CN117979957A - Injectable sustained-release antipsychotic composition - Google Patents

Abstract

A long-acting injectable sustained release composition is provided having at least a drug, a solvent, and a PLGA copolymer. The composition exhibits improved pharmaceutical properties due to the use of advantageous grades of PLGA with improved particle size distribution.

Description

Translated fromChinese

可注射缓释抗精神病组合物Injectable sustained-release antipsychotic composition

技术领域Technical Field

本专利申请涉及用于施用抗精神病药物利培酮和用于治疗利培酮或帕利哌酮反应性病症的可注射缓释组合物。该组合物特别适合于肌内施用，并且原位形成在约28天或更长时间内释放利培酮的植入物。该组合物在重构期间表现出团聚减少和重构时间缩短，并且包含由其粒度分布限定的特别有利等级的PLGA。This patent application relates to an injectable sustained-release composition for administering the antipsychotic drug risperidone and for treating risperidone or paliperidone-responsive conditions. The composition is particularly suitable for intramuscular administration and forms an implant that releases risperidone in about 28 days or longer in situ. The composition exhibits reduced agglomeration and shortened reconstitution time during reconstitution and comprises a particularly advantageous grade of PLGA defined by its particle size distribution.

背景技术Background Art

利培酮及其主要活性代谢物9-羟利培酮(帕利哌酮)适用于治疗精神病性障碍，诸如精神分裂症、分裂情感性障碍、双相情感障碍和双相躁狂症。利培酮可以市售片剂、溶液剂或口腔崩解片剂等剂型经口服给药。Risperidone and its major active metabolite 9-hydroxyrisperidone (paliperidone) are suitable for the treatment of psychotic disorders such as schizophrenia, schizoaffective disorder, bipolar disorder and bipolar mania. Risperidone can be administered orally in the form of commercially available tablets, solutions or orally disintegrating tablets.

已知有以下LAI储库型组合物：授予Siegel等人的专利US 8,221,778(对应于WO2005/070332)；授予Dunn的专利US 5,688,801、US 6,803,055、US 5,770,231、US 7,118,763和US 4,389,330；授予Brodebeck的专利US 4,530,840和US 6,673,767；授予Chandrashekar的专利US 6,143,314；授予QLT USA的专利WO 2004/081196、WO 2001/035929和WO 2008/153611 A2；授予Laboratorios Farmaceuticos ROVI,S.A.的专利WO2000/024374、WO 2002/038185、WO 2008/100576和WO 2011/151355 A1；授予GutierroAduriz的专利WO 2011/42453和US10085936；授予Gutierro Aduriz的专利US10463607；授予Gutierro Aduriz的专利US10182982；授予Gutierro Aduriz的专利US2020/0085728 A1；授予Laboratorios Farmaceuticos ROVI,S.A.的专利EP 2394664 A1；授予LaboratoriosFarmaceuticos ROVI,S.A.的专利WO 2011/151355 A1；授予Gutierro Aduriz的专利US10058504；授予Gutierro Aduriz的专利US10881605；授予Gutierro Aduriz的专利US10195138；授予Laboratorios Farmaceuticos ROVI,S.A.的专利US2021/0077380A1；授予Laboratorios Farmaceuticos ROVI,S.A.的专利EP 2394663 A1；授予LaboratoriosFarmaceuticos ROVI,S.A.的专利WO 2011/151356A2；授予Gutierro Aduriz的专利US10350159；授予Laboratorios Farmaceuticos ROVI,S.A.的专利US2019/0328654 A1；授予Laboratorios Farmaceuticos ROVI,S.A.的专利EP 2529757 A1；授予LaboratoriosFarmaceuticos ROVI,S.A.的专利WO 2013/178811 A1；授予Gutierro Aduriz的专利US10335366；授予Laboratorios Farmaceuticos ROVI,S.A.的专利US2019/0254960 A1；授予Gutierro Aduriz的专利US11007139；授予Laboratorios Farmaceuticos ROVI,S.A.的专利EP 2529756 A2；授予Laboratorios Farmaceuticos ROVI,S.A.的专利WO 2013/178812 A1；授予Wright的专利US2008/0287464 A1；授予McKay的专利US2009/0264491 A1；授予Bodmeier的专利US 2004/0010224A1；授予Luk的专利US2007/0077304 A1；授予Jain的专利US2010/0015195 A1；授予Dadey的专利US2010/0266655 A1；授予Alkermes的专利WO95/29664；授予Alza的专利WO 2004/011054A2；授予Luk的专利WO 2007/041410 A2；授予Bourges的专利WO 2008/059058 A1；以及授予Schoenhammer的专利WO 2010/018159A1。The following LAI reservoir compositions are known: US 8,221,778 to Siegel et al. (corresponding to WO 2005/070332); US 5,688,801, US 6,803,055, US 5,770,231, US 7,118,763 and US 4,389,330 to Dunn; US 4,530,840 and US 6,673,767 to Brodebeck; US 6,143,314 to Chandrashekar; WO 2004/081196, WO 2001/035929 and WO 2008/153611 A2 to QLT USA; WO 2000/024374, WO 2001/035929 and WO 2008/153611 A2 to Laboratorios Farmaceuticos ROVI, S.A. 2002/038185, WO 2008/100576 and WO 2011/151355 A1; WO 2011/42453 and US10085936 granted to Gutierro Aduriz; US10463607 granted to Gutierro Aduriz; US10182982 granted to Gutierro Aduriz; US2020/0085728 A1 granted to Gutierro Aduriz; EP 2394664 A1 granted to Laboratorios Farmaceuticos ROVI, S.A.; WO 2011/151355 A1 granted to Laboratorios Farmaceuticos ROVI, S.A.; US10058504 granted to Gutierro Aduriz; Aduriz’s patent US10881605; Gutierro Aduriz’s patent US10195138; Laboratorios Farmaceuticos ROVI, S.A.’s patent US2021/0077380A1; Laboratorios Farmaceuticos ROVI, S.A.’s patent EP 2394663 A1; Laboratorios Farmaceuticos ROVI, S.A.’s patent WO 2011/151356A2; Gutierro Aduriz’s patent US10350159; Laboratorios Farmaceuticos ROVI, S.A.’s patent US2019/0328654 A1; Laboratorios Farmaceuticos ROVI, S.A.’s patent EP 2529757 A1; Laboratorios Farmaceuticos Patent WO 2013/178811 A1 to ROVI, S.A.; Patent US10335366 to Gutierro Aduriz; Patent US2019/0254960 A1 to Laboratorios Farmaceuticos ROVI, S.A.; Patent US11007139 to Gutierro Aduriz; Patent EP 2529756 A2 to Laboratorios Farmaceuticos ROVI, S.A.; Patent WO 2013/178812 A1 to Laboratorios Farmaceuticos ROVI, S.A.; Patent US2008/0287464 A1 to Wright; Patent US2009/0264491 A1 to McKay; Patent US 2004/0010224A1; US2007/0077304 A1 to Luk; US2010/0015195 A1 to Jain; US2010/0266655 A1 to Dadey; WO95/29664 to Alkermes; WO 2004/011054A2 to Alza; WO 2007/041410 A2 to Luk; WO 2008/059058 A1 to Bourges; and WO 2010/018159A1 to Schoenhammer.

两种含有利培酮的此类LAI药品已获得美国食品药品监督管理局批准。Two such LAI drug products containing risperidone have been approved by the U.S. Food and Drug Administration.

RISPERDAL(NDA N021346；剂量强度：12.5mg/瓶、25mg/瓶、37.5mg/瓶和50mg/瓶；US 6596316、US 6379703、US 6194006、WO 2000/40221)是一种含有利培酮的肌内施用PLGA微粒制剂，旨在通过每两周施用一次来递送治疗水平的利培酮。然而，由于大多数微粒型药品固有的滞后期，在首次施用后的前几周内，患者需按量每日口服利培酮作为补充，即口服补充剂。在单次肌内注射RISPERDAL且同时每日按量口服利培酮后约3周，体循环中的微球体才能释放出充足的利培酮，此时患者方可停止每日按量口服补充治疗。然而，口服补充用药期间可能出现未能按方案进行治疗的风险。而且，体内同时存在两种剂量，可能带来引起不良反应的潜在风险，诸如制剂作用不规律和药物毒性。RISPERDAL (NDA N021346; dosage strengths: 12.5 mg/vial, 25 mg/vial, 37.5 mg/vial and 50 mg/vial; US 6596316, US 6379703, US 6194006, WO 2000/40221) is an intramuscular PLGA microparticle formulation containing risperidone, designed to deliver therapeutic levels of risperidone via biweekly administration. However, due to the inherent lag phase of most microparticle-based drug products, patients need to take daily oral risperidone as a supplement, i.e., oral supplementation, for the first few weeks after the first administration. At the same time, it takes about 3 weeks for the microspheres in the systemic circulation to release sufficient risperidone after daily oral administration of risperidone, at which time the patient can stop daily oral supplementation. However, there may be a risk of failure to follow the treatment plan during oral supplementation. Moreover, the presence of two doses in the body at the same time may bring potential risks of adverse reactions, such as irregular preparation action and drug toxicity.

(NDA N210655；剂量强度：每剂90mg和120mg；US 9180197、US9186413、US 9597402、US10010612、US10058554、US10376590、US10406160)是一种含有利培酮的缓释制剂，旨在用于皮下施用到脂肪组织。 (NDA N210655; dosage strengths: 90 mg and 120 mg per dose; US 9180197, US9186413, US 9597402, US10010612, US10058554, US10376590, US10406160) is a sustained-release formulation containing risperidone intended for subcutaneous administration to adipose tissue.

另一种含有利培酮的LAI药品仍在接受用于治疗精神分裂症的临床评价：Correll等人(NPJ Schizophrenia(2020年11月25日)，6:37)，Edison Investment ResearchLimited(Doria三期试验取得主要疗效指标(Doria Phase III Trial hits primaryendpoint)，Laboratorios Farmaceuticos ROVI,S.A.，2019年3月19日，www.edisongroup.com/publication/doria-phase-iii-trial-hits-primary-endpoint/23705/)，NCT02086786、NCT03160521、NCT01788774、NCT01320410、NCT03870880、NCT03160521、NCT01788774；和Anta等人(利培酮新制剂：关于利培酮ISM的评论(Newerformulations of risperidone:remarks about Risperidone ISM)，CNSDrugs(2020年9月5日)；doi.org/10.1007/s40263-020-00762-0)。这些出版物中没有公开该药品的成分。Another LAI containing risperidone is still undergoing clinical evaluation for the treatment of schizophrenia: Correll et al (NPJ Schizophrenia (November 25, 2020), 6:37), Edison Investment Research Limited (Doria Phase III Trial hits primary endpoint), Laboratorios Farmaceuticos ROVI, S.A., March 19, 2019, www.edisongroup.com/publication/doria-phase-iii-trial-hits-primary-endpoint/23705/), NCT02086786, NCT03160521, NCT01788774, NCT01320410, NCT03870880, NCT03160521, NCT01788774; and Anta et al. (Newer formulations of risperidone: remarks about Risperidone ISM), CNSDrugs (September 5, 2020); doi.org/10.1007/s40263-020-00762-0). The ingredients of the drug product were not disclosed in these publications.

授予Brodbeck的专利U.S.6,331,311还公开了可注射储库型组合物，其包含诸如PLGA等生物相容性聚合物、诸如N-甲基-2-吡咯烷酮等溶剂和诸如药物等有益剂，还包含诸如多元醇等乳化剂。然而，当该有益剂是利培酮时，所公开的组合物不会良好发挥作用。Patent U.S. 6,331,311 to Brodbeck also discloses an injectable depot composition comprising a biocompatible polymer such as PLGA, a solvent such as N-methyl-2-pyrrolidone, and a beneficial agent such as a drug, and an emulsifier such as a polyol. However, when the beneficial agent is risperidone, the disclosed composition does not work well.

授予Dunn等人的专利U.S.4,938,763公开了一种用于可注射原位形成植入物的方法。将与生物活性剂一起溶解在水混溶性溶剂中的生物可降解聚合物或共聚物溶解或分散在聚合物溶液中。一旦该聚合物溶液接触体液，溶剂就会扩散，聚合物就会固化，从而将药物包埋在聚合物基质内。即使Dunn等人公开了使用水混溶性溶剂来获得原位形成聚合物植入物，但其公开了多种聚合物和溶剂甚至不同成分比例，这些聚合物和溶剂甚至不同成分比例不会产生具有适当释放特性的良好植入物，特别是当该植入物含有利培酮作为活性成分时。Patent U.S.4,938,763 to Dunn et al. discloses a method for injectable in situ forming implants. A biodegradable polymer or copolymer dissolved in a water-miscible solvent together with a bioactive agent is dissolved or dispersed in a polymer solution. Once the polymer solution contacts body fluids, the solvent diffuses and the polymer solidifies, thereby embedding the drug in the polymer matrix. Even though Dunn et al. disclose the use of water-miscible solvents to obtain in situ forming polymer implants, they disclose a variety of polymers and solvents and even different component ratios, which do not produce good implants with appropriate release characteristics, especially when the implant contains risperidone as an active ingredient.

用于可注射缓释组合物的PLGA共聚物的粒度尚未被认可与通过粉末重构(即通过将溶剂与粉末状药物和粉末状PLGA共聚物混合)制备LAI缓释组合物相关。The particle size of PLGA copolymers for injectable sustained-release compositions has not been recognized to be relevant for the preparation of LAI sustained-release compositions by powder reconstitution (ie, by mixing a solvent with the powdered drug and the powdered PLGA copolymer).

在对含有DMSO、PLGA和利培酮的对照药LAI储库型组合物进行重构和临床评价的过程中，本发明人在未公开的工作中发现了重大药物潜力限制。研究发现，当通过将DMSO与PLGA和利培酮的粉末状混合物混合来重构粉末时，粉末会发生团聚，从而在临床使用环境中造成潜在障碍，例如施用延迟和/或在施用前PLGA聚合物不完全溶解等。施用前在临床目标混合时间内PLGA不完全溶解尤其成问题，因为它最终可能会对相应固体植入物(释放药物)的性能产生负面影响，从而可能改变活性部分血浆分布并影响疗效。During the reconstitution and clinical evaluation of a control drug LAI reservoir composition containing DMSO, PLGA and risperidone, the inventors discovered significant drug potential limitations in unpublished work. It was found that when the powder was reconstituted by mixing DMSO with a powdered mixture of PLGA and risperidone, the powder agglomerates, causing potential obstacles in the clinical use environment, such as delayed administration and/or incomplete dissolution of the PLGA polymer before administration. Incomplete dissolution of PLGA within the clinical target mixing time before administration is particularly problematic because it may ultimately have a negative impact on the performance of the corresponding solid implant (releasing the drug), thereby potentially changing the plasma distribution of the active portion and affecting the efficacy.

期望提供一种用于形成可注射缓释组合物(或长效可注射储库型组合物)的试剂盒，其中，粉末状PLGA和利培酮在与DMSO混合期间的团聚被减少或消除，并且其中，粉末状PLGA的溶解速率(速度)最大化。换言之，减少完全溶解PLGA所需的时间或使其最小化。此类试剂盒和相应的粉末状材料将有助于减少临床环境中的相关障碍或使其最小化。It is desirable to provide a kit for forming an injectable sustained-release composition (or a long-acting injectable reservoir composition), wherein the agglomeration of powdered PLGA and risperidone during mixing with DMSO is reduced or eliminated, and wherein the dissolution rate (speed) of powdered PLGA is maximized. In other words, the time required for completely dissolving PLGA is reduced or minimized. Such kits and corresponding powdered materials will help reduce or minimize the associated obstacles in clinical settings.

发明内容Summary of the invention

本发明试图克服包含利培酮和/或帕利哌酮的其他可注射缓释组合物的缺点和/或提供改进。本发明包括可注射缓释或储库型组合物、由所述可注射缓释组合物形成的植入物、用于形成(制备)所述植入物的方法、包含用于形成所述可注射缓释组合物的组分的试剂盒、用于制备所述可注射缓释组合物的方法、所述组合物、植入物或试剂盒的治疗用途、用于通过施用所述可注射缓释组合物来施用利培酮和/或帕利哌酮的方法，以及通过施用所述可注射缓释组合物来治疗利培酮和/或帕利哌酮治疗反应性疾病、病症或障碍的方法。The present invention seeks to overcome the disadvantages of other injectable sustained-release compositions containing risperidone and/or paliperidone and/or provide improvements. The present invention includes an injectable sustained-release or reservoir composition, an implant formed from the injectable sustained-release composition, a method for forming (preparing) the implant, a kit comprising components for forming the injectable sustained-release composition, a method for preparing the injectable sustained-release composition, therapeutic uses of the composition, implant or kit, a method for administering risperidone and/or paliperidone by administering the injectable sustained-release composition, and a method for treating risperidone and/or paliperidone-responsive diseases, conditions or disorders by administering the injectable sustained-release composition.

本发明提供了一种用于递送利培酮或另一种抗精神病药物的改进型长效可注射(LAI)储库型组合物。该组合物包含改进级PLGA聚合物，与其他可注射缓释组合物中使用的各等级PLGA相比，该改进级PLGA聚合物具有有利的粒度分布(表现出改进的性能)。The present invention provides an improved long-acting injectable (LAI) reservoir composition for delivering risperidone or another antipsychotic drug. The composition comprises an improved grade of PLGA polymer having a favorable particle size distribution (showing improved performance) compared to various grades of PLGA used in other injectable sustained-release compositions.

本发明涉及一种含有利培酮或含有帕利哌酮的组合物，该组合物适合于形成一个或多个原位肌内植入物，该植入物能够连续维持所需的活性部分(利培酮和/或帕利哌酮)血浆水平达约28天或28+/-5天或28+/-4天或28+/-3天或28+/-2天或28+/-1天或约26-33天或约28-33天。而且，该组合物表现出改进的治疗性能。本文所用术语“植入物”是指基于包埋药物颗粒的固态稳定聚合物基质系统的形成的组合物。该术语用于避免与术语“微粒”混淆，微粒通常是指通过溶剂蒸发或喷雾干燥技术获得的预成型聚合物微粒。本发明的组合物含有悬浮在聚合物溶液中的药物颗粒，在注射时，随着溶剂扩散和聚合物沉淀形成含有药物颗粒的基质，这些药物颗粒被原位包埋在固体聚合物基质中。本文所用术语“植入物”是指储库型或缓释组合物，因为本发明的组合物是一种可注射储库型组合物，特别是在注射时形成缓释储库的缓释可注射组合物。LAI储库型组合物也被视为一种包含悬浮在DMSO和PLGA聚合物溶液中的利培酮颗粒的可注射混悬液(或缓释可注射组合物)，其中，该LAI储库型组合物在施用后形成缓释组合物或储库(植入物)。本文所用术语“储库型”、“缓释”、“延长释放”或“持续释放”不加区别地指含有悬浮在聚合物溶液中的药物颗粒的组合物，在注射时，随着溶剂扩散和聚合物沉淀形成含有药物颗粒的基质，这些药物颗粒被原位包埋在固体聚合物基质中，和/或指形成沉积物的组合物，药物从该沉积物中持续或延长释放。因此，为了本发明的目的，术语“储库型”、“缓释”、“延长释放”或“持续释放”在本文中具有相同含义，可互换使用。The present invention relates to a composition containing risperidone or containing paliperidone, which is suitable for forming one or more in situ intramuscular implants, which can continuously maintain the desired plasma level of active part (risperidone and/or paliperidone) for about 28 days or 28+/-5 days or 28+/-4 days or 28+/-3 days or 28+/-2 days or 28+/-1 day or about 26-33 days or about 28-33 days. Moreover, the composition shows improved therapeutic properties. The term "implant" used herein refers to a composition formed based on a solid stable polymer matrix system that embeds drug particles. This term is used to avoid confusion with the term "microparticles", which generally refer to preformed polymer microparticles obtained by solvent evaporation or spray drying technology. The composition of the present invention contains drug particles suspended in a polymer solution. When injected, a matrix containing drug particles is formed as the solvent diffuses and the polymer precipitates, and these drug particles are embedded in the solid polymer matrix in situ. The term "implant" as used herein refers to a reservoir or sustained-release composition, because the composition of the present invention is an injectable reservoir composition, particularly a sustained-release injectable composition that forms a sustained-release reservoir when injected. The LAI reservoir composition is also considered to be an injectable suspension (or sustained-release injectable composition) comprising risperidone particles suspended in a DMSO and PLGA polymer solution, wherein the LAI reservoir composition forms a sustained-release composition or reservoir (implant) after administration. The terms "reservoir", "slow-release", "extended release" or "sustained release" as used herein refer indiscriminately to a composition containing drug particles suspended in a polymer solution, which, when injected, forms a matrix containing drug particles as the solvent diffuses and the polymer precipitates, and these drug particles are embedded in a solid polymer matrix in situ, and/or to a composition that forms a deposit, from which the drug is continuously or extendedly released. Therefore, for the purposes of the present invention, the terms "reservoir", "slow-release", "extended release" or "sustained release" have the same meaning herein and are used interchangeably.

在施用后，该可注射储库型或缓释组合物从一开始并在至少约28天的时间内连续提供活性部分治疗血浆水平。其无需口服补充利培酮或帕利哌酮，也无需口服利培酮或口服帕利哌酮的负荷剂量来达到活性部分的目标稳态血浆浓度。与使用含有利培酮的其他LAI(长效可注射)储库型组合物不同，本发明的组合物还提供以下优点：在利培酮口服给药方案终止后，通过施用如本文所定义的LAI储库型组合物，可以维持活性部分的治疗血浆浓度。而且，与使用含有利培酮的其他LAI储库型组合物不同，本发明的组合物还提供以下优点：在LAI储库型组合物给药方案终止后，可通过口服施用每日一次剂量的利培酮来维持活性部分的治疗血浆浓度。从给药期的第一天到最后一天均提供治疗水平的活性部分。After administration, the injectable reservoir or sustained-release composition provides therapeutic plasma levels of the active moiety from the beginning and continuously for at least about 28 days. It does not require oral supplementation of risperidone or paliperidone, nor does it require a loading dose of oral risperidone or oral paliperidone to achieve the target steady-state plasma concentration of the active moiety. Unlike the use of other LAI (long-acting injectable) reservoir compositions containing risperidone, the composition of the present invention also provides the following advantages: after the risperidone oral dosing regimen is terminated, the therapeutic plasma concentration of the active moiety can be maintained by administering the LAI reservoir composition as defined herein. Moreover, unlike the use of other LAI reservoir compositions containing risperidone, the composition of the present invention also provides the following advantages: after the LAI reservoir composition dosing regimen is terminated, the therapeutic plasma concentration of the active moiety can be maintained by oral administration of a once-daily dose of risperidone. Therapeutic levels of the active moiety are provided from the first day of the dosing period to the last day.

本发明采用每约28天肌内施用一次75-100mg或25-150mg利培酮(经由如本文所述的LAI储库型组合物)的给药方案。它无需像RISPERDAL CONSTA那样口服补充利培酮。与RISPERDAL CONSTA和PERSERIS不同，它从施用第一天(施用后2-24小时内或8-24小时内)到约27-31天或约27-29天提供治疗有效的利培酮血浆浓度。The present invention adopts a dosing regimen of 75-100 mg or 25-150 mg of risperidone (via a LAI reservoir composition as described herein) administered intramuscularly once every about 28 days. It does not require oral supplementation of risperidone as RISPERDAL CONSTA does. Unlike RISPERDAL CONSTA and PERSERIS, it provides therapeutically effective risperidone plasma concentrations from the first day of administration (within 2-24 hours or within 8-24 hours after administration) to about 27-31 days or about 27-29 days.

通过控制PLGA聚合物的粒度分布，实现了试剂盒、可注射缓释组合物和相应植入物性能的改进。根据先验预测，粒度分布与试剂盒、LAI储库型组合物或由其形成的植入物的性能无关，因为当在施用前制备可注射组合物时，聚合物大概完全溶解在溶剂中。然而，本发明人发现，事实上，聚合物的粒度会影响PLGA/药物混合物的溶解和LAI储库型组合物的临床适用性，并且可能会影响药物从施用LAI储库型组合物后所形成的相应植入物中释放。值得注意的是，这些类型的组合物需要在施用前快速且完全地重构。By controlling the particle size distribution of the PLGA polymer, improvements in the performance of the kit, injectable sustained-release composition and corresponding implants are achieved. According to a priori predictions, the particle size distribution is unrelated to the performance of the kit, the LAI reservoir composition or the implant formed therefrom, because when the injectable composition is prepared before administration, the polymer is approximately completely dissolved in the solvent. However, the inventors have found that, in fact, the particle size of the polymer affects the dissolution of the PLGA/drug mixture and the clinical applicability of the LAI reservoir composition, and may affect the release of the drug from the corresponding implant formed after the LAI reservoir composition is administered. It is worth noting that these types of compositions need to be quickly and completely reconstituted before administration.

本发明所用的PLGA(聚乳酸-乙醇酸)共聚物的粒度分布如下：a)粒度质量分布，其中，当根据USP<786>进行筛分分析测量时，不超过10％的颗粒的粒度大于300μm，优选地不大于250μm；b)粒度体积分布，其中，当进行激光衍射分析测量时，D90不大于300μm，优选地不大于280μm；c)粒度质量分布，其中，当根据USP<786>进行筛分分析测量时，不超过10％的颗粒的粒度大于300μm，优选地不大于250μm，并且其中不超过70％的颗粒的粒度小于150μm；d)粒度质量分布，其中，当根据USP<786>进行筛分分析测量时，不超过70％的颗粒的粒度小于150μm；e)粒度体积分布，其中，当进行激光衍射分析测量时，D90不大于300μm，优选地不大于280μm，并且当进行激光衍射分析测量时，D80不小于135μm；f)粒度体积分布，其中，当进行激光衍射分析测量时，D80不小于135μm；g)D50为约50-150μm；h)D10为约10-50μm；i)D90为约170-300μm；并且/或者j)D50为约50-150μm，D10为约10-50μm，且D90为约170-300μm。本发明考虑了具有这些粒度分布中的两种或更多种的组合的PLGA等级。The particle size distribution of the PLGA (polylactic acid-glycolic acid) copolymer used in the present invention is as follows: a) a particle size mass distribution, wherein, when measured by sieve analysis according to USP<786>, no more than 10% of the particles have a particle size greater than 300 μm, preferably no more than 250 μm; b) a particle size volume distribution, wherein, when measured by laser diffraction analysis, D90 is no more than 300 μm, preferably no more than 280 μm; c) a particle size mass distribution, wherein, when measured by sieve analysis according to USP<786>, no more than 10% of the particles have a particle size greater than 300 μm, preferably no more than 250 μm, and no more than 70% of the particles have a particle size less than 150 μm; d) a particle size mass distribution, wherein, when measured by sieve analysis according to USP<786>, no more than 10% of the particles have a particle size greater than 300 μm, preferably no more than 250 μm, and no more than 70% of the particles have a particle size less than 150 μm. USP<786> When measured by sieve analysis, no more than 70% of the particles have a particle size of less than 150 μm; e) a particle size volume distribution wherein, when measured by laser diffraction analysis, D90 is no greater than 300 μm, preferably no greater than 280 μm, and when measured by laser diffraction analysis, D80 is no less than 135 μm; f) a particle size volume distribution wherein, when measured by laser diffraction analysis, D80 is no less than 135 μm; g) a D50 of about 50-150 μm; h) a D10 of about 10-50 μm; i) a D90 of about 170-300 μm; and/or j) a D50 of about 50-150 μm, a D10 of about 10-50 μm, and a D90 of about 170-300 μm. The present invention contemplates PLGA grades having a combination of two or more of these particle size distributions.

本发明的优选实施方案包括其中PLGA具有如下粒度质量分布的组合：D10的范围为约10μm至约50μm，D50的范围为约50μm至约150μm，并且D90的范围为约170μm至约300μm。Preferred embodiments of the invention include combinations wherein the PLGA has a particle size mass distribution with a D10 ranging from about 10 μm to about 50 μm, a D50 ranging from about 50 μm to about 150 μm, and a D90 ranging from about 170 μm to about 300 μm.

在一些实施方案中，PLGA共聚物已经过粒度分级，即筛分和/或粉碎，以实现所需的粒度分布。合适的粉碎方法包括例如微粉化、碾磨、锤击、压碎、研磨、磨碎和/或粉碎PLGA。In some embodiments, the PLGA copolymer has been size-fractionated, ie, sieved and/or pulverized, to achieve a desired particle size distribution. Suitable pulverization methods include, for example, micronizing, milling, hammering, crushing, grinding, grinding and/or pulverizing the PLGA.

本发明还提供了药物和PLGA共聚物的粉末混合物，其中，该药物是利培酮、帕利哌酮或它们的混合物，并且PLGA共聚物具有如本文所定义的粒度质量分布和/或粒度体积分布。该粉末混合物可以包含在密封容器中，任选地进一步包含在药物试剂盒中。该混合物可以是无菌的，诸如通过β或γ辐射灭菌。The present invention also provides a powder mixture of a drug and a PLGA copolymer, wherein the drug is risperidone, paliperidone or a mixture thereof, and the PLGA copolymer has a particle size mass distribution and/or a particle size volume distribution as defined herein. The powder mixture can be contained in a sealed container, optionally further contained in a pharmaceutical kit. The mixture can be sterile, such as sterilized by beta or gamma radiation.

药物和PLGA的混合物可包含约25mg至约150mg、约25mg至约125mg、约25mg至约100mg、约50mg至约150mg、约50mg至约125mg、约50mg至约100mg、约75mg至约150mg、约75mg至约125mg、约75mg至约100mg、约25mg、约50mg、约75mg、约100mg、约125mg或约150mg药物，其可以是利培酮、帕利哌酮或它们的组合。The mixture of the drug and PLGA may contain about 25 mg to about 150 mg, about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 50 mg to about 150 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 75 mg to about 150 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg of the drug, which may be risperidone, paliperidone, or a combination thereof.

PLGA可以是无菌且可生物降解的热塑性共聚物，其乳酸与乙醇酸(即丙交酯与乙交酯)的单体比率为约50:50至约75:25、约45:55至约75:25、约45:55至约80:20、约65:35至约80:20、约70:30至约80:20；约50:50至约65:35、或约65:35至约75:25、约45:55至约55:45、或约48:52至约52:48、或约50:50，即50:50±10％，或75:25±10％。PLGA包含酸端基或其可被封端。端帽可以是酯基。PLGA可以通过β或γ辐射灭菌，或者如果PLGA以溶液形式灭菌，则可以通过过滤灭菌。PLGA can be a sterile and biodegradable thermoplastic copolymer having a monomer ratio of lactic acid to glycolic acid (i.e., lactide to glycolide) of about 50:50 to about 75:25, about 45:55 to about 75:25, about 45:55 to about 80:20, about 65:35 to about 80:20, about 70:30 to about 80:20; about 50:50 to about 65:35, or about 65:35 to about 75:25, about 45:55 to about 55:45, or about 48:52 to about 52:48, or about 50:50, i.e., 50:50 ± 10%, or 75:25 ± 10%. PLGA contains acid end groups or it can be capped. The end caps can be ester groups. PLGA can be sterilized by beta or gamma radiation, or if PLGA is sterilized in solution, it can be sterilized by filtration.

组合物中PLGA的固有粘度范围可为0.20-0.60dL/g、约0.3-0.58dL/g、约0.30-0.55dL/g、约0.36-0.52dL/g、约0.40-0.58dL/g、约0.36-0.43dL/g，或约0.46-0.51dL/g，在氯仿中于25℃或30℃下以0.1％wt/v或0.5％wt/v的浓度用乌氏0c或0b号玻璃毛细管粘度计测量，或在氯仿中于30℃下以0.5％wt/v的浓度用25号坎农-芬斯克玻璃毛细管粘度计测量(USP<911>粘度——毛细管法或《欧洲药典》第2.2.9.节中所述的毛细管粘度计法)。在一些实施方案中，PLGA已经过灭菌。The intrinsic viscosity of the PLGA in the composition can range from 0.20-0.60 dL/g, about 0.3-0.58 dL/g, about 0.30-0.55 dL/g, about 0.36-0.52 dL/g, about 0.40-0.58 dL/g, about 0.36-0.43 dL/g, or about 0.46-0.51 dL/g, measured at a concentration of 0.1% wt/v or 0.5% wt/v in chloroform at 25°C or 30°C using an Ubbelohde No. 0c or 0b glass capillary viscometer, or at a concentration of 0.5% wt/v in chloroform at 30°C using a No. 25 Cannon-Fenske glass capillary viscometer (USP <911> Viscosity - Capillary Method or the capillary viscometer method described in Section 2.2.9. of the European Pharmacopoeia). In some embodiments, the PLGA has been sterilized.

利培酮与(PLGA+利培酮)的质量比，表示为利培酮的重量相对于利培酮加PLGA的总重量的百分比，通常为约15-40％wt、约25-35％wt、约30-35％wt、约31-35％wt、约32-34％wt，或约33％wt。The mass ratio of risperidone to (PLGA + risperidone), expressed as the weight of risperidone relative to the total weight of risperidone plus PLGA, is typically about 15-40% wt, about 25-35% wt, about 30-35% wt, about 31-35% wt, about 32-34% wt, or about 33% wt.

本发明还提供了一种药物试剂盒，其包括第一容器和第二容器，其中，a)所述第一容器包含DMSO；b)所述第二容器包含药物和PLGA；其中，所述药物是利培酮、帕利哌酮或它们的组合，并且所述PLGA具有如本文所定义的粒度分布和单体比率。LAI储库型组合物通过混合上述容器的内容物而形成。The present invention also provides a drug kit, comprising a first container and a second container, wherein a) the first container comprises DMSO; b) the second container comprises a drug and PLGA; wherein the drug is risperidone, paliperidone or a combination thereof, and the PLGA has a particle size distribution and a monomer ratio as defined herein. The LAI reservoir composition is formed by mixing the contents of the above containers.

该药物试剂盒的另一个实施方案包括第一容器、第二容器和第三容器，其中，a)所述第一容器包含DMSO；b)所述第二容器包含选自利培酮、帕利哌酮或它们的组合的药物；c)所述第三容器包含具有如本文所定义的粒度分布和单体比率的粉末状PLGA。LAI储库型组合物通过混合上述容器的内容物而形成。Another embodiment of the drug kit comprises a first container, a second container and a third container, wherein a) the first container comprises DMSO; b) the second container comprises a drug selected from risperidone, paliperidone or a combination thereof; c) the third container comprises a powdered PLGA having a particle size distribution and a monomer ratio as defined herein. The LAI reservoir composition is formed by mixing the contents of the above containers.

在一些实施方案中，药物试剂盒包含约75mg药物(其为利培酮、帕利哌酮或它们的混合物)、约350mg DMSO和约150mg PLGA，该PLGA的L:G单体摩尔比为约45:55至约55:45(或约50:50)且具有如本文所定义的粒度分布。In some embodiments, the drug kit comprises about 75 mg of the drug (which is risperidone, paliperidone, or a mixture thereof), about 350 mg of DMSO, and about 150 mg of PLGA having a L:G monomer molar ratio of about 45:55 to about 55:45 (or about 50:50) and a particle size distribution as defined herein.

在一些实施方案中，药物试剂盒包含约100mg药物(其为利培酮、帕利哌酮或它们的混合物)、约467mg DMSO和约200mg PLGA，该PLGA的L:G单体摩尔比为约45:55至约55:45(或约50:50)且具有如本文所定义的粒度分布。In some embodiments, the drug kit comprises about 100 mg of the drug (which is risperidone, paliperidone, or a mixture thereof), about 467 mg DMSO, and about 200 mg PLGA having a L:G monomer molar ratio of about 45:55 to about 55:45 (or about 50:50) and a particle size distribution as defined herein.

在一些实施方案中，药物试剂盒包含过量的用于形成LAI储库型组合物的组分。In some embodiments, the pharmaceutical kit comprises an excess of components for forming a LAI depot composition.

对于100mg药物剂量强度，示例性药物试剂盒可包含约115mg(或约100-130mg或约105-125mg或约110-120mg)药物(其为利培酮、帕利哌酮或它们的混合物)、约537mg(或约515-560mg或约520-550mg或约530-545mg)DMSO和约230mg(或约215-245mg或约220-235mg)PLGA，该PLGA的L:G单体摩尔比为约45:55至约55:45(或约50:50)且具有如本文所定义的粒度分布。For a 100 mg drug dosage strength, an exemplary drug kit may include about 115 mg (or about 100-130 mg or about 105-125 mg or about 110-120 mg) of drug (which is risperidone, paliperidone, or a mixture thereof), about 537 mg (or about 515-560 mg or about 520-550 mg or about 530-545 mg) of DMSO, and about 230 mg (or about 215-245 mg or about 220-235 mg) of PLGA having a L:G monomer molar ratio of about 45:55 to about 55:45 (or about 50:50) and having a particle size distribution as defined herein.

对于75mg药物剂量强度，示例性药物试剂盒可包含约90mg(或约75-105mg或约80-100mg或约85-105mg)药物(其为利培酮、帕利哌酮或它们的混合物)、约420mg(或约405-435mg或约415-425mg)DMSO和约180mg(或约165-200mg或约170-190mg或约175-185mg)PLGA，该PLGA的L:G单体摩尔比为约45:55至约55:45(或约50:50)且具有如本文所定义的粒度分布。For a 75 mg drug dosage strength, an exemplary drug kit may comprise about 90 mg (or about 75-105 mg or about 80-100 mg or about 85-105 mg) of drug (which is risperidone, paliperidone, or a mixture thereof), about 420 mg (or about 405-435 mg or about 415-425 mg) of DMSO, and about 180 mg (or about 165-200 mg or about 170-190 mg or about 175-185 mg) of PLGA having a L:G monomer molar ratio of about 45:55 to about 55:45 (or about 50:50) and having a particle size distribution as defined herein.

本发明还提供了一种用于制备LAI储库型组合物的方法，该方法包括混合组分DMSO、药物和PLGA共聚物，从而形成所述组合物，其中，该PLGA的L:G单体(丙交酯单体:乙交酯单体)摩尔比为约45:55至约55:45(或约50:50)且具有如本文所定义的粒度分布。这些组分可以包含在多个容器中，并且可以包含在药物试剂盒中。The present invention also provides a method for preparing a LAI reservoir composition, the method comprising mixing components DMSO, a drug and a PLGA copolymer to form the composition, wherein the PLGA has a L:G monomer (lactide monomer: glycolide monomer) molar ratio of about 45:55 to about 55:45 (or about 50:50) and has a particle size distribution as defined herein. These components can be contained in multiple containers and can be contained in a pharmaceutical kit.

在一些实施方案中，将DMSO和PLGA混合以形成聚合物溶液，然后将该聚合物溶液与药物混合以形成LAI储库型组合物。不包含药物的聚合物溶液可以通过经由标称孔径为0.22μm或更小的过滤介质进行无菌过滤、或通过辐射、或通过它们的组合来灭菌。In some embodiments, DMSO and PLGA are mixed to form a polymer solution, which is then mixed with a drug to form a LAI depot composition. The polymer solution that does not contain a drug can be sterilized by sterile filtration through a filter medium with a nominal pore size of 0.22 μm or less, or by irradiation, or by a combination thereof.

在一些实施方案中，该用于制备LAI持续释放组合物的方法包括：a)将DMSO与PLGA和药物的粉末状混合物混合10分钟或更短时间、5分钟或更短时间、4分钟或更短时间、3分钟或更短时间、2分钟或更短时间、1分钟或更短时间、或者30秒或更短时间，从而形成所述LAI储库型组合物，其中，至少80％wt的药物悬浮在该组合物中，并且其中，PLGA完全溶解在该组合物中。当使用注射器作为容器时，通过将注射器彼此接合并根据需要重复推拉它们各自的柱塞来实现组分的混合。在一些实施方案中，这些柱塞被推拉200次(道次)或更少次数、150次或更少次数、100次或更少次数、75次或更少次数、或50次。推拉是指使液体从一个注射器流到另一个注射器。In some embodiments, the method for preparing a sustained-release LAI composition comprises: a) mixing DMSO with a powdered mixture of PLGA and a drug for 10 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, 1 minute or less, or 30 seconds or less, thereby forming the LAI reservoir composition, wherein at least 80%wt of the drug is suspended in the composition, and wherein PLGA is completely dissolved in the composition. When a syringe is used as a container, the mixing of the components is achieved by engaging the syringes with each other and repeatedly pushing and pulling their respective plungers as needed. In some embodiments, the plungers are pushed and pulled 200 times (passes) or less, 150 times or less, 100 times or less, 75 times or less, or 50 times. Pushing and pulling refers to causing a liquid to flow from one syringe to another.

当使用具有如本文所述的粒度分布特征等级的PLGA时，与使用包含具有超出这些粒度分布特征的PLGA的粉末状混合物相比，在与DMSO混合期间粉末状混合物不会发生团聚或团聚显著减少。因此，与使用其他等级的PLGA实现的效果相比，使用如本文所述的PLGA允许PLGA更快且完全溶解。When using a grade of PLGA having a particle size distribution characteristic as described herein, the powdered mixture does not agglomerate or agglomerates significantly less during mixing with DMSO than when using a powdered mixture containing PLGA having a particle size distribution characteristic exceeding these. Thus, using PLGA as described herein allows for faster and complete dissolution of PLGA than is achieved using other grades of PLGA.

在施用前，LAI储库型组合物的粘度范围通常为约1.0-7.0Pa.s、约1.5-7.0Pa.s或约1.8-6.5Pa.s，于25℃下使用锥板粘度计应用0.1-300Pa.s的剪切应力斜坡进行旋转流变测量测得(USP<912>粘度——旋转法或《欧洲药典》第2.2.10节中所述的粘度——旋转粘度计法)。除非另有说明，本说明书中所述的缓释(储库型)组合物或混悬液的表观粘度值应理解为于25℃下使用锥板粘度计应用0.1-300Pa.s的剪切应力斜坡进行旋转流变测量所得的值。Before administration, the viscosity of the LAI reservoir composition is generally in the range of about 1.0-7.0 Pa.s, about 1.5-7.0 Pa.s or about 1.8-6.5 Pa.s, measured by rotational rheological measurement using a cone and plate viscometer at 25°C with a shear stress slope of 0.1-300 Pa.s (USP <912> Viscosity - Rotational Method or Viscosity - Rotational Viscometer Method described in Section 2.2.10 of the European Pharmacopoeia). Unless otherwise specified, the apparent viscosity value of the sustained-release (reservoir) composition or suspension described in this specification should be understood as the value obtained by rotational rheological measurement using a cone and plate viscometer at 25°C with a shear stress slope of 0.1-300 Pa.s.

在一些实施方案中，DMSO与药物的质量比可为约5:1至约4:1、约4.6:1至约4.8:1、约4.6:1至约4.7:1、约4.67:1、约4.66:1或约4.68:1、或约4.66:1。In some embodiments, the mass ratio of DMSO to drug can be about 5:1 to about 4:1, about 4.6:1 to about 4.8:1, about 4.6:1 to about 4.7:1, about 4.67:1, about 4.66:1, or about 4.68:1, or about 4.66:1.

在一些实施方案中，LAI储库型组合物中DMSO相对于组合物总重量的含量可为约55-65％wt、约57-63％wt、约60-62％wt或约61％wt。In some embodiments, the content of DMSO in the LAI depot composition relative to the total weight of the composition can be about 55-65% wt, about 57-63% wt, about 60-62% wt, or about 61% wt.

在一些实施方案中，LAI储库型组合物中PLGA的浓度可为约24％-50％wt、约24％-40％wt、约25-27％wt或约26％wt(表示为聚合物重量相对于组合物总重量的百分比)。In some embodiments, the concentration of PLGA in the LAI depot composition can be about 24%-50% wt, about 24%-40% wt, about 25-27% wt, or about 26% wt (expressed as a percentage of polymer weight relative to the total weight of the composition).

在一些实施方案中，LAI储库型组合物中药物(特别是利培酮)相对于组合物总重量的含量可为约10-15％wt、约11-14％wt、约12-14％wt或约13％wt。In some embodiments, the content of the drug (particularly risperidone) in the LAI depot composition relative to the total weight of the composition may be about 10-15% wt, about 11-14% wt, about 12-14% wt, or about 13% wt.

LAI储库型组合物中所有组分的总和为100％。The sum of all components in the LAI depot composition is 100%.

在一些实施方案中，在施用前，LAI储库型组合物包含约75mg(或约65-85mg或约70-80mg)药物、DMSO和PLGA，其中，该药物的含量为约10-15％wt，DMSO的含量为约55-65％wt，PLGA的含量为约24-30％wt，并且PLGA的L:G单体比率为约45:55至55:45。In some embodiments, prior to administration, the LAI depot composition comprises about 75 mg (or about 65-85 mg or about 70-80 mg) of the drug, DMSO, and PLGA, wherein the drug is present at about 10-15% wt, the DMSO is present at about 55-65% wt, the PLGA is present at about 24-30% wt, and the L:G monomer ratio of the PLGA is about 45:55 to 55:45.

在一些实施方案中，在施用前，LAI储库型组合物包含约75mg(或约65-85mg或约70-80mg)药物、DMSO和PLGA，其中，该药物的含量为约12-14％wt，DMSO的含量为约57-63％wt，PLGA的含量为约25-27％wt，并且PLGA的L:G单体比率为约45:55至55:45。In some embodiments, prior to administration, the LAI depot composition comprises about 75 mg (or about 65-85 mg or about 70-80 mg) of the drug, DMSO, and PLGA, wherein the drug is present at about 12-14% wt, the DMSO is present at about 57-63% wt, the PLGA is present at about 25-27% wt, and the L:G monomer ratio of the PLGA is about 45:55 to 55:45.

在一些实施方案中，在施用前，LAI储库型组合物包含约100mg(或约85-115mg或约90-110mg或约95-105mg)药物、DMSO和PLGA，其中，该药物的含量为约10-15％wt，DMSO的含量为约55-65％wt，PLGA的含量为约24-30％wt，并且PLGA的L:G单体比率为约45:55至55:45。In some embodiments, prior to administration, the LAI depot composition comprises about 100 mg (or about 85-115 mg or about 90-110 mg or about 95-105 mg) of drug, DMSO and PLGA, wherein the drug is present at about 10-15% wt, the DMSO is present at about 55-65% wt, the PLGA is present at about 24-30% wt, and the L:G monomer ratio of the PLGA is about 45:55 to 55:45.

在一些实施方案中，在施用前，LAI储库型组合物包含约100mg(或约85-115mg或约90-110mg或约95-105mg)药物、DMSO和PLGA，其中，该药物的含量为约12-14％wt，DMSO的含量为约57-63％wt，PLGA的含量为约25-27％wt，并且PLGA的L:G单体比率为约45:55至55:45。In some embodiments, prior to administration, the LAI depot composition comprises about 100 mg (or about 85-115 mg or about 90-110 mg or about 95-105 mg) of drug, DMSO and PLGA, wherein the drug is present at about 12-14% wt, the DMSO is present at about 57-63% wt, the PLGA is present at about 25-27% wt, and the L:G monomer ratio of the PLGA is about 45:55 to 55:45.

在施用前和混合DMSO、药物和PLGA后，该药物可以部分溶解或基本上完全不溶解在LAI储库型组合物中。在一些实施方案中，a)在施用前，≤2.5％、≤5％、≤7.5％、≤10％、≤20％的药物溶解在所述组合物中；和/或b)在施用前，>0％、≥0.5％、≥1％、≥5％、≥10％、≥15％或至多约20％wt的药物溶解在所述组合物中。考虑了这些实施方案的所有组合。Prior to administration and after mixing DMSO, drug and PLGA, the drug may be partially dissolved or substantially completely insoluble in the LAI reservoir composition. In some embodiments, a) ≤2.5%, ≤5%, ≤7.5%, ≤10%, ≤20% of the drug is dissolved in the composition prior to administration; and/or b) >0%, ≥0.5%, ≥1%, ≥5%, ≥10%, ≥15%, or up to about 20%wt of the drug is dissolved in the composition prior to administration. All combinations of these embodiments are contemplated.

本发明还提供了一种用于施用药物的方法，该方法包括向受试者施用如本文所定义的LAI持续释放组合物。该方法还可以包括通过混合其各个组分来形成所述LAI持续释放组合物的步骤。该方法还可以包括提供如本文所定义的药物试剂盒。该药物如本文所定义。本发明还提供了如本文所定义的LAI储库型组合物，其用于治疗有此需要的受试者。此外，本发明提供了如本文所定义的LAI储库型组合物在药物制造中的用途。The present invention also provides a method for administering a drug, the method comprising administering to a subject a LAI sustained-release composition as defined herein. The method may also include a step of forming the LAI sustained-release composition by mixing its components. The method may also include providing a pharmaceutical kit as defined herein. The drug is as defined herein. The present invention also provides a LAI reservoir composition as defined herein for treating a subject in need thereof. In addition, the present invention provides the use of the LAI reservoir composition as defined herein in the manufacture of a drug.

LAI持续释放组合物可以经肌内或皮下施用。它也可以被施用到脂肪组织中。优选肌内施用至臀肌或三角肌。The LAI sustained release composition can be administered intramuscularly or subcutaneously. It can also be administered into adipose tissue. Preferably, it is administered intramuscularly into the gluteal or deltoid muscles.

本发明还提供了一种稳定的LAI持续释放组合物，其适合在施用于受试者后原位形成固体植入物，所述植入物包含约75mg至约100mg利培酮、PLGA和DMSO，其中，利培酮和PLGA包含在第一容器中，DMSO包含在第二容器中，其中，PLGA的浓度相对于生物相容性共聚物和溶剂的重量为20％wt至50％wt，其中，当进行激光衍射分析测量时，利培酮的粒度体积分布中D10等于或大于10μm、D50在60μm和130μm之间，并且D90小于或等于225μm，其特征在于，PLGA已经过粒度分级并且具有如本文所定义的粒度。The present invention also provides a stable LAI sustained-release composition suitable for forming a solid implant in situ after administration to a subject, wherein the implant comprises about 75 mg to about 100 mg of risperidone, PLGA and DMSO, wherein risperidone and PLGA are contained in a first container and DMSO is contained in a second container, wherein the concentration of PLGA is 20%wt to 50%wt relative to the weight of the biocompatible copolymer and the solvent, wherein, when measured by laser diffraction analysis, the particle size volume distribution of risperidone has D10 equal to or greater than 10 μm, D50 between 60 μm and 130 μm, and D90 less than or equal to 225 μm, characterized in that the PLGA has been size-graded and has a particle size as defined herein.

本发明还提供了一种用于治疗利培酮和/或帕利哌酮治疗反应性疾病、病症或障碍的方法，该方法包括向有此需要的受试者施用如本文所定义的LAI储库型组合物。该治疗方法可以包括用于制备该LAI储库型组合物的方法并且还可以包括用于施用该LAI储库型组合物的方法。本发明还提供了如本文所定义的LAI储库型组合物，其用于治疗利培酮和/或帕利哌酮治疗反应性疾病、病症或障碍。本发明还提供了如本文所定义的LAI储库型组合物在制造用于治疗利培酮和/或帕利哌酮治疗反应性疾病、病症或障碍的药物中的用途。The present invention also provides a method for treating a risperidone and/or paliperidone treatment-responsive disease, condition or disorder, the method comprising administering a LAI reservoir composition as defined herein to a subject in need thereof. The treatment method may include a method for preparing the LAI reservoir composition and may also include a method for administering the LAI reservoir composition. The present invention also provides a LAI reservoir composition as defined herein, which is used to treat a risperidone and/or paliperidone treatment-responsive disease, condition or disorder. The present invention also provides the use of a LAI reservoir composition as defined herein in the manufacture of a medicament for treating a risperidone and/or paliperidone treatment-responsive disease, condition or disorder.

本发明提供了一种用于治疗利培酮和/或帕利哌酮治疗反应性疾病、病症或障碍的方法，该方法包括制备LAI持续释放组合物，以及向有此需要的受试者施用该LAI储库型组合物，从而治疗所述疾病、病症或障碍。该方法还可以包括提供本文所述的药物试剂盒的步骤。本发明提供了如本文所定义的LAI储库型组合物，其用于治疗利培酮和/或帕利哌酮治疗反应性疾病、病症或障碍，包括制备该LAI储库型组合物，以及向有此需要的受试者施用该LAI储库型组合物，从而治疗所述疾病、病症或障碍。The present invention provides a method for treating a risperidone and/or paliperidone responsive disease, condition or disorder, the method comprising preparing a LAI sustained release composition, and administering the LAI reservoir composition to a subject in need thereof, thereby treating the disease, condition or disorder. The method may also include the step of providing a pharmaceutical kit as described herein. The present invention provides a LAI reservoir composition as defined herein, which is used to treat a risperidone and/or paliperidone responsive disease, condition or disorder, comprising preparing the LAI reservoir composition, and administering the LAI reservoir composition to a subject in need thereof, thereby treating the disease, condition or disorder.

在一些实施方案中，施用方法包括：a)提供药物试剂盒，其包含装有DMSO的容器和装有药物和PLGA的容器，其中，该PLGA具有如本文所述的粒度分布；b)通过混合该等容器内的组分来制备如本文所述的LAI储库型组合物，从而形成该LAI储库型组合物；以及c)向受试者施用该LAI储库型组合物。In some embodiments, the method of administration comprises: a) providing a drug kit comprising a container containing DMSO and a container containing a drug and PLGA, wherein the PLGA has a particle size distribution as described herein; b) preparing a LAI reservoir composition as described herein by mixing the components in the containers to form the LAI reservoir composition; and c) administering the LAI reservoir composition to a subject.

在一些实施方案中，治疗方法(或组合物的治疗用途)包括：a)提供药物试剂盒，其包含装有DMSO的容器和装有药物和PLGA的容器，其中，该PLGA具有如本文所述的粒度分布；b)通过混合该等容器内的组分来制备如本文所述的LAI储库型组合物，从而形成该LAI储库型组合物；以及c)向有此需要的受试者施用该LAI持续释放组合物。In some embodiments, the method of treatment (or therapeutic use of the composition) includes: a) providing a pharmaceutical kit comprising a container containing DMSO and a container containing a drug and PLGA, wherein the PLGA has a particle size distribution as described herein; b) preparing a LAI reservoir composition as described herein by mixing the components in the containers to form the LAI reservoir composition; and c) administering the LAI sustained-release composition to a subject in need thereof.

在本文所述的方法、治疗用途和试剂盒中，DMSO、PLGA和药物可以分装在药物试剂盒中的两个、三个或更多个容器中。In the methods, therapeutic uses and kits described herein, DMSO, PLGA and the drug may be packaged in two, three or more containers in a drug kit.

示例性疾病、病症或障碍包括例如精神病、妄想性精神病、精神病性抑郁症、强迫性障碍、精神分裂症、双相情感障碍、分裂情感性障碍、非精神分裂性精神病、阿斯伯格综合征、图雷特综合症、创伤后应激障碍、注意力缺陷多动障碍、人格障碍、攻击性、抑郁、痴呆、智力障碍和精神发育迟滞性行为障碍、自闭症、自闭症谱系障碍、焦虑症、进食障碍、神经焦虑、失眠症、特发性肌张力障碍、药物滥用，以及它们的任意组合。上述疾病、病症和障碍急性恶化发作的治疗在本发明的范围内。优选治疗精神分裂症、分裂情感性障碍、双相情感障碍和双相躁狂症。优选治疗精神分裂症，特别是成人精神分裂症，因为成人口服利培酮的耐受性和有效性已被确定。Exemplary diseases, conditions or disorders include, for example, psychosis, delusional psychosis, psychotic depression, obsessive-compulsive disorder, schizophrenia, bipolar disorder, schizoaffective disorder, non-schizophrenic psychosis, Asperger's syndrome, Tourette syndrome, post-traumatic stress disorder, attention deficit hyperactivity disorder, personality disorder, aggression, depression, dementia, intellectual disability and mental retardation behavior disorder, autism, autism spectrum disorder, anxiety, eating disorder, nervous anxiety, insomnia, idiopathic dystonia, drug abuse, and any combination thereof. The treatment of acute exacerbation of the above-mentioned diseases, conditions and disorders is within the scope of the present invention. Preferably, schizophrenia, schizoaffective disorder, bipolar disorder and bipolar mania are treated. Preferably, schizophrenia is treated, particularly adult schizophrenia, because the tolerance and effectiveness of oral risperidone in adults have been determined.

本发明包括本文阐述的各方面、实施方案和子实施方案的所有组合。The present invention includes all combinations of the aspects, embodiments and sub-embodiments set forth herein.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

提供以下附图以帮助解释本发明的目的，但不意味着任何限制。The following drawings are provided to help explain the purpose of the present invention but are not meant to be limiting in any way.

图1：在体外溶解试验中，对照组合物中利培酮随时间推移的累积释放百分比，该对照组合物包含PLGA，当根据USP<786>进行筛分分析测量时，该PLGA的粒度质量分布中超过10％的颗粒的粒度在300μm或以上。Figure 1: Cumulative percent release of risperidone over time in an in vitro dissolution test from a control composition comprising PLGA having a particle size mass distribution in which more than 10% of the particles have a particle size of 300 μm or greater when measured by sieve analysis according to USP <786>.

图2：在体外溶溶解试验中，本发明组合物中利培酮随时间推移的累积释放百分比。Figure 2: Cumulative release percentage of risperidone from the composition of the present invention over time in an in vitro dissolution test.

图3：在体外溶解试验中，组合物中利培酮随时间推移的累积释放百分比，该组合物包含PLGA，当根据USP<786>进行筛分分析测量时，该PLGA的粒度质量分布中至少有70％的颗粒的粒度小于150μm。Figure 3: Cumulative percent release of risperidone over time in an in vitro dissolution test from a composition comprising PLGA having a particle size mass distribution wherein at least 70% of the particles have a particle size less than 150 μm when measured by sieve analysis according to USP <786>.

图4：通过激光衍射分析测量本发明组合物中PLGA的粒度分布。水平轴：以μm为单位的粒度。垂直轴：体积(％)，表示颗粒与相应粒度的体积百分比，用湿分散法在水中通过激光衍射测量，在3000rpm下搅拌分散。Figure 4: Particle size distribution of PLGA in the composition of the invention measured by laser diffraction analysis. Horizontal axis: particle size in μm. Vertical axis: volume (%), representing the volume percentage of particles with the corresponding particle size, measured by laser diffraction in water using the wet dispersion method, with stirring and dispersion at 3000 rpm.

图5A至图5C示出了在新西兰白兔体内由可注射组合物形成的植入物中利培酮随时间(天)推移的累积释放百分比的曲线图：a)图5A——在体内溶解试验中，对照组合物中利培酮的累积释放百分比，该对照组合物包含PLGA，当根据USP<786>进行筛分分析测量时，该PLGA的粒度质量分布中不超过10％的颗粒的粒度在300μm或以上；该组合物包含PLGA(L:G比率为50:50)、DMSO和利培酮；聚合物溶液表观粘度为1.30(Pa.s)；注射相当于15mg利培酮的可注射组合物；b)图5B——在体内溶解试验中，组合物中利培酮的累积释放百分比，该组合物包含PLGA，当根据USP<786>进行筛分分析测量时，该PLGA的粒度质量分布中不超过70％的颗粒的粒度小于150μm；该组合物包含PLGA(L:G比率为50:50)、DMSO和利培酮；聚合物溶液表观粘度为1.30(Pa.s)；注射相当于15mg利培酮的可注射组合物；并且c)图5C——在体内溶解试验中，对照组合物中利培酮的累积释放百分比，该对照组合物包含PLGA，当根据USP<786>进行筛分分析测量时，该PLGA的粒度质量分布中至少有70％的颗粒的粒度在300μm或以上；该组合物包含PLGA(L:G比率为50:50)、DMSO和利培酮；聚合物溶液表观粘度为1.30(Pa.s)；注射相当于15mg利培酮的可注射组合物。Figures 5A to 5C show a graph of the cumulative release percentage of risperidone in implants formed from injectable compositions in New Zealand white rabbits over time (days): a) Figure 5A - Cumulative release percentage of risperidone in a control composition in an in vivo dissolution test, the control composition comprising PLGA, when measured by sieve analysis according to USP<786>, no more than 10% of the particles in the particle size mass distribution of the PLGA have a particle size of 300 μm or above; the composition comprising PLGA (L:G ratio of 50:50), DMSO and risperidone; the polymer solution apparent viscosity of 1.30 (Pa.s); injection of an injectable composition equivalent to 15 mg of risperidone; b) Figure 5B - Cumulative release percentage of risperidone in a composition in an in vivo dissolution test, the composition comprising PLGA, when sieved according to USP<786> When measured analytically, no more than 70% of the particles in the particle size mass distribution of the PLGA have a particle size of less than 150 μm; the composition comprises PLGA (L:G ratio of 50:50), DMSO and risperidone; the polymer solution apparent viscosity is 1.30 (Pa.s); an injectable composition equivalent to 15 mg of risperidone is injected; and c) Figure 5C - Cumulative release percentage of risperidone in a control composition in an in vivo dissolution test, the control composition comprising PLGA, when measured by sieve analysis according to USP<786>, at least 70% of the particles in the particle size mass distribution of the PLGA have a particle size of 300 μm or above; the composition comprises PLGA (L:G ratio of 50:50), DMSO and risperidone; the polymer solution apparent viscosity is 1.30 (Pa.s); an injectable composition equivalent to 15 mg of risperidone is injected.

具体实施方式DETAILED DESCRIPTION

本发明采用特定等级的PLGA来改进用于制备相应LAI储库型组合物的药物试剂盒的药物性能，以改进该相应LAI缓释组合物的制备，并改进在施用该LAI储库型组合物后原位形成的相应植入物的性能。研究发现，当药物和PLGA的混合物与DMSO混合时，该PLGA的粒度可改进其溶解行为。The present invention uses a specific grade of PLGA to improve the drug properties of a drug kit for preparing a corresponding LAI reservoir composition, to improve the preparation of the corresponding LAI sustained-release composition, and to improve the performance of a corresponding implant formed in situ after the LAI reservoir composition is applied. Studies have found that when a mixture of drug and PLGA is mixed with DMSO, the particle size of the PLGA can improve its dissolution behavior.

本文所用术语“稳定”是指药物组合物或试剂盒，其中，在40℃和75％相对湿度(RH)下将该组合物或试剂盒储存6个月期间，药物相关杂质的总含量不会增加至目标水平以上。术语“稳定”还指药物组合物或试剂盒，其中，在所述储存条件期间，PLGA共聚物的固有粘度不会降低至目标水平以下。如果此类组合物在40℃和75％相对湿度(RH)下储存6个月，由利培酮分解产生的杂质的目标总含量不超过5％面积，优选3％面积，更优选2％面积，最优选1％面积，在260nm下通过液相色谱法(HPLC)测定。在所述储存条件下储存6个月后，PLGA的目标最小固有粘度为0.20dL/g。As used herein, the term "stable" refers to a pharmaceutical composition or kit, wherein the total content of drug-related impurities does not increase above a target level during storage of the composition or kit at 40°C and 75% relative humidity (RH) for 6 months. The term "stable" also refers to a pharmaceutical composition or kit, wherein the intrinsic viscosity of the PLGA copolymer does not decrease below a target level during the storage conditions. If such a composition is stored for 6 months at 40°C and 75% relative humidity (RH), the target total content of impurities resulting from the decomposition of risperidone does not exceed 5% area, preferably 3% area, more preferably 2% area, and most preferably 1% area, as determined by liquid chromatography (HPLC) at 260nm. After storage for 6 months under the storage conditions, the target minimum intrinsic viscosity of PLGA is 0.20dL/g.

如本文所用，术语“负荷剂量”是指：a)在多天时间内每天向受试者经口服施用一定剂量的药物，其中，所述负荷剂量足以在该受试者中建立位于治疗范围内的活性部分稳态血浆浓度；和/或b)在施用维持剂量的包含所述药物的LAI储库型组合物之前，施用一种或多种更高剂量的包含所述药物的LAI储库型组合物，其中，在施用所述维持剂量之前，所述一种或多种更高剂量足以在该受试者中建立处于治疗范围内的活性部分稳态血浆浓度。As used herein, the term "loading dose" refers to: a) administering a dose of a drug orally to a subject daily over a period of multiple days, wherein the loading dose is sufficient to establish a steady-state plasma concentration of the active moiety in the subject that is within the therapeutic range; and/or b) administering one or more higher doses of a LAI depot composition comprising the drug prior to administering a maintenance dose of a LAI depot composition comprising the drug, wherein the one or more higher doses are sufficient to establish a steady-state plasma concentration of the active moiety in the subject that is within the therapeutic range prior to administering the maintenance dose.

如本文所用，术语“维持剂量”是指包含特定量药物的LAI储库型组合物的量，其中，从第一次(初次)施用所述LAI储库型组合物到后续施用(约每28天一次或约每月一次)所述LAI储库型组合物，向受试者施用所述量。所述维持剂量足以在该受试者中建立处于治疗范围内的活性部分稳态血浆浓度，而无需施用负荷剂量的包含利培酮的LAI储库型组合物，并且无需口服补充利培酮。As used herein, the term "maintenance dose" refers to the amount of a LAI reservoir composition comprising a specific amount of drug, wherein the amount is administered to a subject from the first (initial) administration of the LAI reservoir composition to subsequent administrations (about once every 28 days or about once a month) of the LAI reservoir composition. The maintenance dose is sufficient to establish a steady-state plasma concentration of the active moiety within the therapeutic range in the subject without the need to administer a loading dose of a LAI reservoir composition comprising risperidone, and without the need for oral supplementation of risperidone.

如本文所用，术语“口服补充”是指在向受试者施用包含所述药物的本发明LAI储库型组合物之后，每天向该受试者经口服施用一定剂量的药物。As used herein, the term "oral supplementation" means that after the LAI depot composition of the present invention comprising the drug is administered to the subject, a dose of the drug is orally administered to the subject every day.

如本文所用且除非另有说明，包含在可注射组合物中的药物或活性成分可以其游离碱、盐、无定形、结晶、无水、水合物、光学纯、光学富集或外消旋形式存在。这些不同形式的组合也在本发明的范围内。还可以包含药物的前药、代谢物(帕利哌酮)或衍生物。As used herein and unless otherwise indicated, the drug or active ingredient contained in the injectable composition can exist in its free base, salt, amorphous, crystalline, anhydrous, hydrate, optically pure, optically enriched or racemic form. Combinations of these different forms are also within the scope of the present invention. Prodrugs, metabolites (paliperidone) or derivatives of the drug may also be included.

在一些实施方案中，利培酮的盐形式可以根据美国公开号20040266791来制备，其相关公开内容通过引用并入本文；然而，可以使用其他已知的盐。In some embodiments, salt forms of risperidone can be prepared according to US Publication No. 20040266791, the relevant disclosure of which is incorporated herein by reference; however, other known salts may be used.

如本文所用，术语“前药”意指以无活性(或低于完全活性)形式施用且随后通过正常代谢过程转化为活性药剂的化合物。前药充当预期药物(例如，利培酮、帕利哌酮或其他药物)的“前体”。As used herein, the term "prodrug" means a compound that is administered in an inactive (or less than fully active) form and subsequently converted to an active agent by normal metabolic processes. A prodrug acts as a "precursor" of a desired drug (e.g., risperidone, paliperidone or other drug).

如本文所用，术语“衍生物”意指通过母体化合物的化学修饰而获得的化合物，使得“衍生物”中包含该母体(或基础)化合物的几乎全部或全部化学结构。衍生物是由类似化合物形成的化合物，或者如果一个原子被另一个原子或原子团取代，则可以想象是由另一种化合物产生的化合物。衍生物是从另一种物质衍生或获得的化合物，并且含有该母体物质的基本元素。衍生物是一种化学化合物，可以通过一个或多个步骤由具有相似结构的另一种化合物产生。As used herein, the term "derivative" means a compound obtained by chemical modification of a parent compound, such that almost all or all of the chemical structure of the parent (or base) compound is contained in the "derivative". A derivative is a compound formed from a similar compound, or a compound that can be imagined to be produced from another compound if one atom is replaced by another atom or group of atoms. A derivative is a compound derived or obtained from another substance and contains the essential elements of the parent substance. A derivative is a chemical compound that can be produced from another compound of similar structure by one or more steps.

如本文所用，术语“给药期”是指从施用剂量后的第一天到施用后至少约28天或到施用后续剂量所测量的数天或数周时间段。在给药期间，植入物将提供约4周或更长时间的药物治疗血浆水平。给药期可以在预定天数期满后或在药物血浆水平降至治疗水平以下后结束。As used herein, the term "dosing period" refers to the period of days or weeks measured from the first day after the administration of a dose to at least about 28 days after the administration or to the administration of subsequent doses. During the dosing period, the implant will provide a therapeutic plasma level of the drug for about 4 weeks or longer. The dosing period can end after the expiration of a predetermined number of days or after the drug plasma level drops below the therapeutic level.

如本文所用，“治疗期”是指向受试者施用本发明的LAI持续释放组合物的周数、月数或年数。治疗期一般包含多个给药期。给药期可以在治疗期间连续或以重叠的方式发生。例如，施用第一剂量的可注射组合物，并且可以在施用该第一剂量之后的某个时间施用第二剂量的可注射组合物，使得每个剂量将具有其相应的给药期，并且这些给药期将重叠。给药期通常是连续的或重叠不超过一或七天。As used herein, "treatment period" refers to the number of weeks, months, or years that a subject is administered a sustained-release LAI composition of the present invention. A treatment period generally includes multiple administration periods. Administration periods may occur continuously or in an overlapping manner during the treatment period. For example, a first dose of an injectable composition is administered, and a second dose of an injectable composition may be administered at a time after the first dose is administered, so that each dose will have its corresponding administration period, and these administration periods will overlap. Administration periods are typically continuous or overlap no more than one or seven days.

可以将肌内给药剂量施用至通常被制药业认可为适合可注射组合物的部位的任何肌肉或肌群。在一些实施方案中，将该组合物施用至臀肌和/或三角肌。还可以将该组合物施用至股四头肌群。可以将剂量施用至单个肌肉部位，或者可以将其分成两个或更多个部分并施用至受试者的两个或更多个肌肉部位。例如，可以将剂量的第一部分施用至受试者的臀肌的第一部分，并且可以将该剂量的第二部分施用至该受试者的臀肌的第二部分。可以在同一天将该可注射组合物施用于受试者的一个或多个注射部位，并且仍然被视为同一给药期的一部分。例如，可以将剂量的一部分施用至第一注射部位，并且可以将相同剂量的另一部分施用至另一注射部位。在每个注射部位都会形成单体植入物。这种在同一天内施用的方式被视为在单一给药期间施用单一剂量。另选地，可以修改施用方式，即将针头扎入受试者皮下的多个注射部位，这可以通过如下操作来实现：第一次扎入皮肤和肌肉并施用一部分剂量，然后部分拔出针头并将其重定向到肌肉的另一部分，同时将针尖保持在皮下，之后将另一部分剂量注射到肌肉的该另一部分。这种施用方式仍被视为在单一给药期间施用单一剂量。The intramuscular dosage can be applied to any muscle or muscle group that is generally recognized by the pharmaceutical industry as a site suitable for injectable compositions. In some embodiments, the composition is applied to the gluteal and/or deltoid muscles. The composition can also be applied to the quadriceps group. The dosage can be applied to a single muscle site, or it can be divided into two or more parts and applied to two or more muscle sites of a subject. For example, the first part of the dosage can be applied to the first part of the gluteal muscle of the subject, and the second part of the dosage can be applied to the second part of the gluteal muscle of the subject. The injectable composition can be applied to one or more injection sites of the subject on the same day and still be considered as part of the same administration period. For example, a part of the dosage can be applied to the first injection site, and another part of the same dosage can be applied to another injection site. Monomer implants can be formed at each injection site. This mode of application on the same day is considered as applying a single dose during a single administration period. Alternatively, the administration may be modified to include multiple injection sites where the needle is inserted into the subject's skin, which may be accomplished by first inserting the skin and muscle and administering a portion of the dose, then partially withdrawing the needle and redirecting it to another portion of the muscle while keeping the needle tip subcutaneous, and then injecting another portion of the dose into the other portion of the muscle. This administration is still considered to be the administration of a single dose during a single dosing period.

可注射组合物的治疗有效量是指包含指定剂量的药物的可注射组合物的量。因此，25-150mg治疗有效量的可注射组合物包含25-150mg利培酮剂量；因此，LAI储库型组合物的实际施用量将大于25-150mg，注射组合物的实际施用量根据该LAI储库型组合物中的药物含量来确定。例如，在包含约13％wt利培酮的治疗有效量LAI储库型组合物中，75mg剂量的利培酮将相当于约575mg的治疗有效量，所述组合物包含DMSO、利培酮和PLGA。类似地，在包含约13％wt利培酮的治疗有效量LAI储库型组合物中，100mg剂量的利培酮将相当于约767mg的治疗有效量，所述组合物包含DMSO、利培酮和PLGA。The therapeutically effective amount of an injectable composition refers to the amount of the injectable composition containing a specified dose of the drug. Therefore, a 25-150 mg therapeutically effective amount of an injectable composition contains a 25-150 mg dose of risperidone; therefore, the actual amount of the LAI reservoir composition administered will be greater than 25-150 mg, and the actual amount of the injectable composition administered is determined based on the drug content in the LAI reservoir composition. For example, in a therapeutically effective amount LAI reservoir composition containing about 13% wt risperidone, a 75 mg dose of risperidone will be equivalent to a therapeutically effective amount of about 575 mg, and the composition contains DMSO, risperidone and PLGA. Similarly, in a therapeutically effective amount LAI reservoir composition containing about 13% wt risperidone, a 100 mg dose of risperidone will be equivalent to a therapeutically effective amount of about 767 mg, and the composition contains DMSO, risperidone and PLGA.

尽管不是必需的，但本发明的可注射组合物还可以包含碱剂。可以包含具有低水溶性(诸如低于0.02mg/mL)的碱剂。该碱剂可以>2/5(药物/碱剂)的摩尔比存在，这意味着该碱剂以相对于药物过量的摩尔量存在。优选的碱剂是碱金属氢氧化物或碱土金属氢氧化物，诸如氢氧化镁或氢氧化铝。由于碱剂的水溶性有限，例如氢氧化镁的粒度分布中d 0.5优选小于10μm。Although not necessary, the injectable composition of the present invention may also include an alkali agent. An alkali agent with low water solubility (such as less than 0.02 mg/mL) may be included. The alkali agent may be present in a molar ratio of >2/5 (drug/alkali agent), which means that the alkali agent is present in an excess molar amount relative to the drug. A preferred alkali agent is an alkali metal hydroxide or an alkaline earth metal hydroxide, such as magnesium hydroxide or aluminum hydroxide. Due to the limited water solubility of the alkali agent, for example, the particle size distribution of magnesium hydroxide has a d 0.5 preferably less than 10 μm.

本发明的组合物可以是适合于在有此需要的受试者中原位形成可生物降解性固体植入物的药物试剂盒的形式。在一些实施方案中，该试剂盒包括：包含利培酮的第一容器；包含生物相容性PLGA共聚物的第二容器；以及包含DMSO的第三容器。通过将该第三容器的内容物与该第二容器的内容物混合，形成聚合物溶液，然后将该溶液与该第一容器的内容物混合以形成如本文所述的可注射组合物。在一些实施方案中，该共聚物和药物(和/或其代谢物和/或前药)包含在第一容器中，并且DMSO包含在第二容器中。在一些实施方案中，上述容器为注射器，并且它们的内容物的混合可以通过直接或间接连接、随后前后移动注射器的柱塞来进行。本发明的实施方案包括：a)药物和/或共聚物在与溶剂混合之前以固体形式存在于容器中；或b)药物和/或共聚物在与溶剂(DMSO)混合之前以颗粒形式或作为冻干物存在于容器中。The composition of the present invention may be in the form of a pharmaceutical kit suitable for forming a biodegradable solid implant in situ in a subject in need thereof. In some embodiments, the kit comprises: a first container comprising risperidone; a second container comprising a biocompatible PLGA copolymer; and a third container comprising DMSO. A polymer solution is formed by mixing the contents of the third container with the contents of the second container, and then the solution is mixed with the contents of the first container to form an injectable composition as described herein. In some embodiments, the copolymer and the drug (and/or its metabolites and/or prodrugs) are contained in a first container, and DMSO is contained in a second container. In some embodiments, the above-mentioned container is a syringe, and the mixing of their contents can be performed by direct or indirect connection, followed by moving the plunger of the syringe back and forth. Embodiments of the present invention include: a) the drug and/or copolymer are present in a solid form in the container before mixing with the solvent; or b) the drug and/or copolymer are present in a container in particulate form or as a lyophilisate before mixing with the solvent (DMSO).

本发明还提供了一种用于制备稳定的LAI储库型组合物的方法，该方法包括在施用前将该组合物的各组分混合约30秒或更短时间、约1分钟或更短时间、约2分钟或更短时间、或最长约3分钟，优选地在施用前最长约2分钟，更优选地在施用前最长约1分钟，从而形成该组合物。在一个优选实施方案中，通过将溶剂(DMSO)与先前的利培酮和生物相容性聚合物(PLGA)的粉末混合物混合来制备该组合物。在一个优选实施方案中，通过在两个器械(优选注射器)之间推拉内容物200次(道次)或更少次数、150次或更少次数、100次或更少次数、75次或更少次数或50次来混合各组分。The present invention also provides a method for preparing a stable LAI reservoir composition, the method comprising mixing the components of the composition for about 30 seconds or less, about 1 minute or less, about 2 minutes or less, or up to about 3 minutes before administration, preferably up to about 2 minutes before administration, more preferably up to about 1 minute before administration, thereby forming the composition. In a preferred embodiment, the composition is prepared by mixing a solvent (DMSO) with a previous powder mixture of risperidone and a biocompatible polymer (PLGA). In a preferred embodiment, the components are mixed by pushing and pulling the contents between two instruments (preferably syringes) 200 times (passes) or less, 150 times or less, 100 times or less, 75 times or less, or 50 times.

如本文所用，术语“聚合物溶液”意指包含溶解于其中的DMSO和PLGA的组合的流体组合物。除非另有说明，该聚合物溶液或可注射组合物的表观粘度值以Pa.s为单位给出。As used herein, the term "polymer solution" means a fluid composition comprising a combination of DMSO and PLGA dissolved therein. Unless otherwise specified, the apparent viscosity values of the polymer solution or injectable composition are given in Pa.s.

该聚合物溶液的表观粘度范围为约0.5至约3.0Pa.s、约0.7至约3.0Pa.s、约0.7至约2.0Pa.s、约1.5至约2.5Pa.s、约1.5至约2.3Pa.s、约1.5至约2.1Pa.s、1.5-2.1±10％Pa.s、1.6-1.9±10％Pa.s、或1.7-1.8±10％Pa.s，于25℃下使用锥板粘度计应用0.1-300Pa.s的剪切应力斜坡进行旋转流变测量(USP<912>粘度——旋转法或《欧洲药典》第2.2.10节中所述的粘度——旋转粘度计法)。在施用前，LAI储库型组合物的表观粘度范围为约1.0-7.0Pa.s、约1.5-7.0Pa.s，或约1.8-6.5Pa.s。在一些实施方案中，这些值可以与指定限值相差约±10％。表观粘度可以主要根据聚合物的分子量(固有粘度)和可注射组合物中聚合物的浓度来控制。The apparent viscosity of the polymer solution is in the range of about 0.5 to about 3.0 Pa.s, about 0.7 to about 3.0 Pa.s, about 0.7 to about 2.0 Pa.s, about 1.5 to about 2.5 Pa.s, about 1.5 to about 2.3 Pa.s, about 1.5 to about 2.1 Pa.s, 1.5-2.1 ± 10% Pa.s, 1.6-1.9 ± 10% Pa.s, or 1.7-1.8 ± 10% Pa.s, measured by rotational rheology at 25°C using a cone and plate viscometer with a shear stress ramp of 0.1-300 Pa.s (USP <912> Viscosity - Rotational Method or Viscosity - Rotational Viscometer Method as described in Section 2.2.10 of the European Pharmacopoeia). Prior to administration, the apparent viscosity of the LAI reservoir composition is in the range of about 1.0-7.0 Pa.s, about 1.5-7.0 Pa.s, or about 1.8-6.5 Pa.s. In some embodiments, these values may vary from the specified limits by about ±10%.The apparent viscosity can be controlled primarily based on the molecular weight (intrinsic viscosity) of the polymer and the concentration of the polymer in the injectable composition.

在一些实施方案中，聚合物溶液与药物的质量比(表示为(聚合物+溶剂)与药物的质量比)的范围为约15:1至约5:1、约12:1至约5:1、约7:1至约6.5:1、约6.5:1至约6.8:1、约6.67:1、约6.66:1，或约6.68:1。In some embodiments, the mass ratio of polymer solution to drug (expressed as the mass ratio of (polymer + solvent) to drug) ranges from about 15:1 to about 5:1, about 12:1 to about 5:1, about 7:1 to about 6.5:1, about 6.5:1 to about 6.8:1, about 6.67:1, about 6.66:1, or about 6.68:1.

在一些实施方案中，聚合物与聚合物溶液的质量比(表示为聚合物相对于聚合物+溶剂的重量的重量百分比)为约25-50％、约25-35％、约30-40％、约28-32％，或约30％。In some embodiments, the mass ratio of polymer to polymer solution (expressed as weight percent of polymer relative to weight of polymer + solvent) is about 25-50%, about 25-35%, about 30-40%, about 28-32%, or about 30%.

在一些实施方案中，溶剂(DMSO)与聚合物溶液的质量比(表示为溶剂相对于聚合物+溶剂的重量的重量百分比)为约50-75％、约65-75％、约60-70％、约68-72％，或约70％。In some embodiments, the mass ratio of solvent (DMSO) to polymer solution (expressed as weight percentage of solvent relative to the weight of polymer + solvent) is about 50-75%, about 65-75%, about 60-70%, about 68-72%, or about 70%.

LAI缓释组合物还可以包含一种或多种适合肌内施用的药用辅料。The LAI sustained-release composition may further comprise one or more pharmaceutically acceptable excipients suitable for intramuscular administration.

肌内施用后，LAI缓释组合物在肌肉组织中原位形成固体植入物。在一些实施方案中，该植入物在施用后约2小时内开始释放利培酮以快速(例如，短于1天、短于18小时、短于12小时、短于6小时、短于3小时)起效并且持续至少约4周。从施用第一天起持续至少约4周的时间内，它提供活性部分(利培酮+9-羟利培酮(帕利哌酮))治疗有效血浆水平。After intramuscular administration, the LAI sustained-release composition forms a solid implant in situ in the muscle tissue. In some embodiments, the implant begins to release risperidone within about 2 hours after administration to quickly (e.g., shorter than 1 day, shorter than 18 hours, shorter than 12 hours, shorter than 6 hours, shorter than 3 hours) take effect and lasts for at least about 4 weeks. It provides active part (risperidone + 9-hydroxyrisperidone (paliperidone)) therapeutic effective plasma levels from the first day of administration for at least about 4 weeks.

本说明书中使用的表述“约50:50”是指基于各自的乳酸和乙醇酸单体的丙交酯和乙交酯二聚体的生物相容性PLGA共聚物中乳酸与乙醇酸的单体比率。L:G单体摩尔比可能存在±10％的标准技术误差。已知市售等级的PLGA共聚物的实际单体比率略有不同，但它们可能标示具有50:50单体比率。例如，指定为具有50:50单体比率的共聚物实际上可能具有45:55至55:45或48:52至52:48范围内的单体比率。因此，每当本文指定“50:50”或“约50:50”单体比率时，45:55至55:45范围内的所有比率都被视为可与其互换。The expression "about 50:50" used in this specification refers to the monomer ratio of lactic acid to glycolic acid in a biocompatible PLGA copolymer of lactide and glycolide dimers based on respective lactic acid and glycolic acid monomers. There may be a standard technical error of ±10% for the L:G monomer molar ratio. The actual monomer ratios of commercially available grades of PLGA copolymers are known to vary slightly, but they may be labeled as having a 50:50 monomer ratio. For example, a copolymer designated as having a 50:50 monomer ratio may actually have a monomer ratio in the range of 45:55 to 55:45 or 48:52 to 52:48. Therefore, whenever a "50:50" or "about 50:50" monomer ratio is specified herein, all ratios in the range of 45:55 to 55:45 are considered interchangeable therewith.

固有粘度可在氯仿中于25℃或30℃下以0.1％wt/v或0.5％wt/v的浓度用乌氏0c或0b号玻璃毛细管粘度计测量，或在氯仿中于30℃下以0.5％wt/v的浓度用25号坎农-芬斯克玻璃毛细管粘度计测量(USP<911>粘度——毛细管法或《欧洲药典》第2.2.9.节中所述的毛细管粘度计法)。如本文所述的合适等级的PLGA共聚物(根据分子量、固有粘度和/或乳酸单体与乙醇酸单体的摩尔比)是封端的(诸如用酯基，例如月桂酯、甲酯)，可从(德国埃森)、Boehringer Ingelheim(德国莱茵河畔英格尔海姆)、ALKERMES(爱尔兰都柏林)或SIGMA ALDRICH(密苏里州圣路易斯)购买，并且以商品名LAKESHOREBIOMATERIALS^TM或销售。由于某些等级的封端PLGA的成分是专有的，因此酯端帽的特性未对外公开。尽管如此，本文所述的各等级PLGA共聚物的性能特性是已知的并且用于表征该材料。Intrinsic viscosity can be measured in chloroform at 25°C or 30°C at a concentration of 0.1% wt/v or 0.5% wt/v using an Ubbelohde No. 0c or No. 0b glass capillary viscometer, or in chloroform at 30°C at a concentration of 0.5% wt/v using a No. 25 Cannon-Fenske glass capillary viscometer (USP <911> Viscosity - Capillary Method or the Capillary Viscometer Method described in Section 2.2.9. of the European Pharmacopoeia). Suitable grades of PLGA copolymers as described herein (based on molecular weight, intrinsic viscosity and/or molar ratio of lactic acid monomers to glycolic acid monomers) are end-capped (such as with ester groups, e.g., lauryl esters, methyl esters) and can be obtained from (Essen, Germany), Boehringer Ingelheim (Ingelheim am Rhein, Germany), ALKERMES (Dublin, Ireland), or SIGMA ALDRICH (St. Louis, Missouri), and sold under the trade name LAKESHORE BIOMATERIALS^TM or Because the composition of some grades of end-capped PLGA is proprietary, the properties of the ester end caps are not disclosed. Nevertheless, the performance properties of the various grades of PLGA copolymers described herein are known and used to characterize the material.

LAI储库型组合物中PLGA聚合物的固有粘度范围可为0.20-0.60dL/g、约0.30-0.55dL/g、约0.36-0.52dL/g、约0.36-0.43dL/g、约0.40-0.58dL/g，或约0.46-0.51dL/g，在氯仿中于25℃或30℃下以0.1％wt/v或0.5％wt/v的浓度用乌氏0c或0b号玻璃毛细管粘度计测量，或在氯仿中于30℃下以0.5％wt/v的浓度用25号坎农-芬斯克玻璃毛细管粘度计测量(USP<911>粘度——毛细管法或《欧洲药典》第2.2.9.节中所述的毛细管粘度计法)。如果PLGA聚合物完全溶解在制剂中，则可以根据USP<912>粘度——旋转法或《欧洲药典》第2.2.10节中所述的粘度——旋转粘度计法测量该聚合物溶液的表观粘度。The intrinsic viscosity of the PLGA polymer in the LAI depot composition can range from 0.20-0.60 dL/g, about 0.30-0.55 dL/g, about 0.36-0.52 dL/g, about 0.36-0.43 dL/g, about 0.40-0.58 dL/g, or about 0.46-0.51 dL/g, measured at a concentration of 0.1% wt/v or 0.5% wt/v in chloroform at 25°C or 30°C using an Ubbelohde No. 0c or 0b glass capillary viscometer, or at a concentration of 0.5% wt/v in chloroform at 30°C using a No. 25 Cannon-Fenske glass capillary viscometer (USP<911> Viscosity - Capillary Method or the capillary viscometer method described in Section 2.2.9. of the European Pharmacopoeia). If the PLGA polymer is completely dissolved in the formulation, the apparent viscosity of the polymer solution can be measured according to USP <912> Viscosity - Rotational Method or the Viscosity - Rotational Viscometer method described in Section 2.2.10 of the European Pharmacopoeia.

PLGA聚合物可以在-40℃和+35℃之间的温度下用约10至约30kGy剂量的β或γ辐射进行辐照。辐射可用于降低该PLGA聚合物的分子量和/或对该PLGA聚合物进行灭菌。在一些实施方案中，在低于35℃、更优选地低于25℃并且更优选地低于8℃的温度下辐射该聚合物。在本发明的一个优选实施方案中，生物相容性共聚物在-40℃至+35℃之间的温度下接受10-30kGy±10％剂量范围的γ或β辐射，以调节其分子量至约27-47kDa、约31-43kDa、约31-40kDa、约30-46kDa或约30-36kDa的范围。在一个更优选的实施方案中，在8℃的温度下以15-25kGy±10％的剂量范围辐射该聚合物。The PLGA polymer can be irradiated with beta or gamma radiation at a dose of about 10 to about 30 kGy at a temperature between -40 ° C and +35 ° C. Radiation can be used to reduce the molecular weight of the PLGA polymer and/or sterilize the PLGA polymer. In some embodiments, the polymer is irradiated at a temperature below 35 ° C, more preferably below 25 ° C, and more preferably below 8 ° C. In a preferred embodiment of the present invention, the biocompatible copolymer is subjected to gamma or beta radiation at a dose range of 10-30 kGy ± 10% at a temperature between -40 ° C and +35 ° C to adjust its molecular weight to a range of about 27-47 kDa, about 31-43 kDa, about 31-40 kDa, about 30-46 kDa, or about 30-36 kDa. In a more preferred embodiment, the polymer is irradiated at a temperature of 8 ° C with a dose range of 15-25 kGy ± 10%.

在施用后，可注射组合物形成植入物，该植入物提供控制良好的药物释放曲线。“控制良好的”释放曲线是指植入物将表现出既不太陡(快)又不太平(慢)的初始释放曲线，太陡会导致血浆水平过高并伴随毒副作用，太平则会导致血浆水平低于治疗浓度。在被放入水相环境后的24小时内，表现出控制良好的初始释放曲线的植入物将释放不超过20％wt、不超过15％wt、不超过12％wt、不超过10％wt、不超过8％wt、不超过6％wt、超过5％wt、不超过4％wt、不超过3％wt、不超过2％wt或不超过1％wt的装药量的药物。在被放入水相环境后的24小时内，其将释放至少0.1％wt、至少0.5％wt、至少1％wt、至少2％wt、至少3％wt或至少4％wt的装药量的药物。本发明包括本文所述实施方案的所有组合。After administration, the injectable composition forms an implant that provides a well-controlled drug release profile. A "well-controlled" release profile means that the implant will exhibit an initial release profile that is neither too steep (fast) nor too flat (slow), too steep will result in too high plasma levels and associated toxic side effects, and too flat will result in plasma levels below therapeutic concentrations. Within 24 hours after being placed in an aqueous environment, an implant exhibiting a well-controlled initial release profile will release no more than 20% wt, no more than 15% wt, no more than 12% wt, no more than 10% wt, no more than 8% wt, no more than 6% wt, more than 5% wt, no more than 4% wt, no more than 3% wt, no more than 2% wt or no more than 1% wt of the drug load. Within 24 hours after being placed in an aqueous environment, it will release at least 0.1% wt, at least 0.5% wt, at least 1% wt, at least 2% wt, at least 3% wt or at least 4% wt of the drug load. The present invention includes all combinations of the embodiments described herein.

给药期间的血浆浓度分布可以表现出一个、两个或更多个最大值和一个、两个或更多个最小值。初始最大值可以由在给药期的最初几天内药物溶解后释放减慢引起，并且另一个最大值可以由在给药期的剩余天数内释放速率加快引起。本发明的实施方案包括：a)血浆分布在给药期的最初1到6天或1到3天内表现出最大值；b)血浆分布在4周给药期的后10至24天内表现出最大值；c)血浆分布在给药期的最初几天内和给药期的剩余几天内表现出最大值；d)在给药期间血浆分布基本上水平(标准偏差在平均值或均值的±30％、±25％、±20％、±15％或±10％以内)；e)血浆分布在给药期的最初2至6天或2至12天内表现出最大值；和/或f)血浆分布在4至5周给药期的后10至28天表现出最大值。The plasma concentration distribution during administration can show one, two or more maximum values and one, two or more minimum values. The initial maximum value can be caused by the slow release after the drug dissolves in the first few days of the administration period, and another maximum value can be caused by the accelerated release rate in the remaining days of the administration period. Embodiments of the present invention include: a) plasma distribution shows a maximum value in the first 1 to 6 days or 1 to 3 days of the administration period; b) plasma distribution shows a maximum value in the last 10 to 24 days of the 4-week administration period; c) plasma distribution shows a maximum value in the first few days of the administration period and the remaining days of the administration period; d) plasma distribution is basically horizontal during administration (standard deviation is within ±30%, ±25%, ±20%, ±15% or ±10% of the mean or average); e) plasma distribution shows a maximum value in the first 2 to 6 days or 2 to 12 days of the administration period; and/or f) plasma distribution shows a maximum value in the last 10 to 28 days of the 4 to 5-week administration period.

在人类中，当施用相当于约20-80mg、约37.5-125mg或约50-100mg利培酮剂量的可注射组合物时，活性部分(利培酮+9-羟利培酮)平均血浆浓度的范围可以为约3-200ng/mL、约5-80ng/mL或约10-60ng/mL。当施用分别相当于约25-150mg、约37.5-125mg或约50-100mg利培酮剂量的可注射组合物时，给药期间平均Cmin的范围为约1-80ng/mL、5-50ng/mL或约5-40ng/mL。当施用分别相当于25-150mg、37.5-125mg或50-100mg利培酮剂量的可注射组合物时，给药期间平均Cmax的范围为约8-300ng/mL、10-150ng/mL或10-120ng/mL。由于健康状况不佳、高龄、代谢受损、肾功能衰竭、疾病等原因，一些个体受试者在当量剂量基础上可能表现出超出本文指定范围的血浆浓度。即便如此，对其施用可注射植入物的患者群体中的大多数受试者将表现出本文指定范围的血浆浓度。In humans, when administering an injectable composition equivalent to a dose of about 20-80 mg, about 37.5-125 mg, or about 50-100 mg risperidone, the average plasma concentration of the active portion (risperidone + 9-hydroxyrisperidone) may range from about 3-200 ng/mL, about 5-80 ng/mL, or about 10-60 ng/mL. When administering an injectable composition equivalent to a dose of about 25-150 mg, about 37.5-125 mg, or about 50-100 mg risperidone, respectively, the average Cmin during administration ranges from about 1-80 ng/mL, 5-50 ng/mL, or about 5-40 ng/mL. When administering an injectable composition equivalent to a dose of 25-150 mg, 37.5-125 mg, or 50-100 mg risperidone, respectively, the average Cmax during administration ranges from about 8-300 ng/mL, 10-150 ng/mL, or 10-120 ng/mL. Some individual subjects may exhibit plasma concentrations outside the ranges specified herein on an equivalent dose basis due to poor health, advanced age, impaired metabolism, renal failure, disease, etc. Even so, the majority of subjects in the patient population to which the injectable implant is administered will exhibit plasma concentrations within the ranges specified herein.

如本文所用，每当提到药物血浆浓度时，这种血浆浓度包括活性部分(即药物连同其活性代谢物)血浆浓度的总和。例如，每当提及利培酮血浆浓度时，这种血浆浓度包括利培酮及其活性代谢物(诸如9-羟利培酮(帕利哌酮))血浆浓度的总和。As used herein, whenever a drug plasma concentration is mentioned, such plasma concentration includes the sum of the plasma concentrations of the active moiety (i.e., the drug together with its active metabolites). For example, whenever risperidone plasma concentration is mentioned, such plasma concentration includes the sum of the plasma concentrations of risperidone and its active metabolites (such as 9-hydroxyrisperidone (paliperidone)).

在一些实施方案中，药物的粒度分布如下：不超过总体积10％的药物颗粒的粒度小于10μm(体积当量直径作为将弗劳恩霍夫理论应用于不规则形状颗粒的函数；通过激光散射测量，诸如使用Malvern Mastersizer 2000)，并且不超过总体积10％的药物颗粒的粒度大于225μm(或235μm)。另外，药物颗粒的d0.5值优选地在约60-130μm范围内。因此，在一些实施方案中，利培酮具有宽粒度分布，其可以是单峰、双峰或三峰。In some embodiments, the particle size distribution of the drug is as follows: no more than 10% of the total volume of the drug particles have a particle size less than 10 μm (volume equivalent diameter as a function of applying the Fraunhofer theory to irregularly shaped particles; measured by laser scattering, such as using a Malvern Mastersizer 2000), and no more than 10% of the total volume of the drug particles have a particle size greater than 225 μm (or 235 μm). In addition, the d0.5 value of the drug particles is preferably in the range of about 60-130 μm. Therefore, in some embodiments, risperidone has a wide particle size distribution, which can be unimodal, bimodal or trimodal.

在其他实施方案中，药物表现出以下粒度分布之一：In other embodiments, the drug exhibits one of the following particle size distributions:

在本发明的另一个实施方案中，药物具有如下粒度分布：In another embodiment of the present invention, the drug has the following particle size distribution:

-不超过总体积10％的颗粒的粒度小于10μm；- no more than 10% of the total volume of particles has a particle size of less than 10 μm;

-不超过总体积10％的颗粒的粒度大于225μm(或235μm)，或者不超过总体积10％的颗粒的粒度大于200μm，并且- not more than 10% of the total volume of particles have a particle size greater than 225 μm (or 235 μm), or not more than 10% of the total volume of particles have a particle size greater than 200 μm, and

-粒度分布中d0.5的范围为约60-130μm、约40-90μm或约40-130μm。- The particle size distribution has a d0.5 in the range of about 60-130 μm, about 40-90 μm or about 40-130 μm.

粒度分布通过激光衍射光散射技术在湿模式下测定。The particle size distribution was determined by laser diffraction light scattering technique in wet mode.

本发明的实施方案包括：a)在与溶剂混合之前，利培酮以固体形式存在于容器中；b)在与溶剂混合之前，利培酮以颗粒形式或作为冻干物存在于容器中；c)利培酮的粒度分布如下：不超过总体积10％的药物颗粒的粒度小于10μm，并且不超过总体积10％的药物颗粒的粒度大于225μm(或235μm)；d)粒度分布中d0.5的范围为约60-130μm；e)可注射组合物中聚合物溶液(聚合物+溶剂)与利培酮的质量比的范围为约15:1至5:1；f)可注射组合物中溶剂与利培酮的质量比(mg溶剂/mg利培酮)的范围为约12:1至4:1；g)试剂盒还包含碱剂；h)利培酮与碱剂的摩尔比的范围为2/3至2/5；i)在施用前对溶剂、聚合物溶液、利培酮和/或可注射组合物进行灭菌；并且/或者j)试剂盒还包含装在一个或两个容器中的碱剂。Embodiments of the present invention include: a) before mixing with a solvent, risperidone is present in a solid form in a container; b) before mixing with a solvent, risperidone is present in a granular form or as a lyophilisate in a container; c) the particle size distribution of risperidone is as follows: no more than 10% of the total volume of drug particles have a particle size less than 10 μm, and no more than 10% of the total volume of drug particles have a particle size greater than 225 μm (or 235 μm); d) the range of d0.5 in the particle size distribution is about 60-130 μm; e) the injectable composition is The mass ratio of the polymer solution (polymer + solvent) to risperidone ranges from about 15:1 to 5:1; f) the mass ratio of the solvent to risperidone in the injectable composition (mg solvent/mg risperidone) ranges from about 12:1 to 4:1; g) the kit further comprises an alkaline agent; h) the molar ratio of risperidone to the alkaline agent ranges from 2/3 to 2/5; i) the solvent, polymer solution, risperidone and/or the injectable composition are sterilized prior to administration; and/or j) the kit further comprises an alkaline agent in one or two containers.

根据另一方面，本发明提供了一种药物试剂盒，其适合于由所要求保护的组合物在体内原位形成可生物降解的植入物，其中，药物和生物相容性聚合物包含在第一容器中，并且溶剂包含在第二单独容器中。优选地，该第一容器和该第二容器中的至少一者为一次性或非一次性注射器、小瓶、器械或药筒，并且更优选地该第一容器和该第二容器两者均为一次性注射器。本发明的这一方面涉及一种试剂盒，其包括第一容器和第二容器，该第一容器优选地为注射器、小瓶、器械或药筒，它们全部供一次性或非一次性使用，其中包含固体形式的聚合物，诸如PLGA和适量的药物，该第二容器同样优选地为注射器、小瓶、器械或药筒，它们全部供一次性或非一次性使用，其中包含水混溶性溶剂。当有需要时，将两个容器的内容物组合，例如通过连接器或通过使用公口-母口注射器并彼此混合，使得根据本发明的组合物被重构，例如通过前后移动注射器的柱塞。According to another aspect, the present invention provides a kind of drug kit, it is suitable for forming a biodegradable implant in situ in vivo by the claimed composition, wherein the drug and biocompatible polymer are contained in a first container, and the solvent is contained in a second separate container. Preferably, at least one of the first container and the second container is a disposable or non-disposable syringe, a vial, an apparatus or a cartridge, and more preferably both the first container and the second container are disposable syringes. This aspect of the present invention relates to a kind of test kit, it includes a first container and a second container, the first container is preferably a syringe, a vial, an apparatus or a cartridge, they are all for disposable or non-disposable use, wherein a polymer in solid form is included, such as PLGA and an appropriate amount of medicine, the second container is also preferably a syringe, a vial, an apparatus or a cartridge, they are all for disposable or non-disposable use, wherein a water-miscible solvent is included. When necessary, the contents of the two containers are combined, such as by a connector or by using a male-female syringe and mixing with each other, so that the composition according to the present invention is reconstructed, such as by moving the plunger of the syringe back and forth.

根据另一个方面，本发明提供了一种用于向有此需要的受试者施用根据本发明的可注射肌内缓释组合物(或如本文所述的LAI储库型组合物)的给药方案方法，该方法包括：According to another aspect, the present invention provides a method for administering a dosing regimen of an injectable intramuscular sustained-release composition according to the present invention (or a LAI depot composition as described herein) to a subject in need thereof, the method comprising:

a)以该LAI储库型组合物的形式向该受试者肌内施用含75mg至100mg利培酮的第一剂量；a) administering to the subject a first dose containing 75 mg to 100 mg of risperidone intramuscularly in the form of the LAI depot composition;

b)在从前一施用日算起的第28天、或第26天至第33天、或第26天至第31天的某一时刻以该LAI储库型组合物的形式向所述患者肌内施用75mg至100mg利培酮；以及b) administering 75 mg to 100 mg of risperidone intramuscularly to the patient in the form of the LAI depot composition at some point on the 28th day, or the 26th to 33rd day, or the 26th to 31st day from the previous administration day; and

c)每当有需要时重复步骤b)。c) Repeat step b) as often as necessary.

在治疗期内，可注射组合物的施用剂量通常大致相同。The dose of the injectable composition administered is generally about the same during the treatment period.

单剂量的施用通常被视为在最长24小时、最长12小时、最长6小时、最长3小时、最长1小时、最长30分钟、最长15分钟或最长5分钟的时间内向受试者施用的可注射组合物的量。A single dose of administration is generally considered to be the amount of the injectable composition administered to a subject over a period of up to 24 hours, up to 12 hours, up to 6 hours, up to 3 hours, up to 1 hour, up to 30 minutes, up to 15 minutes, or up to 5 minutes.

可以将剂量施用至单个肌肉部位，或者可以将其分成两个或更多个部分并施用至受试者的两个或更多个肌肉部位。例如，可以将剂量的第一部分施用至受试者的臀肌的第一部分，并且可以将该剂量的第二部分施用至该受试者的臀肌的第二部分。The dose can be administered to a single muscle site, or it can be divided into two or more portions and administered to two or more muscle sites of a subject. For example, a first portion of a dose can be administered to a first portion of a subject's gluteal muscle, and a second portion of the dose can be administered to a second portion of the subject's gluteal muscle.

如本文所用，术语“初始爆释”或“初始释放”是指从向有此需要的受试者注射/施用该可注射组合物的时刻起直至施用后第三天结束，药物血浆水平加上活性代谢物血浆水平的总和，该总和在本说明书中也被称为“活性部分”(利培酮连同帕利哌酮)。例如，该药物可以是利培酮并且其代谢物可以是帕利哌酮。在一些实施方案中，初始释放期是施用后3天内、2天内、1天内、12小时内、6小时内或2小时内。As used herein, the term "initial burst" or "initial release" refers to the sum of the plasma levels of the drug plus the plasma levels of the active metabolites from the moment of injection/administration of the injectable composition to a subject in need thereof until the end of the third day after administration, which sum is also referred to as the "active portion" (risperidone together with paliperidone) in this specification. For example, the drug can be risperidone and its metabolite can be paliperidone. In some embodiments, the initial release period is within 3 days, within 2 days, within 1 day, within 12 hours, within 6 hours, or within 2 hours after administration.

制备包含各种等级的PLGA但其他方面相同的LAI持续释放组合物，以确定表现出改进性能的合适等级的PLGA。在DMSO与药物和PLGA粉末初始混合期间，它们的团聚程度通过在3分钟混合期间进行目视观察来确定。与对照制剂相比，本发明的制剂未发生团聚或解聚并形成合适LAI储库型组合物的时间更短。对照制剂未充分解聚，或者PLGA在目标3分钟或更短混合时间或200次推拉或更少次数内未完全溶解。Sustained release compositions of LAI containing various grades of PLGA but otherwise identical were prepared to determine the appropriate grade of PLGA that exhibited improved performance. During the initial mixing of DMSO with the drug and PLGA powders, their degree of agglomeration was determined by visual observation during a 3-minute mixing period. The formulations of the present invention did not agglomerate or deagglomerate and formed a suitable LAI reservoir composition in a shorter time than the control formulation. The control formulation was not fully deagglomerated, or the PLGA was not completely dissolved within the target 3 minutes or shorter mixing time or 200 push-pull times or less.

经测定，较小粒度颗粒含量过高的PLGA导致粉末状混合物过度团聚，而较大粒度颗粒含量过高的PLGA则导致PLGA溶解在DMSO中所需的时间显著增加。It was determined that too high a content of PLGA with smaller particle sizes resulted in excessive agglomeration of the powdered mixture, while too high a content of PLGA with larger particle sizes resulted in a significant increase in the time required for PLGA to dissolve in DMSO.

因此，本发明的PLGA等级改进了PLGA在PLGA和药物的粉末状混合物中的溶解性，减少了混合过程中粉末的团聚，并缩短了PLGA的溶解时间。所以，临床医生可在使用前即时制备LAI持续释放组合物，而无需在施用前花费过多时间混合各组分，并且避免了由于团聚导致的剂型失效。Therefore, the PLGA grade of the present invention improves the solubility of PLGA in a powdered mixture of PLGA and a drug, reduces powder agglomeration during mixing, and shortens the dissolution time of PLGA. Therefore, clinicians can prepare LAI sustained-release compositions immediately before use without spending too much time mixing the components before administration, and avoid dosage form failure due to agglomeration.

之后，由其各自的LAI可注射储库型组合物形成植入物。然后在体外测定植入物的药物释放曲线。Afterwards, implants were formed from their respective LAI injectable depot compositions and the drug release profiles of the implants were then determined in vitro.

对于由PLGA 1和PLGA 2(参见实施例)制成且混合不超过3分钟的植入物，药物释放性能不良(图1)。在图1所示组合物中使用的PLGA的粒度质量分布中，根据USP<786>进行筛分分析测得：16.8％的颗粒的粒度大于300μm，并且33.2％的颗粒的粒度小于150μm。通过激光衍射分析测得：在所述PLGA的粒度体积分布中，D90为352μm，并且D80为273μm。较大粒度颗粒含量过高的PLGA等级在3分钟或更短时间的重构过程中表现出PLGA不完全溶解。结果，相应的LAI储库型组合物不适用于药学。但是，对于PLGA 3和PLGA 4(参见实施例)，从其各自的植入物持续释放药物的性能良好(图2)。在图2所示组合物中使用的PLGA的粒度质量分布中，根据USP<786>进行筛分分析测得：1.2％的颗粒的粒度大于300μm，并且53.5％的颗粒的粒度小于150μm。通过激光衍射分析测得：在所述PLGA的粒度体积分布中，D90为250μm，并且D80为193μm(图4)。For implants made of PLGA 1 and PLGA 2 (see Examples) and mixed for no more than 3 minutes, the drug release performance was poor (Figure 1). In the particle size mass distribution of PLGA used in the composition shown in Figure 1, sieve analysis according to USP<786> measured: 16.8% of the particles had a particle size greater than 300μm, and 33.2% of the particles had a particle size less than 150μm. Laser diffraction analysis measured: in the particle size volume distribution of the PLGA, D90 was 352μm and D80 was 273μm. PLGA grades with too high a content of larger particle size particles showed incomplete dissolution of PLGA during reconstruction in 3 minutes or less. As a result, the corresponding LAI reservoir-type compositions are not suitable for pharmacy. However, for PLGA 3 and PLGA 4 (see Examples), the performance of sustained drug release from their respective implants was good (Figure 2). In the particle size mass distribution of PLGA used in the composition shown in Figure 2, 1.2% of the particles had a particle size greater than 300 μm and 53.5% of the particles had a particle size less than 150 μm according to sieve analysis according to USP <786>. By laser diffraction analysis, D90 was 250 μm and D80 was 193 μm in the particle size volume distribution of the PLGA (Figure 4).

当使用PLGA 5和PLGA 6时(参见实施例)，观察到广泛的颗粒团聚，并且无法在不超过3分钟的优选时间内制备合适的LAI储库型组合物。PLGA中较小粒度颗粒含量较高导致过度团聚，并且其在目标3分钟时间内无法解聚。因此，该等组合物被视为不适用于临床。在任何情况下，虽然由于团聚体不允许组合物通过针而未获得可注射组合物，但首先将小瓶中的所有组分混合并通过涡旋将它们混合30分钟来制备组合物，然后对组合物进行分析测定。将等量的该组合物装入注射器中并注射以形成植入物。尽管PLGA 5和PLGA 6未形成可接受的注射用LAI储库型组合物，但它们仍然表现出良好的药物持续释放性能(图3)。在图3所示组合物中使用的PLGA的粒度质量分布中，根据USP<786>进行筛分分析测得：0.3％的颗粒的粒度大于300μm，并且77.2％的颗粒的粒度小于150μm。通过激光衍射分析测得：在所述PLGA的粒度体积分布中，D90为168μm，并且D80为114μm。When PLGA 5 and PLGA 6 were used (see Examples), extensive particle agglomeration was observed and a suitable LAI reservoir composition could not be prepared within the preferred time of no more than 3 minutes. The high content of smaller particle size particles in PLGA resulted in excessive agglomeration, and it could not be deagglomerated within the target 3-minute time. Therefore, such compositions were considered unsuitable for clinical use. In any case, although an injectable composition was not obtained because the agglomerates did not allow the composition to pass through the needle, the composition was first prepared by mixing all the components in the vial and mixing them by vortexing for 30 minutes, and then the composition was analyzed and determined. An equal amount of the composition was loaded into a syringe and injected to form an implant. Although PLGA 5 and PLGA 6 did not form an acceptable LAI reservoir composition for injection, they still showed good sustained drug release performance (Figure 3). In the particle size mass distribution of the PLGA used in the composition shown in Figure 3, 0.3% of the particles had a particle size greater than 300 μm, and 77.2% of the particles had a particle size less than 150 μm, as measured by sieving analysis according to USP<786>. The particle size volume distribution of the PLGA was measured by laser diffraction analysis, and D90 was 168 μm and D80 was 114 μm.

因此，大粒度颗粒含量过高的PLGA造成药物释放不充分，因为该PLGA在混合期间未完全溶解，并且相应的植入物过快完成其药物释放，即三周而非四周。此外，小粒度颗粒含量过高的PLGA造成药学性能不充分，因为在重构期间粉末团聚太广泛，由此既无法形成可接受的LAI储库型组合物也无法形成可接受的植入物。Thus, PLGA with too high a content of large-size particles resulted in inadequate drug release because the PLGA did not completely dissolve during mixing, and the corresponding implant completed its drug release too quickly, i.e., in three weeks instead of four weeks. In addition, PLGA with too high a content of small-size particles resulted in inadequate pharmaceutical performance because the powder agglomerates too extensively during reconstitution, thereby failing to form either an acceptable LAI depot composition or an acceptable implant.

评价了在新西兰白兔体内PLGA粒度分布对药物释放的影响(图5A至图5C)。如本文所述用PLGA共聚物(L:G比率为50:50)、DMSO和利培酮制备可注射组合物，其中，聚合物溶液(由DMSO和利培酮制备)的表观粘度为约1.30Pa.s。评价了粒度分布(根据USP<786>进行筛分分析测得)不同的三个等级的PLGA共聚物：a)1级(图5A)，其中不超过10％的颗粒的粒度为300μm；b)2级(图5B)，其中不超过70％的颗粒的粒度小于150μm；和c)3级(图5C)，其中至少70％的颗粒的粒度为300μm或以上。出乎意料的是，用于形成可注射储库型组合物的PLGA共聚物的粒度分布会对体内药物释放曲线产生影响，因为该PLGA共聚物在被施用于动物或人之前溶解在DMSO中，并且因为用于形成该组合物的聚合物溶液的表观粘度无差异。The effect of PLGA particle size distribution on drug release in New Zealand white rabbits was evaluated (Figures 5A to 5C). An injectable composition was prepared as described herein using PLGA copolymer (L:G ratio of 50:50), DMSO and risperidone, wherein the apparent viscosity of the polymer solution (prepared from DMSO and risperidone) was about 1.30 Pa.s. Three grades of PLGA copolymers with different particle size distributions (measured by sieve analysis according to USP <786>) were evaluated: a) Grade 1 (Figure 5A), wherein no more than 10% of the particles had a particle size of 300 μm; b) Grade 2 (Figure 5B), wherein no more than 70% of the particles had a particle size of less than 150 μm; and c) Grade 3 (Figure 5C), wherein at least 70% of the particles had a particle size of 300 μm or more. Surprisingly, the particle size distribution of the PLGA copolymer used to form the injectable depot composition would have an effect on the in vivo drug release profile because the PLGA copolymer is dissolved in DMSO prior to administration to animals or humans and because there is no difference in the apparent viscosity of the polymer solutions used to form the composition.

总之，体外和体内数据表明，具有根据本发明的粒度分布的PLGA等级能够提供在目标28天期间释放药物的植入物。体外物理化学数据表明，具有根据本发明的粒度分布的PLGA等级未表现出过度团聚。使用本发明的PLGA等级可以减少完全溶解PLGA所需的时间，并且可以避免或显著减少目标混合时间内粉末的团聚。在一些实施方案中，相对于在其他方面相似但采用所要求保护粒度分布之外的PLGA等级的混合物，本发明的PLGA和药物的粉末混合物表现出团聚减少或消除。In summary, the in vitro and in vivo data show that the PLGA grades with the particle size distribution according to the present invention are able to provide implants that release drugs during the target 28 days. The in vitro physicochemical data show that the PLGA grades with the particle size distribution according to the present invention do not show excessive agglomeration. The use of the PLGA grades of the present invention can reduce the time required to completely dissolve the PLGA, and can avoid or significantly reduce the agglomeration of the powder within the target mixing time. In some embodiments, the powder mixture of the PLGA and the drug of the present invention shows reduced or eliminated agglomeration relative to a mixture of PLGA grades that are otherwise similar but use a particle size distribution other than that claimed.

在一些实施方案中，制备药学上可接受的LAI储库型组合物所需的混合时间为3分钟或更短时间、2分钟或更短时间、或者1分钟或更短时间。In some embodiments, the mixing time required to prepare a pharmaceutically acceptable LAI depot composition is 3 minutes or less, 2 minutes or less, or 1 minute or less.

本发明还涉及一种稳定的可注射肌内缓释组合物，其适合原位形成固体植入物，该固体植入物包含75mg至100mg利培酮、丙交酯与乙交酯单体比率为45:55至55:45的生物相容性PLGA共聚物和作为溶剂的DMSO，其中，该利培酮和该生物相容性PLGA包含在第一容器中，该溶剂包含在第二容器中，其中，该生物相容性共聚物的浓度相对于该生物相容性共聚物和该溶剂的重量在20％wt至50％wt之间，其中，当进行激光衍射分析测量时，该利培酮的粒度体积分布中D10等于或大于10μm、D50在60μm和130μm之间，并且D90小于或等于225μm，并且其中，该PLGA具有如本文所定义的粒度分布。The present invention also relates to a stable injectable intramuscular sustained-release composition suitable for in situ formation of a solid implant, the solid implant comprising 75 mg to 100 mg of risperidone, a biocompatible PLGA copolymer having a lactide to glycolide monomer ratio of 45:55 to 55:45, and DMSO as a solvent, wherein the risperidone and the biocompatible PLGA are contained in a first container and the solvent is contained in a second container, wherein the concentration of the biocompatible copolymer is between 20% wt and 50% wt relative to the weight of the biocompatible copolymer and the solvent, wherein the particle size volume distribution of the risperidone, when measured by laser diffraction analysis, has a D10 equal to or greater than 10 μm, a D50 between 60 μm and 130 μm, and a D90 less than or equal to 225 μm, and wherein the PLGA has a particle size distribution as defined herein.

在一个优选实施方案中，当在如本文所述的体外释放试验中进行测量时，相对于组合物中利培酮的总量，该组合物在7天时释放的利培酮小于20％，并且在21天时释放的利培酮小于90％。In a preferred embodiment, the composition releases less than 20% of risperidone at 7 days and less than 90% of risperidone at 21 days relative to the total amount of risperidone in the composition, when measured in an in vitro release assay as described herein.

本发明提供了一种用于治疗利培酮和/或帕利哌酮治疗反应性疾病、障碍或病症的方法。优选治疗的疾病、障碍或病症是精神病。有此需要的受试者可能正在经受首发或复发性精神病，并且在施用LAI持续释放组合物之前可能已经或可能尚未用抗精神病药来稳定。The present invention provides a method for treating a disease, disorder or condition responsive to risperidone and/or paliperidone treatment. Preferably, the disease, disorder or condition treated is a psychotic disorder. A subject in need thereof may be experiencing a first-episode or recurrent psychotic disorder and may or may not have been stabilized with an antipsychotic prior to administration of a LAI sustained-release composition.

在一些实施方案中，该LAI储库型组合物用于治疗精神分裂症，优选成人患者，和/或该组合物用于治疗精神分裂症，优选急性恶化和维持稳定的成人患者，特别是精神分裂症急性恶化伴有中度至重度症状且事先未口服利培酮或帕利哌酮稳定病情的患者。In some embodiments, the LAI depot composition is used to treat schizophrenia, preferably in adult patients, and/or the composition is used to treat schizophrenia, preferably in acutely exacerbated and stable adult patients, particularly patients with acute exacerbation of schizophrenia accompanied by moderate to severe symptoms and who have not been stabilized by oral risperidone or paliperidone.

在一个优选实施方案中，该LAI储库型组合物用于治疗正经受急性恶化发作的精神分裂症受试者，其中，该受试者之前未通过口服抗精神病药稳定病情。在一个具体实施方案中，在施用该组合物之前，受试者未经历口服利培酮剂量滴定。如本文所用，术语“剂量滴定”是指经口服施用利培酮以确定适合所述受试者的剂量。In a preferred embodiment, the LAI reservoir composition is used to treat a schizophrenia subject who is experiencing an acute exacerbation episode, wherein the subject has not been stabilized by oral antipsychotics. In a specific embodiment, the subject has not undergone oral risperidone dose titration prior to administration of the composition. As used herein, the term "dose titration" refers to oral administration of risperidone to determine a dose suitable for the subject.

在一个优选实施方案中，该LAI储库型组合物用于治疗正经受急性恶化发作伴有中度至重度症状的精神分裂症受试者，其中，该受试者之前未通过口服抗精神病药稳定病情。该患者可以即刻或在医学滴定后立即开始治疗，以确保利培酮是所选的治疗方法并且剂量是方便的。In a preferred embodiment, the LAI depot composition is used to treat a schizophrenia subject who is experiencing an acute exacerbation episode with moderate to severe symptoms, wherein the subject has not been previously stabilized by oral antipsychotics. The patient can start treatment immediately or immediately after medical titration to ensure that risperidone is the treatment of choice and the dosage is convenient.

在一个优选实施方案中，该LAI储库型组合物用于持续(维持)治疗稳定的受试者，该受试者已经口服施用或经由长效可注射缓释组合物施用另一种抗精神病药治疗。In a preferred embodiment, the LAI depot composition is used for continued (maintenance) treatment of a stable subject who has been treated with another antipsychotic drug either orally or via a long-acting injectable sustained-release composition.

可以施用于该受试者的其他抗精神病药包括阿立哌唑、奥氮平、布南色林、喹硫平、氟哌啶醇、氟哌噻吨、珠氯哌噻醇、布昔拉唑、卡利拉嗪、伊潘立酮、鲁拉西酮、齐拉西酮、氯丙嗪、氟奋乃静、奋乃静和/或氯氮平。这些抗精神病药可以在施用该LAI储库型组合物之前或之后施用。Other antipsychotics that can be administered to the subject include aripiprazole, olanzapine, blonanserin, quetiapine, haloperidol, flupentixol, zuclopenthixol, buxiprazole, cariprazine, iloperidone, lurasidone, ziprasidone, chlorpromazine, fluphenazine, perphenazine and/or clozapine. These antipsychotics can be administered before or after the administration of the LAI reservoir composition.

本文公开的所有值可能具有±10％的标准技术测量误差(标准偏差)。术语“约”旨在表示相对于指定值的±20％、±15％、±10％、±5％、±2.5％或±1％，即“约”20％表示20±2％、20±1％、20±0.5％或20±0.25％。All values disclosed herein may have a standard technical measurement error (standard deviation) of ±10%. The term "about" is intended to mean ±20%, ±15%, ±10%, ±5%, ±2.5% or ±1% relative to a specified value, i.e., "about" 20% means 20±2%, 20±1%, 20±0.5% or 20±0.25%.

实施例Example

以下实施例是对本发明的说明，并且不应被视为囊括所要求保护的本发明的全部范围和界限。The following examples are illustrative of the invention and should not be construed as encompassing the full scope and ambit of the claimed invention.

实施例1：组合物及其评价Example 1: Composition and evaluation thereof

用于制备各种LAI储库型组合物的组分的量详述于下表中。对照制剂是使用粒度分布超出所要求保护范围的PLGA等级来制备的。本发明的制剂是使用粒度分布在所要求保护范围内的PLGA等级来制备的。PLGA和药物包含在第一容器中，DMSO包含在第二容器中。The amounts of the components used to prepare the various LAI depot compositions are detailed in the table below. The control formulation was prepared using a PLGA grade with a particle size distribution outside the claimed range. The formulations of the present invention were prepared using a PLGA grade with a particle size distribution within the claimed range. The PLGA and drug were contained in a first container and the DMSO was contained in a second container.

制剂1：Preparation 1:

成分Element数量(mg)Quantity (mg)聚乳酸-乙醇酸共聚物(酯端基)50:50Poly(lactic acid-glycolic acid) copolymer (ester end group) 50:50150150二甲亚砜Dimethyl sulfoxide350350利培酮Risperidone7575

制剂2：Preparation 2:

成分Element数量(mg)Quantity (mg)聚乳酸-乙醇酸共聚物(酯端基)50:50Poly(lactic acid-glycolic acid) copolymer (ester end group) 50:50200200二甲亚砜Dimethyl sulfoxide467467利培酮Risperidone100100

经激光衍射分析测定，利培酮的粒径体积分布如下：d(0.1)＝33μm、d(0.5)＝81μm和d(0.9)＝160μm(Malvern Mastersizer 2000，悬浮在水中直至遮光度达到7.4％)。The particle size volume distribution of risperidone was determined by laser diffraction analysis as follows: d(0.1)=33 μm, d(0.5)=81 μm and d(0.9)=160 μm (Malvern Mastersizer 2000, suspended in water until the opacity reached 7.4%).

通过将DMSO放入第一容器并将粉末状利培酮和PLGA放入第二容器，将组分放入药物试剂盒中。优选容器为注射器。The components are placed into a pharmaceutical kit by placing DMSO in a first container and powdered risperidone and PLGA in a second container. Preferably the container is a syringe.

所评价的PLGA等级如下。The PLGA grades evaluated were as follows.

·PLGA 1：碾磨至当根据USP<786>进行筛分分析测量时，粒度质量分布中超过10％的颗粒的粒度大于300μm的PLGA；PLGA 1: PLGA that is milled until more than 10% of the particles in the particle size mass distribution have a particle size greater than 300 μm when measured by sieve analysis according to USP <786>;

·PLGA2：碾磨至当进行激光衍射分析测量时，粒度体积分布中D90大于300μm的PLGA；PLGA2: PLGA that was milled to a particle size volume distribution with a D90 greater than 300 μm when measured by laser diffraction analysis;

·PLGA 3：碾磨至当根据USP<786>进行筛分分析测量时，粒度质量分布中不超过10％的颗粒的粒度大于300μm且不超过70％的颗粒的粒度小于150μm的PLGA；PLGA 3: PLGA that is milled to a particle size distribution where no more than 10% of the particles have a size greater than 300 μm and no more than 70% of the particles have a size less than 150 μm, as measured by sieve analysis according to USP <786>;

·PLGA 4：碾磨至当进行激光衍射分析测量时，粒度体积分布中D90不大于300μm且D80不小于135μm的PLGA；PLGA 4: PLGA that has been milled to a particle size volume distribution with a D90 of no greater than 300 μm and a D80 of no less than 135 μm when measured by laser diffraction analysis;

·PLGA 5：碾磨至当根据USP<786>进行筛分分析测量时，粒度质量分布中超过70％的颗粒的粒度小于150μm的PLGA；PLGA 5: PLGA that is milled to a particle size distribution where more than 70% of the particles have a particle size less than 150 μm when measured by sieve analysis according to USP <786>;

·PLGA 6：碾磨至当进行激光衍射分析测量时，粒度体积分布中D80小于135μm的PLGA。PLGA 6: PLGA milled to a particle size volume distribution with a D80 of less than 135 μm when measured by laser diffraction analysis.

通过连接注射器并通过推拉相应的注射器柱塞来混合其组分，制备LAI储库型组合物。目视观察混合过程中粉末的团聚程度。The LAI depot composition was prepared by connecting a syringe and mixing its components by pushing and pulling the respective syringe plungers. The degree of agglomeration of the powder during mixing was visually observed.

混合(重构过程)在注射前即时进行。分析测定所需的目标最长混合时间为3分钟或更短时间(或200次推拉或更少次数)；然而，本发明制剂的优选目标最长混合时间为2分钟或更短时间、或1分钟或更短时间、或30秒或更短时间(150次推拉或更少次数、100次推拉或更少次数、或50次推拉)。测定粉末解聚和PLGA溶解所需的时间。Mixing (reconstitution process) was performed immediately prior to injection. The target maximum mixing time required for the assay was 3 minutes or less (or 200 pushes or pulls or less); however, the preferred target maximum mixing time for the formulations of the invention was 2 minutes or less, or 1 minute or less, or 30 seconds or less (150 pushes or less, 100 pushes or less, or 50 pushes or pulls). The time required for powder deagglomeration and PLGA dissolution was determined.

通过将持续释放组合物注入磷酸盐缓冲溶液中形成植入物。对该植入物进行如下体外药物溶解(药物释放)试验：以50rpm的速度进行水平轨道运动；介质：PBS，pH 7.4；温度：37±0.5℃。试验溶液中药物的浓度或量采用UV检测器(波长260nm)经HPLC测定。The implant was formed by injecting the sustained release composition into a phosphate buffer solution. The implant was subjected to the following in vitro drug dissolution (drug release) test: horizontal orbital motion at a speed of 50 rpm; medium: PBS, pH 7.4; temperature: 37±0.5°C. The concentration or amount of the drug in the test solution was determined by HPLC using a UV detector (wavelength 260 nm).

实施例2：粒度测量Example 2: Particle size measurement

根据USP<786>进行筛分分析测量Sieve analysis measurements according to USP <786>

采用以下规格的叠层筛测定了PLGA的粒度质量分布：355>300>250>150>125>106>75。振幅为0.65mm，振荡时间为5分钟。The particle size distribution of PLGA was determined using a stacked sieve with the following specifications: 355>300>250>150>125>106>75. The amplitude was 0.65 mm and the oscillation time was 5 minutes.

激光衍射Laser diffraction

PLGA的粒度分布用体积分布表示，用湿分散法通过激光衍射测定。未进行样本预处理。将样本直接加入到分散介质(水)中。分散机理为以3000rpm的转速搅拌，样本稳定30秒后再测量。The particle size distribution of PLGA is expressed as volume distribution and measured by laser diffraction using the wet dispersion method. No sample pretreatment was performed. The sample was directly added to the dispersion medium (water). The dispersion mechanism was stirring at a speed of 3000 rpm and the sample was stabilized for 30 seconds before measurement.

实施例3：组合物Example 3: Composition

用于制备各种LAI储库型组合物的组分的量详述于下表中。本发明的制剂是使用粒度分布在所要求保护范围内的PLGA等级来制备的。各LAI储库型组合物通过混合这些组分而形成。The amounts of the components used to prepare the various LAI depot compositions are detailed in the table below. The formulations of the present invention were prepared using PLGA grades with a particle size distribution within the claimed range. Each LAI depot composition was formed by mixing these components.

制剂3：Formulation 3:

成分Element数量(mg)Quantity (mg)聚乳酸-乙醇酸共聚物(酯端基)75:25Poly(lactic acid-glycolic acid) copolymer (ester end group) 75:25150150二甲亚砜Dimethyl sulfoxide350350利培酮Risperidone7575

制剂4：Preparation 4:

成分Element数量(mg)Quantity (mg)聚乳酸-乙醇酸共聚物(酯端基)75:25Poly(lactic acid-glycolic acid) copolymer (ester end group) 75:25200200二甲亚砜Dimethyl sulfoxide467467利培酮Risperidone100100

制剂5：Preparation 5:

制剂6：Preparation 6:

成分Element数量(mg)Quantity (mg)聚乳酸-乙醇酸共聚物(酯端基)50:50Poly(lactic acid-glycolic acid) copolymer (ester end group) 50:50300300二甲亚砜Dimethyl sulfoxide700700利培酮Risperidone150150

制剂7：Preparation 7:

制剂8：Preparation 8:

制剂9：Preparation 9:

成分Element数量(mg)Quantity (mg)聚乳酸-乙醇酸共聚物(酯端基)50:50Poly(lactic acid-glycolic acid) copolymer (ester end group) 50:50150150二甲亚砜Dimethyl sulfoxide350350帕利哌酮Paliperidone7575

制剂10：Preparation 10:

制剂11：Preparation 11:

成分Element数量(mg)Quantity (mg)聚乳酸-乙醇酸共聚物(酯端基)50:50Poly(lactic acid-glycolic acid) copolymer (ester end group) 50:50120120二甲亚砜Dimethyl sulfoxide228228利培酮Risperidone5656

制剂12：Preparation 12:

PLGA的固有粘度范围为0.20-0.60dL/g、约0.30-0.55dL/g、约0.36-0.52dL/g、约0.36-0.43dL/g、约0.40-0.58dL/g，或约0.46-0.51dL/g，在氯仿中于25℃或30℃下以0.1％wt/v或0.5％wt/v的浓度用乌氏0c或0b号玻璃毛细管粘度计测量，或在氯仿中于30℃下以0.5％wt/v的浓度用25号坎农-芬斯克玻璃毛细管粘度计测量(USP<911>粘度——毛细管法或《欧洲药典》第2.2.9.节中所述的毛细管粘度计法)。The intrinsic viscosity of PLGA ranges from 0.20-0.60 dL/g, about 0.30-0.55 dL/g, about 0.36-0.52 dL/g, about 0.36-0.43 dL/g, about 0.40-0.58 dL/g, or about 0.46-0.51 dL/g, measured at a concentration of 0.1% wt/v or 0.5% wt/v in chloroform at 25°C or 30°C using an Ubbelohde No. 0c or 0b glass capillary viscometer, or at a concentration of 0.5% wt/v in chloroform at 30°C using a No. 25 Cannon-Fenske glass capillary viscometer (USP <911> Viscosity - Capillary Method or the capillary viscometer method described in Section 2.2.9. of the European Pharmacopoeia).

PLGA的粒度分布如下：a)粒度质量分布，其中，当根据USP<786>进行筛分分析测量时，不超过10％的颗粒的粒度大于300μm，优选地不大于250μm；b)粒度体积分布，其中，当进行激光衍射分析测量时，D90不大于300μm，优选地不大于280μm；c)粒度质量分布，其中，当根据USP<786>进行筛分分析测量时，不超过10％的颗粒的粒度大于300μm，优选地不大于250μm，并且不超过70％的颗粒的粒度小于150μm；d)粒度质量分布，其中，当根据USP<786>进行筛分分析测量时，不超过70％的颗粒的粒度小于150μm；e)粒度体积分布，其中，当进行激光衍射分析测量时，D90不大于300μm，优选地不大于280μm，并且当进行激光衍射分析测量时，D80不小于135μm；f)粒度体积分布，其中，当进行激光衍射分析测量时，D80不小于135μm；g)D50为约50-150μm；h)D10为约10-50μm；i)D90为约170-300μm；并且/或者j)D50为约50-150μm，D10为约10-50μm，且D90为约170-300μm。The particle size distribution of PLGA is as follows: a) a particle size mass distribution, wherein no more than 10% of the particles have a particle size greater than 300 μm, preferably no more than 250 μm, when measured by sieve analysis according to USP <786>; b) a particle size volume distribution, wherein, when measured by laser diffraction analysis, D90 is no more than 300 μm, preferably no more than 280 μm; c) a particle size mass distribution, wherein, when measured by sieve analysis according to USP <786>, no more than 10% of the particles have a particle size greater than 300 μm, preferably no more than 250 μm, and no more than 70% of the particles have a particle size less than 150 μm; d) a particle size mass distribution, wherein, when measured by sieve analysis according to USP <786>, no more than 10% of the particles have a particle size greater than 300 μm, preferably no more than 250 μm, and no more than 70% of the particles have a particle size less than 150 μm; When measured by sieve analysis, no more than 70% of the particles have a particle size of less than 150 μm; e) a particle size volume distribution, wherein, when measured by laser diffraction analysis, D90 is not greater than 300 μm, preferably not greater than 280 μm, and when measured by laser diffraction analysis, D80 is not less than 135 μm; f) a particle size volume distribution, wherein, when measured by laser diffraction analysis, D80 is not less than 135 μm; g) D50 is about 50-150 μm; h) D10 is about 10-50 μm; i) D90 is about 170-300 μm; and/or j) D50 is about 50-150 μm, D10 is about 10-50 μm, and D90 is about 170-300 μm.

在形成各植入物之前，由上述组分形成的各LAI储库型组合物的表观粘度范围为约1.0-7.0Pa.s、约1.5-7.0Pa.s，或约1.8-6.5Pa.s(USP<912>粘度——旋转法或《欧洲药典》第2.2.10节中所述的粘度——旋转粘度计法)。Before forming each implant, the apparent viscosity of each LAI reservoir composition formed from the above components ranges from about 1.0-7.0 Pa.s, about 1.5-7.0 Pa.s, or about 1.8-6.5 Pa.s (USP<912> Viscosity - Rotational Method or Viscosity - Rotational Viscometer Method described in Section 2.2.10 of the European Pharmacopoeia).

实施例4：治疗精神病的方法Example 4: Method for treating mental illness

以根据本实施例制备的LAI储库型组合物的形式对患有精神分裂症的受试者肌内施用75mg或100mg剂量的利培酮。对该受试者进行评价和监测以确定该受试者对利培酮的治疗反应。如果确定治疗反应不充分，则将给予更大剂量的利培酮。A 75 mg or 100 mg dose of risperidone is administered intramuscularly to a subject suffering from schizophrenia in the form of a LAI reservoir composition prepared according to this example. The subject is evaluated and monitored to determine the subject's therapeutic response to risperidone. If it is determined that the therapeutic response is inadequate, a larger dose of risperidone will be administered.

在遵循相同程序之后可以皮下施用该LAI储库型组合物，例如施用至该受试者的脂肪组织。The LAI depot composition may be administered subcutaneously following the same procedure, for example, to the adipose tissue of the subject.

上述方法用于治疗双相情感障碍和本文公开的其他利培酮和/或帕利哌酮治疗反应性障碍。The above methods are useful for treating bipolar disorder and other risperidone and/or paliperidone treatment responsive disorders disclosed herein.

实施例5：施用方法Example 5: Method of administration

以根据本实施例制备的LAI持续释放组合物的形式对受试者肌内施用75mg或100mg剂量的利培酮。对该受试者进行评价和监测以确定该受试者对利培酮的临床反应。A dose of 75 mg or 100 mg of risperidone was administered intramuscularly to the subject in the form of a LAI sustained-release composition prepared according to this example. The subject was evaluated and monitored to determine the subject's clinical response to risperidone.

在遵循相同程序之后可以皮下施用该LAI储库型组合物，例如施用至该受试者的脂肪组织。The LAI depot composition may be administered subcutaneously following the same procedure, for example, to the adipose tissue of the subject.

实施例6：体内评价Example 6: In vivo evaluation

由本文所述的各可注射组合物形成的植入物的性能评价如下。The performance of implants formed from each of the injectable compositions described herein was evaluated as follows.

可植入制剂通过直接重构两个预充式注射器来制备，第一个注射器含有聚合物和利培酮混合物，第二个注射器含有溶剂。连接注射器并将其内容物混合以形成缓释可注射持续释放组合物。将该组合物肌内注射至平均重3公斤的新西兰白兔。注射量相当于15mg利培酮的剂量，并且使用具有20G针头的注射器将该组合物肌内注射至左后腿中。注射后，在0、4小时、1天、2天、3天、5天、7天、10天以及定期最长达28天获得血浆水平。结果详述于图5A至图5C中。Implantable formulations are prepared by directly reconstructing two prefilled syringes, the first syringe containing a polymer and risperidone mixture, and the second syringe containing a solvent. The syringes are connected and their contents are mixed to form a slow-release injectable sustained-release composition. The composition is injected intramuscularly into New Zealand white rabbits weighing an average of 3 kilograms. The injection volume is equivalent to a dose of 15mg risperidone, and the composition is injected intramuscularly into the left hind leg using a syringe with a 20G needle. After injection, plasma levels are obtained at 0, 4 hours, 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, and regularly up to 28 days. The results are detailed in Figures 5A to 5C.

Claims (22)

1. A powder mixture comprising a powdered drug and a powdered PLGA copolymer, wherein,

A) The drug is selected from the group consisting of risperidone, paliperidone, or mixtures thereof; and

B) The PLGA copolymer has a lactide (L) to glycolide (G) monomer ratio of 50:50±10% to 75:25±10%, 50:50±10% or 75:25±10% and its particle size distribution is selected from the group consisting of:

i) A particle size mass distribution wherein no more than 10% of the particles have a particle size greater than 300 μm, preferably no greater than 250 μm, as measured by sieve analysis according to USP <786 >;

ii) a particle size volume distribution wherein D90 is not more than 300 μm, preferably not more than 280 μm, when measured by laser diffraction analysis;

iii) A particle size mass distribution wherein no more than 10% of the particles have a particle size greater than 300 μm, preferably no more than 250 μm, and no more than 70% of the particles have a particle size less than 150 μm, as measured by sieve analysis according to USP <786 >;

iv) a particle size mass distribution wherein no more than 70% of the particles have a particle size of less than 150 μm as measured by sieve analysis according to USP <786 >;

v) a particle size volume distribution wherein D90 is not more than 300 μm, preferably not more than 280 μm, when measured by laser diffraction analysis and D80 is not less than 135 μm, when measured by laser diffraction analysis;

vi) a particle size volume distribution wherein D80 is not less than 135 μm when measured by laser diffraction analysis;

vii) a particle size volume distribution wherein D50 is about 50-150 μm;

viii) a particle size volume distribution wherein D10 is about 10-50 μm;

ix) a particle size volume distribution wherein D90 is about 170-300 μm;

x) a particle size volume distribution wherein D50 is about 50-150 μm, D10 is about 10-50 μm, and D90 is about 170-300 μm; and

Xi) combinations of any of the above.

2. A pharmaceutical kit comprising DMSO and the powder mixture of claim 1.

3. A method for preparing a slow release injectable suspension, the method comprising

A) Mixing DMSO, PLGA copolymer, and a drug to form the injectable suspension, wherein particles of the drug are suspended in a polymer solution formed from the DMSO and the PLGA copolymer, and wherein,

B) The drug is selected from the group consisting of risperidone, paliperidone, or mixtures thereof; and

C) The PLGA copolymer has a lactide (L) to glycolide (G) monomer ratio of 50:50±10% to 75:25±10%, 50:50±10% or 75:25±10% and its particle size distribution is selected from the group consisting of:

i) A particle size mass distribution wherein no more than 10% of the particles have a particle size greater than 300 μm, preferably no greater than 250 μm, as measured by sieve analysis according to USP <786 >;

ii) a particle size volume distribution wherein D90 is not more than 300 μm, preferably not more than 280 μm, when measured by laser diffraction analysis;

iii) A particle size mass distribution wherein no more than 10% of the particles have a particle size greater than 300 μm, preferably no more than 250 μm, and no more than 70% of the particles have a particle size less than 150 μm, as measured by sieve analysis according to USP <786 >;

iv) a particle size mass distribution wherein no more than 70% of the particles have a particle size of less than 150 μm as measured by sieve analysis according to USP <786 >;

v) a particle size volume distribution wherein D90 is not more than 300 μm, preferably not more than 280 μm, when measured by laser diffraction analysis and D80 is not less than 135 μm, when measured by laser diffraction analysis;

vi) a particle size volume distribution wherein D80 is not less than 135 μm when measured by laser diffraction analysis;

vii) a particle size volume distribution wherein D50 is about 50-150 μm;

viii) a particle size volume distribution wherein D10 is about 10-50 μm;

ix) a particle size volume distribution wherein D90 is about 170-300 μm;

x) a particle size volume distribution wherein D50 is about 50-150 μm, D10 is about 10-50 μm, and D90 is about 170-300 μm; and

Xi) combinations of any of the above.

4. A slow release injectable suspension prepared according to the method of claim 3.

5. The slow release injectable suspension of claim 4 having

A) About 25mg to about 150mg of the drug;

b) An apparent viscosity in the range of about 1.0pa.s to about 7.0 pa.s;

c) A mass ratio of the DMSO to the drug from about 5:1 to about 4:1; and

D) The mass ratio of the drug to (the PLGA + the drug) is from about 15% wt to about 40% wt expressed as a percentage of the weight of the drug relative to the total weight of the drug plus the PLGA.

6. The slow release injectable suspension of claim 4 having

A) A drug content of about 10% wt to about 15% wt;

b) DMSO content of about 55% wt to about 65% wt; and

C) A PLGA content of about 24% wt to about 30% wt; the percentages are based on the total weight of the composition.

7. The slow release injectable suspension of any one of claims 4, 5 or 6 for use in treating a subject in need thereof.

8. A sustained release injectable suspension for use according to claim 7 for the treatment of risperidone and/or paliperidone for the treatment of a reactive disease, condition or disorder.

9. The sustained release injectable suspension for use according to any one of claims 7 or 8, wherein upon administration thereof it forms an implant that continuously provides active moiety therapeutic plasma levels for at least about 28 days from the first day.

10. The slow release injectable suspension for use according to any one of claims 8 or 9, wherein the disease, condition or disorder is selected from the group consisting of: psychosis, delusional psychosis, psychotic depression, obsessive-compulsive disorder, schizophrenia, bipolar disorders, schizoaffective disorders, non-schizopsychotic disorders, asperger's syndrome, tourette's syndrome, post-traumatic stress disorder, attention deficit hyperactivity disorder, personality disorders, aggression, depression, dementia, intellectual and mental retardation disorders, autism spectrum disorders, anxiety disorders, eating disorders, anxiety, insomnia, idiopathic dystonia, drug abuse, and any combination thereof.

11. The slow release injectable suspension for use according to any one of claims 10 or 11, wherein the disease, condition or disorder is selected from the group consisting of: schizophrenia, schizoaffective disorder, bipolar affective disorder and bipolar mania.

12. A slow release injectable suspension for use according to any one of claims 10 or 11 for use in the treatment of an acute exacerbation episode of the disease, condition or disorder.

13. The slow release injectable suspension for use according to any one of claims 7 to 12, wherein the slow release injectable suspension is administered intramuscularly.

14. A pharmaceutical kit comprising a drug, DMSO and PLGA copolymer, wherein,

A) The drug is selected from the group consisting of risperidone, paliperidone, or mixtures thereof; and

B) The PLGA copolymer has a lactide (L) to glycolide (G) monomer ratio of 50:50±10% to 75:25±10%, 50:50±10% or 75:25±10% and its particle size distribution is selected from the group consisting of:

i) A particle size mass distribution wherein no more than 10% of the particles have a particle size greater than 300 μm, preferably no greater than 250 μm, as measured by sieve analysis according to USP <786 >;

ii) a particle size volume distribution wherein D90 is not more than 300 μm, preferably not more than 280 μm, when measured by laser diffraction analysis;

iii) A particle size mass distribution wherein no more than 10% of the particles have a particle size greater than 300 μm, preferably no more than 250 μm, and no more than 70% of the particles have a particle size less than 150 μm, as measured by sieve analysis according to USP <786 >;

iv) a particle size mass distribution wherein no more than 70% of the particles have a particle size of less than 150 μm as measured by sieve analysis according to USP <786 >;

v) a particle size volume distribution wherein D90 is not more than 300 μm, preferably not more than 280 μm, when measured by laser diffraction analysis and D80 is not less than 135 μm, when measured by laser diffraction analysis;

vi) a particle size volume distribution wherein D80 is not less than 135 μm when measured by laser diffraction analysis;

vii) a particle size volume distribution wherein D50 is about 50-150 μm;

viii) a particle size volume distribution wherein D10 is about 10-50 μm;

ix) a particle size volume distribution wherein D90 is about 170-300 μm;

x) a particle size volume distribution wherein D50 is about 50-150 μm, D10 is about 10-50 μm, and D90 is about 170-300 μm; and

Xi) combinations of any of the above.

15. The kit of claim 14, comprising two or more containers, wherein,

A) The DMSO is contained in a first container and the PLGA and the drug are contained together in a second container; or alternatively

B) The DMSO is contained in a first container, the PLGA is contained in a second container, and the drug is contained in a third container.

16. Kit according to claim 14 or 15, wherein,

A) The amount of the drug is from about 25mg to about 150mg;

b) The mass ratio of the drug to (the plga+the drug), expressed as a percentage of the weight of the drug relative to the total weight of the risperidone plus the PLGA, is about 15% wt to about 40% wt; and/or

C) The mass ratio of DMSO to the drug is about 5:1 to about 4:1.

17. The kit of claim 14, 15 or 16, wherein,

A) The amount of drug was about 100mg, the amount of DMSO was about 467mg, and the amount of PLGA was about 200mg;

b) The amount of drug is about 75mg, the amount of DMSO is about 350mg, and the amount of PLGA is about 150mg;

c) The amount of the drug is about 115mg (or about 100-130mg or about 105-125mg or about 110-120 mg), the amount of the DMSO is about 537mg (or about 515-560mg or about 520-550mg or about 530-545 mg), and the amount of the PLGA is about 230mg (or about 215-245mg or about 220 or about 235 mg); or alternatively

D) The amount of drug is about 90mg (or about 75-105mg or about 80-100mg or about 85-105 mg), the amount of DMSO is about 420mg (or about 405-435mg or about 415-425 mg), and the amount of PLGA is about 180mg (or about 165-200mg or about 170-190mg or about 175-185 mg).

18. The invention of any one of claims 1 to 17, wherein the PLGA has been size fractionated.

19. The invention of claim 18, wherein the PLGA has been sieved and/or crushed.

20. The invention of claim 19, wherein the PLGA has been micronized, milled, hammered, crushed, ground, milled and/or crushed.

21. The invention of any one of claims 1 to 20, wherein the PLGA is capped with an ester group.

22. The invention of any one of claims 1 to 21, wherein D10 is equal to or greater than 10 μιη, D50 is between 60 μιη and 130 μιη, and D90 is less than or equal to 225 μιη in the particle size volume distribution of the drug when measured by laser diffraction analysis.