table 1-1 and Table 1-2, when a single pH 6.8 medium is used to simulate human absorption after eating, the dissolution amount of Comparative Examples 1, 2, 3, 4, 5 and 6 is only 1%-49%. Further, when the pH 6.8 medium is transferred after acid resistance for half an hour, Comparative Examples 1, 2, 3 and 4 show obvious precipitation effect, which cannot reduce the risk of precipitation of the drug dissolved in the stomach in the small intestine, and the final dissolution amount is extremely low, only 1%-15%; the final dissolution amount of Comparative Examples 5 and 6 is only 18%-48%.

可见，上述的药物制剂在小肠中溶出量很低，可能影响药物在小肠的吸收，不能消除盐酸鲁拉西酮的食物效应。It can be seen that the dissolution amount of the above-mentioned drug preparations 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.

实施例1：不同处方盐酸鲁拉西酮固体分散体研究Example 1: Study on Lurasidone Hydrochloride Solid Dispersions with Different Prescriptions

不同处方的固体分散体中各组分及其用量如下：
The components and their dosages in the solid dispersions of different prescriptions are as follows:

采用溶剂挥干法制备固体分散体：Preparation of solid dispersions by solvent evaporation method:

称取处方量的盐酸鲁拉西酮和载体置烧瓶中，加入一定量二氯甲烷-甲醇(二氯甲烷:甲醇的质量比＝2:1)，室温搅拌溶解至澄清透明，然后70～80℃，真空度-0.03～-0.1MPa旋蒸除去二氯甲烷-甲醇(二氯甲烷:甲醇的质量比＝2:1)，取出内容物置烘箱中40℃干燥完全后，过筛即得盐酸鲁拉西酮固体分散体。灌胶囊即得。每粒标示量40mg。Weigh the prescribed amount of lurasidone hydrochloride and carrier into a flask, add a certain amount of dichloromethane-methanol (mass ratio of dichloromethane:methanol = 2:1), stir and dissolve at room temperature until clear and transparent, then remove dichloromethane-methanol (mass ratio of dichloromethane:methanol = 2:1) by rotary evaporation at 70-80°C and vacuum degree -0.03--0.1MPa, take out the contents and dry them completely in an oven at 40°C, then sieve to obtain lurasidone hydrochloride solid dispersion. Fill capsules to obtain. The labeled amount of each capsule is 40mg.

采用介质体积900±9ml、介质温度37.0±0.5℃、浆法、50rpm/min，测定处方F1、F2、F3、F4、F5和F6的体外溶出特性。结果参见表2-1和表2-2。The in vitro dissolution characteristics of formulations F1, F2, F3, F4, F5 and F6 were determined using a medium volume of 900±9 ml, a medium temperature of 37.0±0.5°C, a paddle method, and 50 rpm/min. The results are shown in Tables 2-1 and 2-2.

表2-1：处方F1～F6和参比制剂药物释放结果(％)

Table 2-1: Drug release results of prescriptions F1 to F6 and reference preparations (%)

表2-2：处方F1～F6和参比制剂药物释放结果(％)
Table 2-2: Drug release results of prescriptions F1 to F6 and reference preparations (%)

由表2-1和表2-2的结果可知，采用单独pH6.8介质模拟进食后的人体吸收，处方F1、F2、F3、F4、F5溶出量极低，仅为1％-8％左右，因此该处方F1、F2、F3、F4、F5在进食后的小肠溶出量很低，小肠吸收受限。采用单独pH6.8介质模拟进食后的人体吸收，实施例F6溶出量较高，约为38％-67％。采用耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，处方F1、F2、F3、F4、F5和F6溶出量均较低，因此该处方F1～F6在空腹给药后，小肠溶出量很低，可能影响药物在小肠的吸收。From the results of Table 2-1 and Table 2-2, it can be seen that when a single pH 6.8 medium is used to simulate human absorption after eating, the dissolution amount of prescriptions F1, F2, F3, F4, and F5 is extremely low, only about 1%-8%. Therefore, the small intestinal dissolution amount of prescriptions F1, F2, F3, F4, and F5 after eating is very low, and small intestinal absorption is limited. When a single pH 6.8 medium is used to simulate human absorption after eating, the dissolution amount of Example F6 is relatively high, about 38%-67%. When the acid-resistant pH 6.8 medium is transferred after half an hour to simulate human absorption after fasting, the dissolution amount of prescriptions F1, F2, F3, F4, F5, and F6 is low. Therefore, after the fasting administration of prescriptions F1 to F6, the small intestinal dissolution amount is very low, which may affect the absorption of the drug in the small intestine.

综上，处方F1、F2、F3、F4、F5、F6都没有消除盐酸鲁拉西酮的pH依赖性，不能改善药物体内吸收。In summary, prescriptions F1, F2, F3, F4, F5, and F6 did not eliminate the pH dependence of lurasidone hydrochloride and could not improve the absorption of the drug in vivo.

实施例2：不同处方盐酸鲁拉西酮固体分散体研究Example 2: Study on Lurasidone Hydrochloride Solid Dispersions with Different Prescriptions

测定处方F7、F8、F9、F10、F11和F12在pH6.8介质及耐酸的体外溶出特性。结果参见表3-1和表3-2。The in vitro dissolution characteristics of formulations F7, F8, F9, F10, F11 and F12 in pH 6.8 medium and acid resistance were determined. The results are shown in Table 3-1 and Table 3-2.

表3-1：处方F7～F12和参比制剂药物释放结果(％)
Table 3-1: Drug release results of prescriptions F7 to F12 and reference preparations (%)

表3-2：处方F7～F12和参比制剂药物释放结果(％)

Table 3-2: Drug release results of prescriptions F7 to F12 and reference preparations (%)

由表3-1和表3-2的结果可知，采用单独pH6.8介质模拟进食后的人体吸收，处方F7、F8、F10、F11和F12溶出改善并不明显；而处方F9溶出量较高，约为64％-75％。但采用耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，处方F7、F8、F9、F10、F11和F12有较为明显的析出效应。From the results of Table 3-1 and Table 3-2, it can be seen that when using a single pH 6.8 medium to simulate human absorption after eating, the dissolution improvement of prescriptions F7, F8, F10, F11 and F12 is not obvious; while the dissolution of prescription F9 is relatively high, about 64%-75%. However, when using the acid-resistant medium after half an hour and then transferring to pH 6.8 to simulate human absorption after fasting, prescriptions F7, F8, F9, F10, F11 and F12 have a more obvious precipitation effect.

综上，处方F7、F8、F9、F10、F11和F12没有消除盐酸鲁拉西酮的pH依赖性，不能改善药物体内吸收。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.

实施例3：不同处方盐酸鲁拉西酮固体分散体研究Example 3: Study on Lurasidone Hydrochloride Solid Dispersions with Different Prescriptions

测定实施例F13、F14、F15、F16和F17在pH6.8介质及耐酸的体外溶出特性。结果参见表4-1和表4-2。The in vitro dissolution characteristics of Examples F13, F14, F15, F16 and F17 in pH 6.8 medium and acid resistance were measured. The results are shown in Table 4-1 and Table 4-2.

表4-1：处方F13～17和参比制剂药物释放结果(％)

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

表4-2：处方F13～17和参比制剂药物释放结果(％)
Table 4-2: Drug release results of prescriptions F13-17 and reference preparations (%)

由表4-1和表4-2的结果可知，采用单独pH6.8介质模拟进食后的人体吸收，处方F13、F14、F15、F16和F17溶出改善并不明显。采用耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，处方F13、F14、F15、F16和F17有较为明显的析出效应。From the results of Table 4-1 and Table 4-2, it can be seen that when using a single pH 6.8 medium to simulate human absorption after eating, the dissolution improvement of prescriptions F13, F14, F15, F16 and F17 is not obvious. When using an acid-resistant medium transferred to pH 6.8 after half an hour to simulate human absorption after fasting, prescriptions F13, F14, F15, F16 and F17 have a more obvious precipitation effect.

综上，处方F13、F14、F15、F16和F17没有消除盐酸鲁拉西酮的pH依赖性，不能改善药物体内吸收。In summary, prescriptions F13, F14, F15, F16, and F17 did not eliminate the pH dependence of lurasidone hydrochloride and could not improve the absorption of the drug in vivo.

实施例4：不同处方盐酸鲁拉西酮固体分散体研究Example 4: Study on Lurasidone Hydrochloride Solid Dispersions with Different Prescriptions

测定处方F18、F19、F20、F21、F22、F23、F24、F25和F26在pH6.8介质及耐酸的体外溶出特性。结果参见表5-1和表5-2。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.

表5-1：处方F18～F26和参比制剂药物释放结果(％)
Table 5-1: Drug release results of prescriptions F18 to F26 and reference preparations (%)

表5-2：处方F18～F26和参比制剂药物释放结果(％)

Table 5-2: Drug release results of prescriptions F18 to F26 and reference preparations (%)

由表5-1和表5-2的结果可知，采用单独pH6.8介质模拟进食后的人体吸收，处方F18、F19、F20、F21、F22、F23、F24、F25和F26溶出改善并不明显。采用耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，与实施例1、实施例2和实施例3中的处方(均没有析出效应)相比，处方F18、F19、F20、F21、F23、F25和F26有较为明显的改善。From the results of Table 5-1 and Table 5-2, it can be seen that the dissolution improvement of prescriptions F18, F19, F20, F21, F22, F23, F24, F25 and F26 was not obvious when using a single pH 6.8 medium to simulate human absorption after eating. When the acid-resistant medium was transferred to pH 6.8 after half an hour to simulate human absorption after fasting, compared with the prescriptions in Example 1, Example 2 and Example 3 (all of which had no precipitation effect), prescriptions F18, F19, F20, F21, F23, F25 and F26 had more obvious improvements.

综上，尽管处方F18、F19、F20、F21、F22、F23、F24、F25和F26没有消除盐酸鲁拉西酮的pH依赖性，不能改善药物体内吸收。但是发明人意外的发现，对比实施例1-4，处方中采用聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)作为载体，可以降低盐酸鲁拉西酮在胃中溶解的药物在小肠析出的风险，有利于改善空腹后药物在小肠中的吸收。In summary, although the prescriptions F18, F19, F20, F21, F22, F23, F24, F25 and F26 did not eliminate the pH dependence of lurasidone hydrochloride and could not improve the absorption of the drug in vivo, the inventor unexpectedly found that, compared with Examples 1-4, the use of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) as a carrier in the prescription can reduce the risk of lurasidone hydrochloride dissolved in the stomach precipitating in the small intestine, which is beneficial to improve the absorption of the drug in the small intestine after fasting.

实施例5：不同处方盐酸鲁拉西酮固体分散体研究Example 5: Study on Lurasidone Hydrochloride Solid Dispersions with Different Prescriptions

测定实施例F27、F28、F29、F30、F31和F32在pH6.8介质及耐酸的体外溶出特性。结果参见表6-1和表6-2。The in vitro dissolution characteristics of Examples F27, F28, F29, F30, F31 and F32 in pH 6.8 medium and acid resistance were measured. The results are shown in Table 6-1 and Table 6-2.

表6-1：处方F19、F21、F27～F32和参比制剂药物释放结果(％)

Table 6-1: Drug release results of prescriptions F19, F21, F27~F32 and reference preparations (%)

表6-2：处方F19、F21、F27～F32和参比制剂药物释放结果(％)
Table 6-2: Drug release results of prescriptions F19, F21, F27~F32 and reference preparations (%)

由表6-1和表6-2的结果可知，采用单独pH6.8介质模拟进食后的人体吸收，处方F32溶出量最高，相比处方F19溶出量改善显著。高分子筛选考察发现，HPMCAS HF作为混搭载体时，起到了非常意外的效果，能显著改善进食后的小肠吸收受限。采用耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，数据显示在加入HPMCAS HF后，在酸中的溶出有所减慢，但是不影响转入pH6.8介质后的溶出平台。综上，实施例F32能消除盐酸鲁拉西酮的pH依赖性，能改善药物体内吸收。 From the results of Table 6-1 and Table 6-2, it can be seen that when a single pH 6.8 medium is used to simulate human absorption after eating, the dissolution amount of prescription F32 is the highest, and the dissolution amount is significantly improved compared to prescription F19. The polymer screening investigation found that when HPMCAS HF is used as a mixed carrier, it has a very unexpected effect and can significantly improve the limited absorption of the small intestine after eating. The acid-resistant medium was transferred to pH 6.8 after half an hour to simulate human absorption after fasting. The data showed that after the addition of HPMCAS HF, the dissolution in acid slowed down, but it did not affect the dissolution platform after transferring to pH 6.8 medium. In summary, Example F32 can eliminate the pH dependence of lurasidone hydrochloride and improve the absorption of the drug in vivo.

实施例6：不同处方盐酸鲁拉西酮固体分散体研究Example 6: Study on Lurasidone Hydrochloride Solid Dispersions with Different Prescriptions

测定实施例F33、F34、F35、F36和F37在pH6.8介质及耐酸的体外溶出特性。结果参见表7-1和表7-2。The in vitro dissolution characteristics of Examples F33, F34, F35, F36 and F37 in pH 6.8 medium and acid resistance were determined. The results are shown in Table 7-1 and Table 7-2.

表7-1：处方F32～F37和参比制剂药物释放结果(％)
Table 7-1: Drug release results of prescriptions F32 to F37 and reference preparations (%)

表7-2：处方F32～F37和参比制剂药物释放结果(％)

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

由表7-1和表7-2的结果可知，采用单独pH6.8介质模拟进食后的人体吸收，相比处方F32和F33，处方F34、F35、F36和F37溶出更低。采用耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，仅有处方F34和F35与处方F32溶出相当。综上，处方F33～F37并不能消除盐酸鲁拉西酮的pH依赖性，能改善药物体内吸收。From the results of Table 7-1 and Table 7-2, it can be seen that when using a single pH 6.8 medium to simulate human absorption after eating, the dissolution of prescriptions F34, F35, F36 and F37 is lower than that of prescriptions F32 and F33. When using an acid-resistant medium that is transferred to a pH 6.8 medium after half an hour to simulate human absorption after fasting, only prescriptions F34 and F35 have dissolution comparable to that of prescription F32. In summary, prescriptions F33 to F37 cannot eliminate the pH dependence of lurasidone hydrochloride, but can improve the absorption of the drug in vivo.

实施例7：不同处方盐酸鲁拉西酮固体分散体研究Example 7: Study on Lurasidone Hydrochloride Solid Dispersions with Different Prescriptions

不同处方的固体分散体中各组分及其用量如下：
The components and their dosages in the solid dispersions of different formulations are as follows:

测定处方F38、F39、F40、F41、F42、F43、F44、F45和F46在pH6.8介质及耐酸的体外溶出特性。结果参见表8-1和表8-2。 The in vitro dissolution characteristics of formulations F38, F39, F40, F41, F42, F43, F44, F45 and F46 in pH 6.8 medium and acid resistance were determined. The results are shown in Tables 8-1 and 8-2.

表8-1：处方F32、F38～F46和参比制剂药物释放结果(％)
Table 8-1: Drug release results of prescriptions F32, F38~F46 and reference preparations (%)

表8-2：处方F32、F38～F46和参比制剂药物释放结果(％)

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

表8-1和表8-2的结果可知，采用单独pH6.8介质模拟进食后的人体吸收，相比处方F32，处方F38、F40、F41和F42溶出速率改善显著。采用耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，相比处方F32，只有处方F40(加入了Kolliphor RH40)溶出速率改善显著。The results of Table 8-1 and Table 8-2 show that when a single pH 6.8 medium is used to simulate human absorption after eating, the dissolution rates of prescriptions F38, F40, F41 and F42 are significantly improved compared with prescription F32. When the pH 6.8 medium is transferred after half an hour of acid resistance to simulate human absorption after fasting, only prescription F40 (with Kolliphor RH40 added) has a significant improvement in dissolution rate compared with prescription F32.

综上，处方F40能进一步显著改善体内的吸收。In summary, prescription F40 can further significantly improve absorption in the body.

实施例8：不同处方盐酸鲁拉西酮固体分散体研究Example 8: Study on Lurasidone Hydrochloride Solid Dispersions with Different Prescriptions

测定处方F47、F48、F49和F50在pH6.8介质及耐酸的体外溶出特性。结果参见表9-1和表9-2。The in vitro dissolution characteristics of formulations F47, F48, F49 and F50 in pH 6.8 medium and acid resistance were determined. The results are shown in Tables 9-1 and 9-2.

表9-1：处方F32、F40、F47～F50和参比制剂药物释放结果(％)

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

表9-2：处方F32、F40、F47～F50和参比制剂药物释放结果(％)
Table 9-2: Drug release results of prescriptions F32, F40, F47~F50 and reference preparations (%)

表9-1和表9-2的结果可知，无论单独pH6.8介质模拟进食后的人体吸收、还是耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，处方F40和F47的溶出相当。因此，本实施例的结果可说明醋酸羟丙甲纤维素琥珀酸酯HF和醋酸羟丙甲纤维素琥珀酸酯HG不同粒径溶出区别不大，二者可以等量替换。The results of Table 9-1 and Table 9-2 show that the dissolution of prescriptions F40 and F47 is similar, whether the pH 6.8 medium alone simulates human absorption after eating, or the pH 6.8 medium is transferred to simulate human absorption after fasting after acid resistance for half an hour. Therefore, the results of this example can show that the dissolution of different particle sizes of HPMC succinate HF and HPMC succinate HG is not much different, and the two can be replaced in equal amounts.

并且，相较于参比制剂，无论单独pH6.8介质模拟进食后的人体吸收、还是耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，处方F47～50的溶出均有显著提升。Moreover, compared with the reference preparation, the dissolution of prescriptions F47-50 was significantly improved, whether using pH 6.8 medium alone to simulate human absorption after eating, or transferring to pH 6.8 medium after acid resistance for half an hour to simulate human absorption after fasting.

采用单独pH6.8介质模拟进食后的人体吸收，相比处方F32和F40，处方F47、F48、F49和F50溶出更低；采用耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，处方F47、F48、F49和F50溶出相当。Using a single pH 6.8 medium to simulate human absorption after eating, the dissolution of prescriptions F47, F48, F49 and F50 was lower than that of prescriptions F32 and F40. Using an acid-resistant medium transferred to pH 6.8 after half an hour to simulate human absorption after fasting, the dissolution of prescriptions F47, F48, F49 and F50 was equivalent.

实施例9：以Soluplus和HPMCAS HF为载体的盐酸鲁拉西酮固体分散体研究Example 9: Study on Lurasidone Hydrochloride Solid Dispersion Using Soluplus and HPMCAS HF as Carriers

测定处方F51、F52、F53、F54、F55、F56、F57、F58、F59和F60在pH6.8介质及耐酸的体外溶出特性。结果参见表10-1和表10-2。The in vitro dissolution characteristics of the 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.

表10-1：处方F32、F40、F51～F60和参比制剂药物释放结果(％)
Table 10-1: Drug release results of prescriptions F32, F40, F51~F60 and reference preparations (%)

表10-2：处方F32、F40、F51～F60和参比制剂药物释放结果(％)

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

表10-1和表10-2的结果可知，相较于处方F51、F58～F60，无论单独pH6.8介质模拟进食后的人体吸收、还是耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，处方F52～F57的溶出均有显著提升。因此，当盐酸鲁拉西酮和载体的质量比为1:4-1:24，且Soluplus：HPMCAS HF质量比1:(0.5～5)时，能显著改善体内的吸收。The results of Table 10-1 and Table 10-2 show that compared with prescriptions F51, F58-F60, the dissolution of prescriptions F52-F57 was significantly improved, whether it was a single pH 6.8 medium to simulate human absorption after eating, or a half-hour acid resistance and then a transfer to a pH 6.8 medium to simulate human absorption after fasting. Therefore, when the mass ratio of lurasidone hydrochloride to the carrier is 1:4-1:24, and the mass ratio of Soluplus: HPMCAS HF is 1:(0.5-5), the absorption in the body can be significantly improved.

实施例10：以Soluplus和HPMCAS HF为载体的盐酸鲁拉西酮固体分散体研究Example 10: Study on Lurasidone Hydrochloride Solid Dispersion Using Soluplus and HPMCAS HF as Carriers

不同处方的固体分散体中各组分及其用量(mg)如下：

The components and their dosage (mg) in the solid dispersions of different prescriptions are as follows:

测定处方F61、F62、F63、F64、F65、F66、F67、F68、F69、F70、F71、F72、F73、F74和F75在pH6.8介质及耐酸的体外溶出特性。结果参见表11-1和表11-2。The in vitro dissolution characteristics of the formulations F61, F62, F63, F64, F65, F66, F67, F68, F69, F70, F71, F72, F73, F74 and F75 in pH 6.8 medium and acid resistance were determined. The results are shown in Tables 11-1 and 11-2.

表11-1：处方F61～F75和参比制剂药物释放结果(％)
Table 11-1: Drug release results of prescriptions F61 to F75 and reference preparations (%)

表11-2：处方F61～F75和参比制剂药物释放结果(％)
Table 11-2: Drug release results of prescriptions F61 to F75 and reference preparations (%)

表11-1和表11-2的结果可知，无论采用单独pH6.8介质模拟进食后的人体吸收，还是采用耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，，处方F61、F62、F63、F67、F69、F70、F72和F75的溶出均有显著提升。因此，Kolliphor RH40在处方中的质量占比约为5.08％-14.75％时，能显著改善体内的吸收。The results of Table 11-1 and Table 11-2 show that whether the pH 6.8 medium alone is used to simulate the absorption of the human body after eating, or the pH 6.8 medium is transferred to simulate the absorption of the human body after fasting after half an hour of acid resistance, the dissolution of prescriptions F61, F62, F63, F67, F69, F70, F72 and F75 is significantly improved. Therefore, when the mass proportion of Kolliphor RH40 in the prescription is about 5.08%-14.75%, it can significantly improve the absorption in the body.

实施例11：鲁拉西酮游离碱固体分散体研究Example 11: Study on Lurasidone Free Base Solid Dispersion

测定实施例F75和实施例F76在pH6.8介质及耐酸的体外溶出特性。结果参见表12-1和表12-2。The in vitro dissolution characteristics of Example F75 and Example F76 in pH 6.8 medium and acid resistance were measured. The results are shown in Table 12-1 and Table 12-2.

表12-1：处方F40、F76、F77和参比制剂药物释放结果(％)
Table 12-1: Drug release results of prescriptions F40, F76, F77 and reference preparations (%)

表12-2：处方F40、F76、F77和参比制剂药物释放结果(％)
Table 12-2: Drug release results of prescriptions F40, F76, F77 and reference preparations (%)

由表12-1和表12-2的结果可知，采用单独pH6.8介质模拟进食后的人体吸收，相比实施例F40，实施例F76和实施例F77溶出量较低，溶出量仅为19％-52％。进一步采用耐酸半小时后转移pH6.8介质模拟空腹后的人体吸收，相比实施例F40，实施例F76和实施例F77溶出量较低，溶出量为61％-89％。From the results of Table 12-1 and Table 12-2, it can be seen that when the pH 6.8 medium alone is used to simulate the absorption of the human body after eating, the dissolution amount of Example F76 and Example F77 is lower than that of Example F40, and the dissolution amount is only 19%-52%. Further, when the pH 6.8 medium is transferred after half an hour of acid resistance to simulate the absorption of the human body after fasting, the dissolution amount of Example F76 and Example F77 is lower than that of Example F40, and the dissolution amount is 61%-89%.

综上，区别于对比例5和对比例6，发明人发现采用盐酸鲁拉西酮的形式，能更好的改善体内的吸收。In summary, different from Comparative Examples 5 and 6, the inventors found that the use of lurasidone hydrochloride can better improve the absorption in the body.

实施例12：盐酸鲁拉西酮固体分散体微丸研究

Example 12: Study on Lurasidone Hydrochloride Solid Dispersion Micropellets

制备实施例F78：采用层级上药制备盐酸鲁拉西酮固体分散体：1)称取F32处方量的盐酸鲁拉西酮和载体置烧杯中，加入一定量二氯甲烷-甲醇(二氯甲烷:甲醇＝2:1，质量比)，室温搅拌溶解至澄清透明；2)将处方量的丸芯(蔗糖丸芯)加入流化床中作为填充剂；3)将混合溶液均匀喷洒于蔗糖丸芯上，流化床的喷液速度为6.0g/ml，雾化压力为2.0-3.0bar，进风温度为30-50℃，空气流量控制在50～80m³/h，干燥后过35目筛；4)将制得的盐酸鲁拉西酮固体分散体微丸灌胶囊即得。每粒标示量40mg。Preparation Example F78: Preparation of lurasidone hydrochloride solid dispersion by layered drug application: 1) Weigh the amount of lurasidone hydrochloride and carrier in the prescription of 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 prescription amount of pellets (sucrose pellets) into a fluidized bed as a filler; 3) Spray the mixed solution evenly on the sucrose pellets, the fluidized bed spray rate is 6.0g/ml, the atomization pressure is 2.0-3.0bar, the inlet temperature is 30-50℃, the air flow rate is controlled at ^50-80m3 /h, and after drying, pass through a 35-mesh sieve; 4) Fill the obtained lurasidone hydrochloride solid dispersion micro-pellets into capsules. The labeled amount of each pellet is 40mg.

制备实施例F79或实施例F80：采用层级上药制备盐酸鲁拉西酮固体分散体：1)称取F40处方量的盐酸鲁拉西酮和载体置烧杯中，加入一定量二氯甲烷-甲醇(二氯甲烷:甲醇＝2:1，质量比)，室温搅拌溶解至澄清透明；2)将处方量的丸芯(蔗糖丸芯或微晶纤维素丸芯)加入流化床中作为填充剂；3)将混合溶液均匀喷洒于蔗糖丸芯上，流化床的喷液速度为6.0g/ml，雾化压力为2.0-3.0bar，进风温度为30-50℃，空气流量控制在50～80m³/h，干燥后过35目筛；4)将制得的盐酸鲁拉西酮固体分散体微丸灌胶囊即得。每粒标示量40mg。Preparation Example F79 or Example F80: Preparation of lurasidone hydrochloride solid dispersion by layered drug application: 1) Weigh the lurasidone hydrochloride and carrier in the amount prescribed in F40 and place them in 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 pellets (sucrose pellets or microcrystalline cellulose pellets) into a fluidized bed as a filler; 3) Spray the mixed solution evenly on the sucrose pellets, the fluidized bed spray rate is 6.0g/ml, the atomization pressure is 2.0-3.0bar, the inlet temperature is 30-50℃, the air flow rate is controlled at ^50-80m3 /h, and after drying, pass through a 35-mesh sieve; 4) Fill the obtained lurasidone hydrochloride solid dispersion micro-pellets into capsules. The labeled amount of each pellet is 40mg.

制备实施例F81、实施例F82或实施例F83：采用流化床制粒制备固体分散体：1)称取F40处方量的盐酸鲁拉西酮和载体置烧杯中，加入一定量二氯甲烷-甲醇(二氯甲烷:甲醇＝2:1，质量比)，室温搅拌溶解至澄清透明；2)将处方量的制粒底物(微晶纤维素、磷酸钙或甘露醇)加入流化床中作为填充剂；3)将混合溶液均匀喷洒于填充剂中，流化床的喷液速度为8.0g/ml，雾化压力为1.5bar，进风温度为30-50℃，空气流量控制在20～50m³/h，颗粒干燥后过40目筛整粒；4)将制得的流化床固体分散体颗粒与适量硬脂酸镁混合均匀后，灌胶囊即得。每粒标示量40mg。Preparation Example F81, Example F82 or Example F83: Prepare solid dispersion by fluidized bed granulation: 1) Weigh the amount of lurasidone hydrochloride and carrier in F40 prescription and place them in a beaker, add a certain amount of dichloromethane-methanol (dichloromethane:methanol=2:1, mass ratio), stir and dissolve at room temperature until clear and transparent; 2) Add the prescription amount of granulation substrate (microcrystalline cellulose, calcium phosphate or mannitol) into the fluidized bed as a filler; 3) Spray the mixed solution evenly on the filler, the fluidized bed spray speed is 8.0g/ml, the atomization pressure is 1.5bar, the inlet temperature is 30-50℃, the air flow rate is controlled at ^20-50m3 /h, and the particles are dried and sieved through a 40-mesh sieve; 4) The obtained fluidized bed solid dispersion particles are evenly mixed with an appropriate amount of magnesium stearate, and then filled into capsules. The labeled amount of each particle is 40mg.

制备实施例F84：采用喷雾干燥法制备固体分散体：1)称取F40处方量的盐酸鲁拉西酮和载体置烧杯中，加入一定量二氯甲烷-甲醇(二氯甲烷:甲醇＝2:1，质量比)，室温搅拌溶解至澄清透明；2)将混合溶液经过喷雾干燥固化，喷雾干燥工艺预设参数：进风温度170℃、出风温度60℃、风机频率50HZ、雾化器频率45HZ、泵速为35rpm、固含量为15％；3)将制得的盐酸鲁拉西酮喷雾干燥固体分散体颗粒过40目筛整粒，与适量硬脂酸镁混合均匀后，灌胶囊即得。每粒标示量40mg。Preparation Example F84: Prepare solid dispersion by spray drying: 1) Weigh the amount of lurasidone hydrochloride and carrier in F40 prescription and place them in a beaker, add a certain amount of dichloromethane-methanol (dichloromethane: methanol = 2:1, mass ratio), stir and dissolve at room temperature until clear and transparent; 2) The mixed solution is spray dried and solidified, and the preset parameters of the spray drying process are: inlet air temperature 170°C, outlet air temperature 60°C, fan frequency 50HZ, atomizer frequency 45HZ, pump speed 35rpm, solid content 15%; 3) The obtained lurasidone hydrochloride spray dried solid dispersion particles are sieved through a 40-mesh sieve, mixed evenly with an appropriate amount of magnesium stearate, and then filled into capsules. The labeled amount of each particle is 40mg.

测定实施例F78、F79、F80、F81、F82、F83和F84在pH6.8介质及耐酸的体外溶出特性。结果参见表13-1和表13-2。The in vitro dissolution characteristics of Examples F78, F79, F80, F81, F82, F83 and F84 in pH 6.8 medium and acid resistance were determined. The results are shown in Tables 13-1 and 13-2.

表13-1：F32、F40、F78～F84和参比制剂药物释放结果(％)

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

表13-2：F32、F40、F78～F84和参比制剂药物释放结果(％)
Table 13-2: Drug release results of F32, F40, F78-F84 and reference preparations (%)

由表13-1和表13-2的结果可知，采用单独pH6.8介质模拟进食后的人体吸收，相比处方F32，处方F78溶出变化不大；相比处方F40，处方F79和F80溶出提高。采用耐酸半小时后转移pH6.8介质进行评估，处方F78、F79、F80溶出变化不大，且显著优于处方F81、F82、F83和F84。综上，实施例F78、实施例F79、实施例F80溶出受影响较小，可后续考虑采用流化床层级上药工艺进行固化。From the results of Table 13-1 and Table 13-2, it can be seen that the dissolution of prescription F78 did not change much compared with prescription F32 when using a single pH 6.8 medium to simulate human absorption after eating; the dissolution of prescriptions F79 and F80 was improved compared with prescription F40. After acid resistance for half an hour and then transferring to a pH 6.8 medium for evaluation, the dissolution of prescriptions F78, F79, and F80 did not change much, and was significantly better than prescriptions F81, F82, F83, and F84. In summary, the dissolution of Example F78, Example F79, and Example F80 was less affected, and the fluidized bed layered drug application process can be considered for subsequent solidification.

采用流化床层级上药工艺进行固化时，相比实施例F78，实施例F79在单独pH6.8介质中最终溶出量高18％；在耐酸半小时后转移pH6.8介质中最终溶出量相当。综上，特定工艺下，表面活性剂聚氧乙烯40氢化蓖麻油(Kolliphor RH40)的加入能改善药物体内吸收。 When the fluidized bed layered drug application process is used for solidification, the final dissolution amount of Example F79 in a single pH 6.8 medium is 18% higher than that of Example F78; the final dissolution amount in a pH 6.8 medium after acid resistance for half an hour is equivalent. In summary, under a specific process, the addition of the surfactant polyoxyethylene 40 hydrogenated castor oil (Kolliphor RH40) can improve the absorption of drugs in vivo.

实施例13：盐酸鲁拉西酮固体分散体微丸制备工艺研究
Example 13: Study on the preparation process of lurasidone hydrochloride solid dispersion micropellets

制备实施例F84、实施例F85、实施例F86或实施例F87：采用层级上药制备盐酸鲁拉西酮固体分散体：Preparation Example F84, Example F85, Example F86 or Example F87: Preparation of Lurasidone Hydrochloride Solid Dispersion by Layered Drug Delivery:

1)称取F40处方量的盐酸鲁拉西酮和载体置烧杯中，加入一定量二氯甲烷-甲醇(二氯甲烷:甲醇＝2:1，质量比)，室温搅拌溶解至澄清透明；1) Weigh the amount of lurasidone hydrochloride and carrier in the F40 prescription and place them in 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)将处方量的丸芯(蔗糖丸芯或微晶纤维素丸芯)加入流化床中作为填充剂；2) adding the prescribed amount of pellets (sucrose pellets or microcrystalline cellulose pellets) into the fluidized bed as a filler;

3)将混合溶液均匀喷洒于蔗糖丸芯上，流化床的喷液速度为6.0g/ml，雾化压力为2.0-3.0bar，进风温度为30-50℃，空气流量控制在50～80m³/h，干燥后过35目筛；3) Spray the mixed solution evenly on the sucrose pellet core, the fluidized bed spray rate is 6.0g/ml, the atomization pressure is 2.0-3.0bar, the air inlet temperature is 30-50℃, the air flow rate is controlled at ^50-80m3 /h, and after drying, pass through a 35-mesh sieve;

4)将制得的盐酸鲁拉西酮固体分散体微丸灌胶囊即得。每粒标示量40mg。4) The obtained lurasidone hydrochloride solid dispersion pellets are filled into capsules. The labeled weight of each pellet is 40 mg.

测定实施例F85、F86、F87和F88在pH6.8介质及耐酸的体外溶出特性。结果参见表14-1和表14-2The in vitro dissolution characteristics of Examples F85, F86, F87 and F88 in pH 6.8 medium and acid resistance were measured. The results are shown in Table 14-1 and Table 14-2

表14-1：F79、F85～F88和参比制剂药物释放结果(％)
Table 14-1: Drug release results of F79, F85-F88 and reference preparations (%)

表14-2：F79、F85～F88和参比制剂药物释放结果(％)

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

由表14-1和表14-2的结果可知，采用单独pH6.8介质模拟进食后的人体吸收，相比处方F79，处方F85、F86、F87和F88溶出变化不大。采用耐酸半小时后转移pH6.8介质进行评估，相比处方F79，F85、F86、F87和F88溶出变化不大。From the results of Table 14-1 and Table 14-2, it can be seen that when using a single pH 6.8 medium to simulate human absorption after eating, the dissolution of prescriptions F85, F86, F87 and F88 did not change much compared to prescription F79. When the pH 6.8 medium was transferred after half an hour of acid resistance, the dissolution of F85, F86, F87 and F88 did not change much compared to prescription F79.

综上，采用流化床层级上药工艺制备盐酸鲁拉西酮组合物时，雾化压力设定为：2.0bar-3.0bar；物料温度设定为30℃-50℃。In summary, when the lurasidone hydrochloride composition is prepared by the fluidized bed layered drug application process, the atomization pressure is set to: 2.0 bar-3.0 bar; the material temperature is set to 30°C-50°C.

实施例14：固态分析XRD数据Example 14: Solid State Analysis XRD Data

XRD：X-射线粉末衍射。XRD: X-ray powder diffraction.

考察盐酸鲁拉西酮的存在形式。具体操作步骤为：分别取适量盐酸鲁拉西酮原料药，处方F1、F4、F10、F11、F12、F15、F20、F30、F31、F32、F37、F38、F40、F52、F54、F55、F60、和F76进行考察，固态分析XRD图谱如图1-19所示。The existence form of lurasidone hydrochloride was investigated. The specific operation steps were as follows: appropriate amounts of lurasidone hydrochloride raw materials, formulations F1, F4, F10, F11, F12, F15, F20, F30, F31, F32, F37, F38, F40, F52, F54, F55, F60, and F76 were taken for investigation, and the solid state analysis XRD spectrum was shown in Figure 1-19.

图1-19的XRD图谱结果表明，盐酸鲁拉西酮原料药呈晶体，处方F1、F4、F10、F11、F12、F15、F20、F30、F31、F32、F37、F38、F40、F52、F54、F55、F60、和F76均呈无定型。The XRD spectrum results in Figure 1-19 indicate that the lurasidone hydrochloride raw material is crystalline, while formulations F1, F4, F10, F11, F12, F15, F20, F30, F31, F32, F37, F38, F40, F52, F54, F55, F60, and F76 are all amorphous.

实施例15：稳定性研究Example 15: Stability Study

分别取5粒处方F40和F58，置于200mL量瓶中，加入pH6.8缓冲液6mL，振摇20min(振幅为8)，加入0.1M HCl 15mL振摇1.5h(振幅为8)，加入乙腈90mL振摇30min(振幅为4)，用乙腈稀释至刻度，摇匀，离心(10000rpm，10min)，精密移取上清液5mL至10mL量瓶中，用0.1M HCl稀释至刻度，摇匀，离心(10000rpm，10min)，取上清液即得。平行制备2份，取第一份检测有关物质，结果见表15-1。Take 5 tablets of prescription F40 and F58 respectively, place in a 200mL volumetric flask, add 6mL of pH6.8 buffer, shake for 20min (amplitude 8), add 15mL of 0.1M HCl and shake for 1.5h (amplitude 8), add 90mL of acetonitrile and shake for 30min (amplitude 4), dilute to scale with acetonitrile, shake well, centrifuge (10000rpm, 10min), accurately transfer 5mL of supernatant to a 10mL volumetric flask, dilute to scale with 0.1M HCl, shake well, centrifuge (10000rpm, 10min), and take the supernatant. Prepare 2 portions in parallel, take the first portion to detect related substances, the results are shown in Table 15-1.

测定处方F40和F58在pH6.8介质及耐酸体外溶出特性，结果见表15-2和表15-3。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.

表15-1：处方F40和F58加速稳定性过程有关物质结果
Table 15-1: Results of related substances in the accelerated stability process of formulations F40 and F58

表15-2：处方F40和F58加速稳定性过程药物释放结果(％)

Table 15-2: Drug release results of accelerated stability process of formulations F40 and F58 (%)

表15-3：处方F40和F58加速稳定性过程药物释放结果(％)
Table 15-3: Drug release results of accelerated stability process of formulations F40 and F58 (%)

表15-1、表15-2和表15-3中结果表明：本发明制备得到的一种盐酸鲁拉西酮制剂F40，0天至加速6个月的有关物质稳定，没有增长；单独pH 6.8介质和耐酸半小时转pH 6.8介质中F40的溶出稳定性较好，F58单独pH 6.8介质和耐酸半小时转pH 6.8介质的溶出稳定性较差。The results in Tables 15-1, 15-2 and 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, and there is no increase; the dissolution stability of F40 in a single pH 6.8 medium and an acid-resistant medium converted to pH 6.8 for half an hour is good, and the dissolution stability of F58 in a single pH 6.8 medium and an acid-resistant medium converted to pH 6.8 for half an hour is poor.

实施例16：比格犬体内的药物代谢动力学研究Example 16: Pharmacokinetic Study in Beagle Dogs

比格犬PK研究：将处方F78、F79和参比制剂(商品名：Latuda)进行比格犬的三制剂交叉药动学实验(健康比格犬18只，雌雄各半，分为3组，每组6只，进食和空腹，一天给药1次)，考察食物对其药动的影响。其中空腹条件下采用五肽胃泌素(用于促进胃酸分泌，比格犬空腹条件下胃pH4-6，人体空腹条件下胃pH 1.3)预处理。LC-MS-MS检测比格犬血浆中鲁拉西酮的含量，并采用WinNonlin 6.3软件非房室模型法计算药动学参数。结果如表16和图20。Beagle PK study: The prescriptions F78, F79 and the reference preparation (trade name: Latuda) were subjected to a three-preparation crossover pharmacokinetic experiment in beagles (18 healthy beagles, half male and half female, divided into 3 groups, 6 in each group, fed and fasted, once a day) to investigate the effect of food on their pharmacokinetic. Among them, pentagastrin (used to promote gastric acid secretion, gastric pH 4-6 under fasting conditions for beagles, gastric pH 1.3 under fasting conditions for humans) was used for pretreatment. LC-MS-MS was used to detect the content of lurasidone in beagle plasma, and the pharmacokinetic parameters were calculated using the non-compartmental model method using WinNonlin 6.3 software. The results are shown in Table 16 and Figure 20.

表16：处方F78、F79和参比制剂在比格犬体内的药代动力学

Table 16: Pharmacokinetics of Formulations F78, F79, and Reference Products in Beagle Dogs

审评报告报道，食物可以显著提高盐酸鲁拉西酮的生物利用度。由上表可知，参比制剂在比格犬中空腹时暴露量和Cmax与进食时差异较大，进食暴露量为空腹的2.50倍，进食Cmax为空腹的3.25倍，食物效应较为显著。处方F79进食暴露量为空腹的1.02倍，进食Cmax为空腹的1.07倍，且生物利用度相比参比制剂有所提高。而处方F78进食暴露量为空腹的1.07倍，进食Cmax为空腹的1.21倍，且生物利用度相比参比制剂有所提高。The review report reported that food can significantly increase the bioavailability of lurasidone hydrochloride. As can be seen from the table above, the exposure and Cmax of the reference preparation in beagle dogs when fasting are quite different from those when fed. The exposure after feeding is 2.50 times that of fasting, and the Cmax after feeding is 3.25 times that of fasting. The food effect is more significant. The exposure of prescription F79 after feeding is 1.02 times that of fasting, and the Cmax after feeding is 1.07 times that of fasting, and the bioavailability is improved compared with the reference preparation. The exposure of prescription F78 after feeding is 1.07 times that of fasting, and the Cmax after feeding is 1.21 times that of fasting, and the bioavailability is improved compared with the reference preparation.

进一步对比处方F78和F79在单独pH6.8介质和耐酸半小时转pH6.8介质的溶出数据，说明采用流化床工艺进行固化，表面活性剂聚氧乙烯40氢化蓖麻油(Kolliphor RH40)的加入能改善体内吸收，食物效应下降。Further comparison of the dissolution data of prescriptions 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 addition of surfactant Kolliphor RH40 (Kolliphor RH40) during solidification using fluidized bed process could improve in vivo absorption and reduce food effect.

在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means 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 may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。 Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

A composition, characterized in that it comprises lurasidone hydrochloride and a carrier;

Wherein, the carrier comprises:

Soluplus, and

At least one of HPMCAS HG and HPMCAS HF.

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).

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%.

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, K ₂ SO ₄ and KH ₂ PO ₄ ;

Optionally, the weight ratio of lurasidone hydrochloride to the inorganic salt is 1:(0.1-2), preferably 1:(0.5-1).

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.

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,

80-200 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

80-200 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).

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.

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,

80-140 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,

80-140 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,

80-140 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,

80-140 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,

10-20 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,

10-20 parts by weight of Kolliphor RH40, and

30-40 parts by weight of K ₂ SO ₄ ;

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,

10-20 parts by weight of Kolliphor RH40, and

30-40 parts by weight of KH ₂ PO ₄ .

A method for preparing the composition according to any one of claims 1 to 8, characterized in that it comprises:

The carrier and lurasidone hydrochloride are mixed to obtain the composition.

The method according to claim 9, further comprising: 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.