检索问题
阿立哌唑2个月长效注射剂的专利保护内容是什么？具体工艺是什么？
根据提供的证据，无法直接找到关于阿立哌唑2个月长效注射剂的具体专利保护内容。
然而，可以从以下方面推断一些与阿立哌唑长效注射剂（包括2个月长效注射剂）相关的技术和工艺信息：
1. 阿立哌唑长效注射剂的配方和给药技术：
- 剂型特点：阿立哌唑2个月长效注射剂（Ari 2MRTU 960）是一种新型长效注射型抗精神病药物制剂，设计用于每2个月臀部注射一次 。
- 给药间隔：现有长效注射剂的改进包括阿立哌唑月度单水合物，以及阿立哌唑月度制剂（AOM），支持每4周注射一次的临床使用 。阿立哌唑2个月长效注射剂的出现则进一步延长了给药间隔 。
- 成分特性：
- 阿立哌唑单水合物（AM）悬浮液的稳定性是长效注射剂的关键 。
- 注射剂通常是水性悬浮液 。
- 在制备阿立哌唑长效注射用干粉时，会涉及单水合物阿立哌唑（MA）和多晶无水阿立哌唑（AA）III型晶体的重结晶 。
- 制备的微米级粉末中，MA粉末的平均尺寸更小（2.126 μm）、分布更窄（span = 1.90），并且比AA干粉具有更高的稳定性 。
- 阿立哌唑长效注射剂的制备需要优化“自上而下”的方法，以控制晶体形式和形态，包括颗粒的形状和大小，因为这些因素会影响药物的溶解度和物理稳定性，进而影响治疗效果和安全性 。
2. 生产和制备工艺：
- 微米和纳米悬浮液：长效注射剂常使用微米和纳米悬浮液来提高生物利用度，但这些悬浮液的热力学不稳定性会带来颗粒聚集和生长等挑战 。
- 制备工艺优化：
- 研究表明，在阿立哌唑单水合物（AM）悬浮液的制备中，车辆热处理（vehicle thermal treatment）和高剪切均质（high-shear homogenization）对稳定性有显著影响 。
- 车辆热处理对羧甲基纤维素钠（CMCNa）的分子量影响最小，保持了其功能性 。
- 在珠磨过程中进行高剪切均质可以显著减少颗粒聚集，从而改善粒径分布（PSD）并降低粘度 。
- 结合车辆热处理和珠磨过程中的高剪切均质可以产生协同效应，从而在储存期间实现更优异的稳定性和最小的粒径分布和粘度变化 。
- 没有这些辅助工艺的批次，其颗粒尺寸和粘度随时间增加，表明悬浮液稳定性降低 。
- 这些发现强调了优化实验室规模工艺对确保药物悬浮液质量和安全性的重要性 。
- 聚合物胶束：有研究探索将阿立哌唑封装在Pluronic F127胶束中以提高其水溶性。采用薄膜水化技术制备载药胶束，并通过响应面法优化处方。优化后的胶束具有良好的药物载量和包封效率，并表现出较快的体外药物释放速率，是阿立哌唑潜在的递送载体 。
- 注射技术：对于某些阿立哌唑长效注射剂，例如阿立哌唑劳西尔（aripiprazole lauroxil），其配方为水性悬浮液，适用于预充式注射器。注射前需要敲击和摇晃注射器以重新悬浮药物颗粒，并要求快速注射以确保最佳注射效果 。这表明药物颗粒的均匀悬浮和分散是其给药成功的关键。
- 制剂-药代动力学关系：制剂开发对于弥合分子发现与临床评估之间的差距至关重要，特别是在难溶化合物的配方策略和长效注射制剂方面。合理的重新配方和工艺优化可以显著提高药代动力学的一致性和治疗效果，如阿立哌唑长效注射剂的案例所示 。
3. 临床应用和患者依从性：
- 长效注射剂的优势：长效注射型抗精神病药物（LAIs）是治疗精神分裂症和其他严重精神疾病的有效但可能未充分利用的治疗方案 。
- 依从性改善：LAIs通过在更长时间内维持治疗药物水平来提高患者依从性 。
- 启动方案：阿立哌唑400mg月度制剂（AOM 400）的两针启动方案（AOM 400-TIS）允许在一次就诊中开始治疗，无需14天口服阿立哌唑补充 。
- 临床疗效和安全性：
- AOM 400-TIS在改善依从性、预防复发和提高患者生活质量方面有显著目标 。
- 欧洲医护人员报告AOM 400-TIS易于管理、耐受性良好并改善了治疗效果 。
- 阿立哌唑2个月长效注射剂（Ari 2MRTU 960）在精神分裂症或I型双相障碍成人患者中通常耐受性良好，其安全性与AOM 400相当，且阿立哌唑暴露量与其等效 。
虽然现有信息没有直接揭示阿立哌唑2个月长效注射剂的专利文本或具体权利要求，但可以合理推断其专利保护可能涵盖以下创新点：
- 延长给药间隔的特殊配方：实现2个月一次给药的药物微晶或纳米颗粒的特定尺寸、形态、结晶形式和分散技术 。
- 制备工艺的改进：包括优化车辆热处理、高剪切均质、珠磨等步骤的组合，以确保悬浮液的长期稳定性和均匀性，克服粒子聚集和生长等挑战 。
- 药物递送系统：如特殊的聚合物载体（如Pluronic F127胶束）用于提高阿立哌唑的溶解度或控制释放 。
- 注射剂的特定组成：包括稳定剂（如CMCNa）、渗透压调节剂（如甘露醇）和缓冲剂（如磷酸氢二钠）在水中的特定配比 。
- 特定晶型或结晶状态：确保药物在体内缓慢释放并维持治疗水平的特定晶体形式（如单水合物）或其与无水形式的组合 。
总而言之，阿立哌唑2个月长效注射剂的专利保护内容很可能围绕其独特的制剂配方、延长药物释放的机制、克服物理稳定性和生物利用度挑战的创新制造工艺以及确保其安全有效给药的特定技术展开。
References
1Single- and multiple-dose pharmacokinetics, safety, and tolerability of Aripiprazole once-monthly, long-acting intramuscular injection for Chinese adults with schizophrenia.PubMed
Fang Dong, Feifei Wang, Xiaofei Yuan, et al.
BACKGROUND: Aripiprazole once-monthly (AOM), a long-acting injectable antipsychotic, is increasingly used in managing schizophrenia. However, to date, there has been no disclosure of pharmacokinetic data for AOM long-acting injection in the Chinese population. The present study aimed to evaluate the pharmacokinetics of AOM of Chinese patients with schizophrenia. METHODS: The single-administration part of the study was single-center and multiple-dose, in which 300/400-mg AOM was administered to 24 patients with schizophrenia. In the multiple-administration part of the study, 400-mg of AOM was administered once every 4 weeks for 20 consecutive weeks to 12 subjects. Pharmacokinetic parameters (e.g., e.g., Cmax, tmax, AUC0-∞, t1/2, and CL/F) were derived via non-compartmental analysis using actual sampling times, with bootstrap-derived confidence intervals for non-normal data. Safety evaluation included monitoring of adverse events (AEs), physical examinations, vital signs, and clinical laboratory tests. RESULTS: Following single administration of AOM (300-mg or 400-mg), maximum plasma concentration (C) values of aripiprazole were 85.05 ± 42.11 and 175.25 ± 67.84 ng/mL, respectively; median times to achieve C (t) were 816.17 and 588.84 h, respectively; and elimination half-life (t) values were 647.18 ± 234.59 and 547.17 ± 258.48 h, respectively. Following multiple administration of AOM, the C of aripiprazole was 270.18 ± 113.37 ng/mL, the median t was118.83, and the t was 1138.78 ± 998.77 h. In vivo exposure to aripiprazole increased with the AOM dose. No severe AEs were observed in single- or multiple-administration studies. CONCLUSIONS: The pharmacokinetics of AOM support its clinical use as a 4-week injectable regimen, with favorable tolerability and safety profiles observed in Chinese patients with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: Single-administration NCT03287505 first submitted on 15 May 2017, Multiple-administration NCT03285503 first submitted on 11 Sep 2017.
2Switching to long-acting injectable antipsychotics: pharmacological considerations and practical approaches.PubMed
Mikkel Højlund, Christoph U Correll
INTRODUCTION: Long-acting injectable antipsychotics (LAIs) are an effective, but potentially underutilized treatment option in schizophrenia and other severe mental illnesses. Prescribing information typically focuses on how to initiate treatment from the corresponding oral formulations. However, in clinical practice other scenarios, such as switching from other oral antipsychotics or other LAIs, occur frequently, requiring guidance. AREAS COVERED: Pharmacodynamic properties of antipsychotics and their relation to rebound symptoms. Pharmacokinetic properties of LAIs and their implications for switching approaches. Specific approaches to switching to LAIs. EXPERT OPINION: The LAI landscape has evolved significantly in the last decade with more formulations available, longer dosing intervals, and extended indications. However, currently available LAIs have various shortcomings, e.g. short dosing intervals, need for oral supplementation, loading regimens, deep intramuscular injection and/or restricted indications. Recent improvements include a one-day initiation option for aripiprazole lauroxil, aripiprazole monohydrate once-monthly, risperidone in situ microparticles and subcutaneous risperidone. Future LAI developments should focus on longer dosing intervals, subcutaneous administration, expansion of LAIs beyond currently available antipsychotic agents and indications beyond schizophrenia and bipolar disorder. In the future, LAIs might become a first-line treatment after initial oral stabilization for chronic mental disorders with need for maintenance treatment and presence of significant non-adherence.
3A Randomized, Open-Label, Multiple-Dose, Parallel-Arm, Pivotal Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Aripiprazole 2-Month Long-Acting Injectable in Adults With Schizophrenia or Bipolar I Disorder.PubMed
Matthew Harlin, Murat Yildirim, Pedro Such, et al.
BACKGROUND: Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for gluteal administration every 2 months, currently being investigated for the treatment of schizophrenia and bipolar I disorder (BP-I). The objectives of this trial were to evaluate the safety and tolerability of Ari 2MRTU 960, and the similarity of aripiprazole plasma concentrations following administration of Ari 2MRTU 960 or aripiprazole once-monthly 400 mg (AOM 400), in adults with schizophrenia or BP-I. METHODS: This was a 32-week open-label study. Eligible participants were randomized 1:1 to receive Ari 2MRTU 960 every 56 ± 2 days (four injections scheduled) or AOM 400 every 28 ± 2 days (eight injections scheduled). Participants received overlapping oral antipsychotic treatment with the first administration of study drug (there was no oral overlap for participants stabilized on AOM 400). Safety, tolerability, and pharmacokinetics (PK) were evaluated throughout the study. Primary safety endpoints included reported adverse events, injection site reactions, and extrapyramidal symptoms. Primary PK endpoints were plasma concentration of aripiprazole 56 days after the fourth dose of Ari 2MRTU 960 and 28 days after the eighth dose of AOM 400, and area under the concentration-time curve (AUC) from Day 0 to 56 postdose after the fourth dose of Ari 2MRTU 960, or AUC from Day 0 to 28 after the seventh and eighth doses of AOM 400. RESULTS: Of the 266 participants enrolled (schizophrenia, n = 185; BP-I, n = 81), 132 were randomized to receive Ari 2MRTU 960 and 134 were randomized to receive AOM 400. The majority (66.2%) of participants were male; 72.9% were Black or African American, and mean age was 47.3 years; demographic characteristics and baseline disease characteristics were generally well balanced between groups. Study completion rate was 77.3% in the Ari 2MRTU 960 group and 68.7% in the AOM 400 group. The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (71.2%) and AOM 400 (70.9%). The most frequently reported TEAEs were increased weight (Ari 2MRTU 960: 22.7%; AOM 400: 20.9%) and injection-site pain (Ari 2MRTU 960: 18.2%; AOM 400: 9.0%). The geometric means ratio (GMR) of aripiprazole plasma concentrations on the last day following the final dosing for Ari 2MRTU 960 versus AOM 400 was 1.011 (90% confidence interval [CI] 0.893-1.145), and the GMR of aripiprazole plasma exposure (area under the concentration-time curve) over the fourth Ari 2MRTU 960 dosing interval versus the seventh and eighth AOM 400 dosing intervals was 1.006 (90% CI 0.851-1.190). CONCLUSIONS: Ari 2MRTU 960 was generally well tolerated in adults with schizophrenia or BP-I, with a safety profile comparable with that of AOM 400, and aripiprazole exposure equivalent to that with AOM 400 (ClinicalTrials.gov identifier: NCT04030143, registered on 23 July 2019).
4Morphological and Crystalline Transitions in Monohydrous and Anhydrous Aripiprazole for a Long-Acting Injectable Suspension.PubMed
Xinyi Tan, Yue Zhong, Luying He, et al.
Many formulation and manufacturing processes can lead to morphological and crystalline transitions in many polycrystalline drugs, changing the properties of active pharmaceutical ingredients (APIs) such as solubility and physical stability which influence their therapeutic effects and safety and so limit their usefulness. Here, we report significant changes in crystal forms and morphology, including the shape and size of particles during the manufacture of off-white aripiprazole (APZ) dry powders used for long-acting and injectable suspensions. With the optimal top-down approach, powders were prepared by recrystallizing uniform monohydrous APZ (MA) and polycrystalline anhydrous APZ (AA) form III, characterized by thermal analysis, PXRD, and FT-IR. However, powders involving MA (MAP) with a lower mean size (2.126 μm), narrower distribution (span = 1.90), and higher stability compared with AA dry powders (AAP) were found to exhibit dehydration behavior and morphological changes after completion of the preparation processes based on the results of thermal analysis. In the case of APZ powders, we wished to obtain more information to guide in the industrial production and experimental design of suspensions in the future.
5Initiation of aripiprazole once-monthly via a two‑injection start in adult patients diagnosed with schizophrenia: real-world experiences of healthcare professionals from five European countries.PubMed
Clodagh Beckham, Murat Yildirim, Andrea Fagiolini, et al.
BACKGROUND: The aripiprazole once-monthly 400 mg two-injection start (AOM 400-TIS) enables treatment initiation at a single clinic visit, without the need for 14 days of concurrent oral aripiprazole supplementation. Previously, results from a survey outlined the views and experiences of healthcare professionals (HCPs) with the AOM 400-TIS in a real-world setting in Europe. The current work extends these findings to include a broader pool of participants from more European countries. METHODS: This was a non-interventional, cross-sectional survey of HCPs from Germany, Italy, the United Kingdom, Denmark, and Sweden. Participants were licensed nurses/physicians with experience prescribing and/or administering the AOM 400-TIS to patients diagnosed with schizophrenia. Two waves of survey data were pooled and analysed using descriptive methods. RESULTS: Data from 229 HCPs were evaluated. Poor treatment adherence (88.6%), relapse (51.1%), and patient preference (47.6%) were common reasons for using the AOM 400-TIS, while patients not wanting two injections at the same time (52.4%) and concerns about safety (34.1%) and tolerability (33.6%) were common barriers. Among HCPs, 86.0% agreed/strongly agreed they were satisfied with outcomes of patients treated with the AOM 400-TIS, with most agreeing/strongly agreeing that patients appeared satisfied in general (73.4%) and with sustained quality of life and functioning (66.4%). CONCLUSIONS: This survey provides a pan-European account of HCPs' views and experiences with the AOM 400-TIS in adults diagnosed with schizophrenia. Initiatives to overcome barriers to AOM 400-TIS use include providing clearer evidence and education on its efficacy and safety and consideration of how the regimen is presented in patient-provider discussions.
6Effectiveness of aripiprazole once-monthly in schizophrenia patients pretreated with oral aripiprazole: a 6-month, real-life non-interventional study.PubMed
Daniel Schöttle, Wolfgang Janetzky, Daniel Luedecke, et al.
BACKGROUND: In this study, the treatment of schizophrenia patients with aripiprazole once-monthly (AOM) was evaluated under real-life conditions in a naturalistic setting. METHODS: This multicenter, prospective, non-interventional study included 242 patients (age = 43.1 ± 15.1 years, 55.0% male) who were monitored during 6 months of AOM treatment. Endpoints included measurements of psychopathology (Brief Psychiatric Rating Scale, BPRS) and severity of illness scales (Clinical Global Impressions-Severity, CGI-S, and -Improvement, CGI-I). Furthermore, treatment-related adverse events (TRAEs) were recorded. RESULTS: At baseline, the mean BPRS total score was 54.1 ± 15.6, the mean CGI-S was 4.8 ± 0.8 and the most frequent illness category was 'markedly ill' (41.7%). Patients had been pretreated with oral aripiprazole for a mean duration of 9.7 months (SD: 22.3) and 87.9% were deemed by their clinician as "clinically stable" and for a mean of 5.9 months. The difference in global BPRS after 6 months was - 13.8 (SD: 16.0; 95% CI: [- 15.9; - 11.7]; p < 0.001). The proportion of patients with high CGI-S scores decreased and the proportion of patients with low scores increased significantly (p < 0.001, respectively). BPRS scores improved numerically especially well in younger patients ≤35 years, CGI-S scores decreased significantly more in this population. TRAEs were rare, with low incidences of extrapyramidal symptoms (2.9%) or weight increase (0.4%). CONCLUSIONS: Treatment with AOM showed satisfying effectiveness in outpatients with further improvement of psychopathology after oral aripiprazole treatment for a considerable duration and even after having achieved clinically judged "stability". Our findings indicate a robust therapeutic effect of AOM and substantiate previous results from randomized controlled trials under real-world routine conditions.
7Relative effectiveness of antidepressant treatments in treatment-resistant depression: a systematic review and network meta-analysis of randomized controlled trials.PubMed
Johan Saelens, Anna Gramser, Victoria Watzal, et al.
This systematic review and network meta-analysis (NMA) sought to compare different antidepressant treatments for treatment-resistant depression (TRD) in order to facilitate evidence-based choices. A literature search of PubMed, Cochrane Library, and Embase from inception until April 13th, 2023 identified randomized, controlled trials (RCTs) of adults with depression who had not responded to at least two antidepressant trials; all RCTs had ≥10 participants per study arm, and participants with bipolar or psychotic depression were excluded. The Cochrane Risk of Bias Tool-2 was used to assess study quality. Response rate was the primary outcome measure. Odds ratios (ORs) using a random effects NMA are reported. From 8234 records, 69 RCTs were included in this analysis, encompassing 10,285 participants (5662 F/4623 M) and 25 separate treatments. Six of the 25 treatments demonstrated a higher response rate versus placebo or sham treatment: electroconvulsive therapy (ECT), minocycline, theta-burst stimulation (TBS), repetitive transcranial magnetic stimulation (rTMS), ketamine, and aripiprazole. ORs ranged from 1.9 (95%CI = [1.25; 2.91]) for aripiprazole to 12.86 (95%CI = [4.07; 40.63]) for ECT. Moderate heterogeneity of the model was observed (I = 47.3% (95%CI [26.8-62%]). Of the included studies, 12.5% were rated as having high risk of bias, 28.13% as having low risk, and 59.38% as showing some concerns. Several effective treatments for TRD showed robust treatment effects across outcomes (ECT, TBS, rTMS, and ketamine), and others showed promising results for some, but not all, outcomes (minocycline, aripiprazole). These findings may help guide evidence-based treatment choices for TRD. Study Registration: PROSPERO (#CRD42023420584).
8Safety and Efficacy of Aripiprazole 2-Month Ready-to-Use 960 mg: Secondary Analysis of Outcomes in Adult Patients With Schizophrenia in a Randomized, Open-label, Parallel-Arm, Pivotal Study.PubMed
Leslie Citrome, Pedro Such, Murat Yildirim, et al.
Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for administration every 2 months. A randomized, open-label, 32-week trial evaluated the safety, tolerability, and pharmacokinetics of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (per criteria). This secondary analysis evaluated the safety and efficacy of Ari 2MRTU 960 in the subpopulation of patients with schizophrenia. Patients were randomized to receive Ari 2MRTU 960 every 56 ± 2 days (4 injections scheduled) or aripiprazole once-monthly 400 mg (AOM 400) every 28 ± 2 days (8 injections scheduled). Data were collected during August 2019-July 2020 across 16 US sites. Primary endpoints included safety and tolerability, evaluated throughout. Secondary endpoints for efficacy in patients with schizophrenia included change from baseline at week 32 in Positive and Negative Syndrome Scale, Clinical Global Impression - Severity, and Subjective Well-being under Neuroleptic Treatment - Short Form scores, along with Clinical Global Impression - Improvement at week 32. Patients with schizophrenia were randomized to Ari 2MRTU 960 (n = 92) or AOM 400 (n = 93). The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (66.3%) and AOM 400 (63.4%). The most frequently reported TEAE was increased weight (Ari 2MRTU 960: 21.7%; AOM 400: 18.3%). Patients in both treatment groups remained clinically stable throughout, with minimal change from baseline observed in efficacy parameters at week 32. Ari 2MRTU 960 was well tolerated in clinically stable patients with schizophrenia, with efficacy similar to AOM 400. ClinicalTrials.gov identifier: NCT04030143.
9The Impact of a Manufacturing Process on the Stability of Microcrystalline Long-Acting Injections: A Case Study on Aripiprazole Monohydrate.PubMed
Tomasz Pietrzak, Ziemowit Szendzielorz, Joanna Borychowska, et al.
Long-acting injections (LAIs) are innovative drug delivery systems that improve patient compliance by maintaining therapeutic drug levels over extended periods. Micro- and nanosuspensions are commonly used in LAIs to enhance bioavailability, but their thermodynamic instability poses challenges, including particle aggregation and growth. This study aimed to evaluate the impact of two helping processes-vehicle thermal treatment and high-shear homogenization-on the stability and manufacturing efficiency of aripiprazole monohydrate (AM) suspensions. AM suspensions containing sodium carboxymethyl cellulose (CMCNa), mannitol and disodium phosphate in water for injections (WFIs) were prepared using a combination of thermal treatment of the vehicle solution, high-shear homogenization and bead milling. Four manufacturing variants were tested to assess the influence of these processes on particle size distribution (PSD), viscosity and stability during a 3-month accelerated stability study. Molecular weight changes in CMCNa from thermal treatment were analyzed using size exclusion chromatography with multiangle scattering (SEC-MALS), and PSD was measured using laser diffraction. Thermal treatment of the vehicle solution had minimal impact on CMCNa molecular weight, preserving its functionality. High-shear homogenization during bead milling significantly reduced particle aggregation, resulting in improved PSD and reduced viscosity. Synergistic effects of the two helping processes used in one manufacturing process were observed, which led to superior stability and minimal changes in PSD and viscosity during storage. Batches without the helping processes exhibited increased particle size and viscosity over time, indicating reduced suspension stability. Incorporating vehicle thermal treatment and high-shear homogenization during bead milling enhances the stability and manufacturing efficiency of AM suspensions. These findings underscore the importance of optimizing laboratory-scale processes to ensure the quality and safety of pharmaceutical suspensions.
10Survey on the Initiation of Aripiprazole Once-Monthly via a Two-Injection Start in Adult Patients with Schizophrenia: Experience of European Healthcare Professionals.PubMed
Andrea Fagiolini, Karolina Leopold, Sofia Pappa, et al.
INTRODUCTION: Aripiprazole once-monthly 400 mg (AOM 400) is a long-acting injectable (LAI) for the maintenance treatment of adults with schizophrenia. The AOM 400 two-injection start initiation regimen (AOM 400-TIS) is an alternative to treatment initiation with one injection of AOM 400 plus 14 days of oral aripiprazole supplementation. This survey investigated the real-world experiences of European healthcare professionals (HCPs) with AOM 400-TIS. METHODS: Physicians and nurses in Germany, Italy, and the United Kingdom who had prescribed and/or administered AOM 400-TIS ≥ 3 times to patients with schizophrenia were invited to participate in an online survey. The primary objective was to investigate HCPs' experiences and satisfaction with AOM 400-TIS. Descriptive analysis was performed on data collected between 1 February and 21 March 2024. RESULTS: Data from 94 HCPs were analysed. Most were psychiatrists (62.8%) or psychiatric nurses (29.8%) who worked in specialist mental health clinics/centres (59.6%) or hospitals (inpatient, 36.2%; outpatient, 23.4%). Median duration in clinical practice was 21.0 years. Common reasons for initiating AOM 400-TIS were poor adherence (85.1%), relapse (59.6%), and high hospitalisation rates (48.9%). Common prescribing goals for AOM 400-TIS included improving adherence (70.2%), preventing relapses (69.1%), and improving patient quality of life (62.8%). Barriers to AOM 400-TIS were patients not wanting two injections (66.0%), tolerability concerns (30.9%), and safety concerns regarding administration of a high dose on a single day (28.7%). Key factors influencing prescription of AOM 400-TIS were prior treatment adherence (55.3%) and efficacy (48.9%). Most HCPs agreed/strongly agreed that AOM 400-TIS was easy to administer (79.8%) and had a similar safety/tolerability profile to the one-injection start regimen (69.1%), with the majority satisfied with patient outcomes with AOM 400-TIS (84.0%). CONCLUSIONS: European HCPs reported that AOM 400-TIS was easy to administer, well tolerated, and improved treatment outcomes. Barriers to its use included patient reluctance and perceived safety concerns.
11Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.PubMed
George I Papakostas, Madhukar H Trivedi, Richard C Shelton, et al.
Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.
12Best Practices for Aripiprazole Lauroxil Administration: From Formulation Development to Injection Technique.PubMed
Sarah Farwick, Magali B Hickey, Gwen Jacobs, et al.
Long-acting injectable (LAI) antipsychotics are an important treatment option for patients with schizophrenia. Advances and variability in formulation technology have provided several LAI antipsychotic treatment options for schizophrenia, with a wide range of doses and dose intervals. However, clinical reviews of LAIs have not focused on formulation development despite its clinical relevance to injection safety and technique. This article reviews the relationship between formulation technology and clinical practices for LAIs, with a focus on aripiprazole lauroxil, a long-acting atypical antipsychotic indicated for the treatment of schizophrenia. The formulation developed for aripiprazole lauroxil is an aqueous-based suspension suitable for use as a prefilled syringe that, after injection, will release aripiprazole slowly into the plasma. The clinical relationship between the aripiprazole lauroxil formulation and proper injection techniques is explained, including why tapping and shaking the syringe to resuspend the drug particles and rapid injection speed are key steps for best injection practices for this formulation.
13Aripiprazole-Loaded Polymeric Micelles: Fabrication, Optimization and Evaluation using Response Surface Method.PubMed
Payal H Patil, Pooja R Wankhede, Hitendra S Mahajan, et al.
AIMS AND BACKGROUND: The fundamental objective of current study was to encapsulate Aripiprazole (ARP) within Pluronic F127 micelles to improve its aqueous solubility. The recent patents on Aripiprazole (JP2013136621) and micelles (WO2016004369A1) facilitated selection of drug and polymer. MATERIALS AND METHODS: The drug-laden micelles were fabricated using thin-film hydration technique. Optimization of the micellar formulation was done by using response surface method (RSM). The Pluronic F127 concentration of 150 mg and 75 rpm rotational speed of rotary evaporator were found to be optimized conditions for formulating micelles. RESULTS: The prepared batches were further characterized for PDI (polydispersity index), zeta potential, % DLC (% Drug loading content), % EE (% Entrapment Efficiency) and % drug release study; results of these parameters were found to be 0.228, -4.04 mV and 76.50 % and 18.56 % respectively. It was observed from the In vitro release study that 97.37 ± 1.81 % drug had released from micelles after 20h which were found about thrice as compared to that of pure drug. The optimized ARP micellar formulation was characterized using DSC (Differential Scanning Colorimetry), FT-IR (Fourier Transformed Infrared Spectroscopy), P-XRD (Powdered X-ray Diffraction Study) and TEM (Transmission Electronic Microscopy) studies. ARP-loaded micelles displayed a hydrodynamic diameter of 170.3 nm and a sphere-shaped morphology as determined by dynamic light scattering as well as TEM study. CONCLUSION: It is concluded that the prepared polymeric micellar system has an excellent potential to be used as a delivery carrier for Aripiprazole with increased solubility.
14The role of pharmaceutical formulation development in clinical trials of new medicinal products.PubMed
Barbara Owczarek, Magdalena Markowicz- Piasecka
The discovery and development of new active pharmaceutical ingredients (APIs) is a complex and resource-intensive process characterized by high attrition rates and significant translational uncertainty. While advances in computational chemistry and AI have accelerated early-stage candidate identification, successful clinical translation depends not only on pharmacological activity but also on appropriate pharmaceutical formulation. This review examines the critical role of formulation development in bridging molecular discovery with clinical evaluation, emphasizing physicochemical characterization, enabling formulation strategies for poorly soluble compounds, and integration of mechanistic tools such as physiologically based pharmacokinetic (PBPK) and physiologically based biopharmaceutics modeling (PBBM). Particular attention is given to modified-release systems, amorphous solid dispersions, and long-acting injectable formulations, highlighting how formulation design directly influences systemic exposure, variability, and clinical reliability. Case studies of posaconazole and long-acting injectable aripiprazole demonstrate how rational reformulation and process optimization can significantly improve pharmacokinetic consistency and therapeutic performance while introducing technological and regulatory complexity. Emerging trends indicate a paradigm shift toward formulation-informed and model-integrated drug development, where AI, mechanistic modeling, and Quality by Design (QbD) principles are increasingly used to predict formulation performance and support clinical and regulatory decision-making. Integration of formulation science with predictive modeling and data-driven approaches enables earlier identification of translational risks, improves development efficiency, and enhances the probability of clinical success. Overall, formulation development should be regarded as a central determinant of clinical outcomes and regulatory success, rather than a downstream technical activity, supporting more predictive and efficient pharmaceutical development.