主要研究目的：研究空腹状态下单次舌下含服受试制剂丁丙诺啡纳洛酮舌下片（规格：8mg/2mg，宜昌人福药业有限责任公司生产）与参比制剂丁丙诺啡纳洛酮舌下片（商品名：Suboxone ，规格：8mg/2mg；Indivior Europe Limited持证）在健康受试者体内的药代动力学，评价空腹状态使用两种制剂的生物等效性。次要研究目的：评价受试制剂丁丙诺啡纳洛酮舌下片（规格：8mg/2mg）和参比制剂丁丙诺啡纳洛酮舌下片（商品名：Suboxone ，规格：8mg/2mg）在健康受试者中的安全性。

开始日期2024-10-06

申办/合作机构

宜昌人福药业有限责任公司

NCT05450718 / Recruiting临床4期IIT

A Pilot Randomized Controlled Trial of Low-dose Buprenorphine Initiation for Opioid Use Disorder

The purpose of this study is to test whether low-dose buprenorphine initiation for treatment of opioid use disorder is safe and effective.

开始日期2024-10-01

申办/合作机构

Montefiore Medical Center

NCT06576843 / Recruiting临床2期

An Open-label, Multicentre Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Repeated Doses of INDV-6001 in Adults with Moderate to Severe Opioid Use Disorder

The current study will evaluate the pharmacokinetics, safety, and tolerability of INDV-6001 following multiple doses in participants with opioid use disorder in order to select optimum dosing regimens for future studies. Prior to receiving INDV-6001, participants will be stabilised on 12-16 mg of transmucosal BUP (SUBOXONE®) or will transition from a monthly maintenance dose of subcutaneous extended-release BUP (SUBLOCADE®). This study will also evaluate the use of alternative injection sites (thigh, back of upper arm), which may be desirable in this patient population for the anticipated extended durations of treatment.

开始日期2024-09-17

申办/合作机构

Indivior, Inc.

100 项与丁丙诺啡纳洛酮相关的临床结果

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100 项与丁丙诺啡纳洛酮相关的转化医学

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100 项与丁丙诺啡纳洛酮相关的专利（医药）

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项与丁丙诺啡纳洛酮相关的文献（医药）

2024-12-01·Dialogues in health

An Indigenous-led buprenorphine-naloxone treatment program to address opioid use in remote Northern Canada

Article

作者: Spence, Nicholas D ; Moriarity, Robert J ; Tsuji, Leonard J.S. ; Spence, Nicholas D. ; Charania, Nadia A. ; Sutherland, Celine ; Zuk, Aleksandra M ; Liberda, Eric N. ; Zuk, Aleksandra M. ; Moriarity, Robert J. ; Tsuji, Leonard J S ; Ahmed, Fatima ; Charania, Nadia A ; Kataquapit, Gisele ; Liberda, Eric N

Background/purpose:

In response to the opioid use challenges exacerbated from the COVID-19 pandemic, Fort Albany First Nation (FAFN), a remote Cree First Nation community situated in subarctic Ontario, Canada, implemented a buprenorphine-naloxone program. The newly initiated program was collaboratively developed by First Nations' nurses and community leaders, driven by the community's strengths, resilience, and forward-thinking approach. Using the First Nations Information Governance Centre strengths-based model, this article examines discussions with four community leaders to identify key strengths and challenges that emerged during the implementation of this program.

Methods:

this qualitative study amplify the positive aspects and community strengths through the power of oral narratives. We conducted 20 semi-structured face-to-face interviews with community members who helped lead FAFN's COVID-19 pandemic response. Utilizing the Medicine Wheel framework, this work introduces a holistic model for the buprenorphine-naloxone program that addresses the cognitive, physical, spiritual, and emotional dimensions of well-being.

Results:

Recommendations to support this initiative included the need for culturally competent staff, customized education programs, and the expanding of the program. Additionally, there is a pressing need for increased funding to support these initiatives effectively and sustainably. The development of this program, despite challenges, underscores the vital role of community leadership and cultural sensitivity to address the opioid crisis in a positive and culturally safe manner.

Conclusion:

The study highlights the successes of the buprenorphine-naloxone program, which was developed in response to the needs arising from the pandemic, specifically addressing community members suffering from opioid addiction. The timely funding for this program came as the urgent needs of community members became apparent due to pandemic lockdowns and isolation. Holistic care, including mental health services and fostering community relations, is important. By centering conversations on community strengths and advocating for culturally sensitive mental health strategies that nurture well-being, resilience, and empowerment, these findings can be adapted and expanded to support other Indigenous communities contending with opioid addiction.

2024-11-01·INTERNATIONAL JOURNAL OF LEGAL MEDICINE

Buprenorphine deaths confirmed by toxicology reveal a low proportion of opioid agonist treatment before death in Finland

Article

作者: Häkkinen, Margareeta ; Kriikku, Pirkko ; Ojanperä, Ilkka ; Mariottini, Claudia

Abstract:

We studied opioid agonist treatment (OAT) status before buprenorphine-related death in Finland, where buprenorphine is the principal OAT medicine and also the most misused opioid, through a retrospective population-based study using medico-legal cause-of-death investigation and OAT patient records. The study included all death cases (N = 570) between 2018 and 2020 with a buprenorphine or norbuprenorphine finding in post-mortem toxicology and with known drug misuse history or concomitant findings of illicit drugs. Of the deceased, 10% had received OAT in the year before death. Less than 1% of individuals < 25 years had received OAT, whereas the proportion in individuals ≥ 25 years was 13% (p < 0.001). There were significantly more females and more fatal poisonings (p < 0.001) among those < 25 years than among those ≥ 25 years. OAT medication at the time of death was sublingual buprenorphine-naloxone in 74% and subcutaneous buprenorphine in 23%. Except for significantly fewer benzodiazepine findings among those receiving OAT, minimal differences were found in terms of age, gender, cause and manner of death, or concomitant substance use between the deceased in and outside of OAT. Concomitant misuse of benzodiazepines, psychostimulants, alcohol, and gabapentinoids was frequent both in and outside of OAT and likely contributed to the death. These results suggest that access to OAT especially for young people and treatment of multiple addictions should be improved. Comprehensive information from medico-legal cause-of-death investigation as a starting point, combined with subsequent ante-mortem patient records, proved to be a successful approach to shed light on the Finnish scene of buprenorphine mortality.

2024-10-01·Journal of substance use and addiction treatment

Dissemination of health content through social networks: YouTube and opioid use disorders

Review

作者: Tofighi, Babak ; Cheng, Anna ; Lee, Joshua D ; Holmes, Perry ; O'Kelly, Bridget

INTRODUCTION:

Most Americans now access social media platforms, including YouTube, to obtain health information. However, few studies have evaluated the quality of YouTube content related to opioid use disorder (OUD), including medications for OUD (MOUD; buprenorphine) and harm reduction resources (e.g., naloxone). The purpose of this cross-sectional analysis was to assess the quality, accuracy, and reliability of MOUD and harm reduction-related video content available on YouTube.

METHODS:

The study team conducted a YouTube search between June 2022 and July 2022 using key words related to MOUD and harm reduction content (e.g., "suboxone," "methadone," "Narcan"). The 5 most viewed videos from each search term were analyzed for quality (i.e., Global Quality Scale; GQS), accuracy (i.e., JAMA Benchmark Criteria), and reliability (i.e., DISCERN). Videos that were non-English, duplicate, or that did not directly mention OUD, MOUD, or harm reduction were excluded from the review (N = 6).

RESULTS:

YouTube videos (N = 70) were mostly produced by medical professionals (27.1 %), independent nonmedical users (21.4 %; e.g., vloggers, individuals documenting their experiences), medical organizations (17.1 %; e.g., hospitals, treatment programs), and/or media (14.3 %; e.g., news agencies). The target audience was primarily the general public (65.7 %), people who use opioids (20.0 %), and healthcare providers (10.0 %). Videos containing MOUD content (N = 64, 61.4 %) mostly focused on suboxone (25.0 %), methadone (23.4 %), Sublocade (14.1 %), and subutex/buprenorphine (14.1 %). The median quality score was 2 based on the GQS with 3 videos receiving the highest quality rating (5). Two videos were highly rated for accuracy per all three JAMA Benchmark criteria. Videos produced by nonmedical educational channels had the highest overall reliability scores on the DISCERN criteria (median 4), followed by medical professionals (median 3), and medical organizations (median 2.5).

CONCLUSION:

The overall quality, accuracy, and reliability of MOUD and harm reduction related content posted on YouTube is poor. The lack of evidence-based content posted on YouTube reinforces the need for public health expert involvement in disseminating guideline-based content on social media.

项与丁丙诺啡纳洛酮相关的新闻（医药）

2024-10-25

·药研

CDE老师文章｜化学药品口颊膜剂的开发与评价探讨

（点击图片查看详情）摘要:口颊膜系指粘贴于口腔,经黏膜吸收后起全身作用的膜剂。口颊膜作为口腔黏膜给药的代表性剂型之一,具有起效快、避免药物胃肠道降解和肝脏首过效应、提高患者依从性等优势。结合近年来国内外口颊膜药物的开发和上市情况,对口颊膜处方工艺、质量研究和控制等方面进行了探讨。希望能够助力现阶段对此类产品的开发和评价,助推有临床价值的高质量口颊膜产品获批上市。膜剂根据给药部位不同,可分为口用膜、眼用膜、阴道膜等。其中口用膜可分为口溶膜、口颊膜、舌下膜和口腔贴膜。口颊膜系指粘贴于口腔,经黏膜吸收后起全身作用的膜剂[１] 。口颊膜是口腔黏膜给药系统的代表性剂型之一,目前全球已批准上市数个口颊膜产品,国内也有数个口颊膜产品开发和申报。本文对口颊膜类药物的基本情况进行介绍,结合审评工作,对口颊膜处方工艺开发、质量控制等方面进行探讨,希望为此类产品的开发和评价提供借鉴。１　基本情况１.１　定义、特点和分类　 2023年3月国家药典委员会对«中国药典»丸剂和膜剂通则修订草案公开征求意见[１] ,进一步将膜剂进行分类,膜剂根据给药部位不同,可分为口用膜、眼用膜、阴道膜等。其中口用膜可分为口溶膜、口颊膜、舌下膜和口腔贴膜。其中指出口颊膜系指粘贴于口腔,经黏膜吸收后起全身作用的膜剂;口颊膜应具有一定的黏附性;应进行溶出度或释放度检查。«欧洲药典»黏膜黏附制剂收载了口颊膜,其通常含有亲水聚合物,与唾液沾湿后会产生粘在口腔黏膜上的水凝胶;口颊膜可溶解,由单层或多层材料组成。«美国药典»指出口腔膜是将药物递送至口腔或将药物递送至胃肠道以供吸收。其中口颊膜可促进近端黏膜的吸收,避免胃肠道代谢或降解,并快速起效。与传统口服给药剂型相比,口颊膜具有自身的特点。其优点包括药物起效较快;便于携带、易于使用、剂量准确;通常可避免与胃肠道等可能引起药物降解的酸性环境接触,避免肝脏的首过效应;不需要吞咽或咀嚼、对有吞咽困难的儿童和老年人有良好的患者依从性[２] 。其局限性包括唾液的分泌会影响药物的吸收,有部分药物可能会被吞咽;服药时通常限制饮食饮水(与低ｐＨ液体同服可能会导致最大血药浓度和生物利用度下降[３] );活性成分本身的味道、刺激性可能会对口感产生的影响;药物的分子量、解离度、脂溶性和水溶性等理化性质会影响药物穿透口腔黏膜的难易程度;载药量(一般小于２０ｍｇ[４] )有一定限制等。口颊膜按照释放机理,通常分为３类[５] ,具体见图１。Ⅰ型:单层多向释药,吞咽时会造成部分药物进入胃肠道。此类口颊膜可能有胃肠道和黏膜两种吸收途径,开发此类产品时建议根据药物生物学特性谨慎考虑。Ⅱ型:双层结构,药物位于黏附层中,在黏附层的顶部叠加不透水的背衬层,防止药物从顶表面流失到口腔中。Ⅲ型:双层单向释药,药物仅从靠近颊黏膜的一侧释放,除了与口腔黏膜接触的一面外,其他每一面均被覆盖,药物损失最小化。１.２　国内外开发和上市情况美国批准上市５款可用于口颊黏膜的膜剂[６] ,具体见表１。其中３个为口颊膜,且均为Ⅱ型双层口颊膜。双层口颊膜包含背衬层和黏附层,药物位于黏附层中,通过口颊的黏膜进行吸收,背衬层防止黏附层的药物在唾液中溶解。国内目前有盐酸多塞平口颊膜和盐酸帕洛诺司琼口颊膜,按２.２类批准临床试验,尚无口颊膜类产品上市。药品出海东南亚、WHO、EU及TGA全流程指导（苏州）２　药学开发与评价关注点２.１　处方开发　典型的口颊膜处方通常包括药物活性成分、成膜材料、增塑剂、渗透促进剂、矫味剂等。不同于传统口溶膜,口颊膜多设计为双层膜,其处方由含药层和背衬层组成。含药层应具有黏膜黏附性,延长药物在口腔黏膜的停留时间,增加药物的黏膜吸收;背衬层起阻隔和屏蔽的作用,减少由于唾液冲洗和吞咽引起的药物损失,以实现药物向口腔黏膜的单向释放。表2汇总了FDA批准上市的Onsolis、Belbuca、Bunavail 3个产品处方信息。通过以上已上市产品处方的梳理,可了解口颊膜产品处方的常规组成,对研发和评价具有一定参考价值。Belbuca FDA Chemistry Reviews[7]显示,FDA批准的Onsolis、Belbuca、Bunavail 3个产品,均采用相同的生物可黏膜(BEMA)技术平台制备,产品由柔性水溶性聚合物膜组成,该膜黏附在湿润的口腔黏膜上并溶解,黏膜上无残留。应结合目标产品的质量概况(ＱＴＰＰ)的分析,选择适宜的候选药物,并对原料药关键理化特性及生物学特性进行研究。通常活性成分应具有合适的渗透性、可递送性和可吸收性,关注相关的理化性质,如分子量、ｐＫａ、溶解性等;此外还应关注口味、黏膜刺激性、粒度及粒度分布、晶型及晶型稳定性、化学稳定性等影响产品关键质量属性的指标。处方开发可参考ＩＣＨＱ８[１１] 指导原则,以制剂关键质量属性为指标,科学设计实验,对处方辅料种类及其用量进行筛选和优化。处方中所选择的辅料应无毒、无刺激性,保证产品可迅速黏附在颊黏膜处,并保持较长时间释药[５] 。口颊膜处方研究中需重点关注成膜材料、渗料透促进剂的选择和用量。成膜材料是处方中最重要的成分之一,作为药物载体可在湿润环境下提供黏附性能,口颊膜中常用的成膜材料包括胶类(如果胶)、纤维素类(如羧甲基纤维素钠、羟丙基纤维素)、聚丙烯酸聚合物类(聚丙烯酸、聚卡波菲)等[５] 。膜渗透是许多药物在口腔黏附给药系统中的限制因素,促进口腔黏膜渗透的物质称为渗透促进剂,口颊膜中常用的渗透促进剂包括表面活性剂(如十二烷基硫酸钠)、醇类(如丙二醇)、胆盐(如牛磺胆酸钠)、聚合物(如聚氧乙烯)等[１２] 。适宜的增塑剂可降低口颊膜的玻璃化转变温度,提高柔韧性,改善机械性能[１３] 。口颊膜中常用的增塑剂有丙二醇、柠檬酸、聚乙二醇(ＰＥＧ４００)等。有研究表明,处方中增塑剂与成膜材料的比例对膜剂的机械性能(断裂伸长率、杨氏模量、折叠耐久性)、厚度、溶出度等关键质量属性产生显著影响[１４] 。辅料选择时应考虑选择合适的矫掩味技术,例如,甜味剂或矫味剂的使用,可使用体外评估方法(如电子舌)和/ 或成人口尝试验对口感进行初步考察;在临床研究阶段,在目标治疗人群中进行口感评估,收集依从性和觅药行为数据以验证口感设计的合理性。背衬层起阻隔和屏蔽的作用,减少唾液冲洗和吞咽引起的药物损失,以实现药物向口腔黏膜的单向释放。口颊膜中常用的水不溶性背衬层材料为乙基纤维素。开发用于儿童人群的口颊膜时,应关注儿童用药开发指导原则[１５] 相关要求。口腔黏膜制剂的正确使用和可接受性取决于儿童患者的年龄以及在规定的时间内维持制剂处于口腔特定部位的能力。应结合药物的使用位置进行口腔黏膜制剂的黏附性研究。对于儿童药物而言,味道是决定黏膜接触时间的重要因素之一,因此对于口感的评估更加应该关注。此外,选择合适的辅料是儿童药品药学开发中的关键要素之一,开发时应尽可能使用最少种类和最低用量的辅料,应关注潜在致敏或过敏性的辅料,评估辅料的在目标儿童人群使用的安全性。２.２　生产工艺及过程控制　工艺开发时应对参照ＩＣＨＱ８[１１] 对生产工艺和工艺参数进行全面的筛选研究,以加强对产品性能和工艺的理解,建立工艺参数与制剂关键质量属性(如薄膜厚度、溶化时限、溶出度、黏附性、水分、含量和含量均匀度、机械性能等)之间的关系,并采取有效的过程控制措施。膜剂的制备工艺主要包括涂膜法、热熔挤出法、半固体溶剂浇铸法、固体分散挤压法和滚圆法等[１６] 。其中涂膜法是制备膜剂常用的方法,该方法制备工艺简单,加工成本低,易于使用[１７] 。涂膜法首先将成膜材料溶解于水或有机溶剂或两者的混合溶剂中,形成具有一定黏度的透明状溶液。当药物活性成分为水溶性时,应与成膜材料制成具有一定黏度的溶液;当药物活性成分为水不溶或难溶时,应将其粉碎并与成膜材料等混合均匀。再将药物和其他辅料溶解或分散到上述溶液中,真空脱气,倒入涂膜机中涂膜,真空干燥除去水分,脱模后裁剪成所需规格,即得[１８] 。采用涂膜法制备双层口颊膜时,涂布工艺原理和关注点与单层膜相似。影响药品关键质量属性的高风险工艺步骤通常为配液、脱泡、涂布和干燥。应根据前期开发积累的知识和经验,根据不同工艺的风险点,对关键工艺参数进行研究和确认,并针对性地开展过程控制、中间体控制。此外,双层膜的制备需重点关注双层膜的组合方式。可先分别配制各层的涂布液,采用多次涂布的方式(第一层薄膜完全干燥后,再在第一层膜上面涂第二层)[１９] ,或者分别涂布成膜后通过有机溶剂粘贴的方式组合[２０] 。双层膜制备时应关注处方和工艺对每层薄膜的机械性能、均匀性的影响;当工艺中使用有机溶剂时,关注溶剂残留量。２.３　包装　口颊膜自身特点导致可能对环境的湿度较为敏感,应选择阻隔性能符合要求的包装材料。常见的包装材料为中间隔铝的复合膜材料,单片独立包装。包装设计应能方便使用者使用,且在打开包装、运输和保存中能够确保膜的完整性[２１] 。可选择易揭型复合膜或设计易撕口,必要时增加防儿童误开的设计。２.４　质量研究　 «中国药典»２０２０年版(四部)０１２５膜剂通则中规定[２２] ,膜剂外观应完整光洁、厚度一致、色泽均匀、无明显气泡。多剂量的膜剂,分格压痕应均匀清晰,并能按压痕撕开。除另有规定外,膜剂应进行重量差异(凡进行含量均匀度检查的膜剂,一般不再进行重量差异检查)、微生物限度(微生物计数法和控制菌检查法及非无菌药品微生物限度标准检查,应符合规定)的检查。国家药典委员会发布关于征求«中国药典»丸剂和膜剂通则修订草案公开征求意见[１] 中对膜剂在生产与贮藏期间的要求进行修订,增加了口感、口腔黏膜刺激性、水分、机械性能、微生物限度、溶出度、含量均匀度及残留溶剂方面的要求。除常规口服制剂质量控制项目外,根据剂型的特点及关键质量属性,建议在处方工艺开发和研究中重点评价口颊膜的黏附性、水分、溶出度、溶化时限以及机械性能。黏附性:包括黏附时间和黏附强度。黏附时间为口颊膜贴于口腔直至完全脱落或消失所需的时间。常用测定方法包括体外法和体内法。体外法是将口颊膜与贴在动物的新鲜口腔黏膜上,并在玻片上固定,放入烧杯或溶出杯,搅拌介质,记录开始至口颊膜分离或完全腐蚀的时间[２１] 。体内法是将口颊膜黏附于健康成年志愿者颊黏膜处,评估其体内停留时间[２３] 。黏附强度为分离口颊膜所需的最大力,反映口颊膜与口腔黏膜的黏附性。目前尚无统一的测定方法,可设计开发适宜的方法,测量将制剂从黏膜或黏膜模拟物上分离所需的力。水分:口颊膜中应含有适量的水分,以保障口溶膜具有适宜的机械性能,建议设定水分的上下限,保证既不会因为水分过多导致膜产生粘连,也不会因为水分过少导致膜片变脆易碎。溶出度:溶出度可用于评估药物释放行为和制剂性能,应针对口腔黏膜生理环境设计和开发适宜的溶出方法。溶出度方法开发应关注但不限于:漏槽条件、设备和装置、溶出介质、搅拌转速等。应对所选溶出方法的区分力进行合理论证。表３汇总了ＦＤＡ已上市口颊膜品种的溶出方法,对溶出方法的选择和开发具有一定参考价值。溶化时限:建议模拟口颊膜使用方法及口腔环境,建立可行的溶化时限检查方法(少量溶剂),结合临床试验中在受试者口腔中的溶化时限及相关性考察,为方法及限度提供合理性依据。建议订入放行标准,酌情订入注册标准。机械性能:应具有适宜的机械强度,以避免包装、运输、使用过程中发生磨损或破碎。机械性能的评价指标可包含但不限于抗拉强度、伸长率、抗撕裂性、杨氏模量、耐折度等[１８] 。机械性能研究可助于指导处方工艺开发。３　结语作为口腔黏膜给药的代表性剂型之一,口颊膜与传统口服给药剂型相比,具有起效快、避免药物胃肠道降解和肝脏首过效应、提高患者依从性等优势。本文汇总了国内外药典对于口颊膜的定义和要求,汇总分析美国已批准上市产品,结合审评工作,重点对口颊膜处方工艺开发、质量研究和控制等方面进行探讨。处方开发重点关注成膜材料、渗透促进剂、增塑剂、背衬材料的选择;工艺研究根据各工艺风险点评估及口颊膜特性影响研究对关键工艺参数进行研究和确认,并针对性地开展过程控制和中间体控制,尤其关注两层膜的结合方式研究;质量研究应基于口颊膜特性,重点关注黏附性、水分、口感、溶出度以及机械性能等项目的研究。希望通过上述探讨,能够助力现阶段对此类产品的开发和评价,助推有临床价值的高质量口颊膜产品获批上市。参考文献 [１]　国家药典委员会.征求«中国药典» 丸剂和膜剂通则修订草案意见.[ＥＢ/ ＯＬ].(２０２３－０３－１４) [２０２４－６－２０].ｈｔｔｐｓ:/ / ｗｗｗ.ｃｈｐ.ｏｒｇ.ｃｎ/ ＃/ ｂｕｓｉｎｅｓｓ/ ｓｔａｎｄａｒｄ. [２] ＳＨＩＦＡＨ,ＳＨＥＥＬＡＹ,ＲＥＥＳＨＡＢ,ｅｔａｌ.Ｂｕｃｃａｌｆｉｌｍ:ａｎｏｖｅｌａｐｐｒｏａｃｈｆｏｒｏｒａｌｍｕｃｏｓａｌｄｒｕｇｄｅｌｉｖｅｒｙｓｙｓｔｅｍ[Ｊ].ＡｓｉａｎＪＰｈａｒｍＣｌｉｎＲｅｓ,２０２１,１４(１):２７－３５. [３] ＦＤＡ.２０５６３７Ｏｒｉｇ１ｓ０００ＣｌｉｎｉｃａｌＰｈａｒｍａｃｏｌｏｇｙａｎｄＢｉｏｐｈａｒｍａｃｅｕｔｉｃｓＲｅｖｉｅｗ(ｓ)[ＥＢ/ ＯＬ].(２０１４－０６－０６)[２０２４－０６－２０].ｈｔｔｐｓ:// ｗｗｗ. ａｃｃｅｓｓｄａｔａ. ｆｄａ. ｇｏｖ/ ｄｒｕｇｓａｔｆｄａ＿ｄｏｃｓ/ ｎｄａ/２０１４/２０５６３７Ｏｒｉｇ１ｓ０００ＣｌｉｎＰｈａｒｍＲ.ｐｄｆ. [４] ＪＡＧＴＡＰＶＤ.Ｂｕｃｃａｌｆｉｌｍａｒｅｖｉｅｗｏｎｎｏｖｅｌｄｒｕｇｄｅｌｉｖｅｒｙｓｙｓｔｅｍ[Ｊ].ＩｎｔＪＲｅｓＲｅｖ,２０２０(７):１７－２８. [５] ＭＩＴＵＬＰ,ＡＳＩＦＫ,ＰＲＡＴＩＫＳ,ｅｔａｌ.Ｂｕｃｃａｌｄｒｕｇｄｅｌｉｖｅｒｙｓｙｓｔｅｍ:ｔｈｅｃｕｒｒｅｎｔｉｎｔｅｒｅｓｔ[ Ｊ]. ＩＲＪＰ,２０１１,３( ３): ２９１－３０３. [６] ＦＤＡ.ＦＤＡ－ＡｐｐｒｏｖｅｄＤｒｕｇｓ [ ＤＢ/ ＯＬ].[ ２０２４－６－２０].ｈｔｔｐｓ:/ / ｗｗｗ.ａｃｃｅｓｓｄａｔａ.ｆｄａ.ｇｏｖ/ ｓｃｒｉｐｔｓ/ ｃｄｅｒ/ ｄａｆ/ . [７] ＦＤＡ.２０７９３２Ｏｒｉｇ１ｓ０００Ｃｈｅｍｉｓｔｒｙｒｅｖｉｅｗ(ｓ) [ＥＢ/ ＯＬ].(２０１５－１０－２３)[２０２４－０６－２０].ｈｔｔｐｓ:/ / ｗｗｗ.ａｃｃｅｓｓｄａｔａ.ｆｄａ.ｇｏｖ/ ｄｒｕｇｓａｔｆｄａ＿ｄｏｃｓ/ ｎｄａ/２０１５/２０７９３２Ｏｒｉｇ１ｓ０００ＣｈｅｍＲ.ｐｄｆ. [８] ＦＤＡ.ＢｅｌｂｕｃａＬａｂｅｌ[ＥＢ/ ＯＬ].(２０１５－１０－２３)[２０２４－０６－２０].ｈｔｔｐｓ:/ / ｗｗｗ.ａｃｃｅｓｓｄａｔａ.ｆｄａ.ｇｏｖ/ ｄｒｕｇｓａｔｆｄa＿ｄｏｃｓ/ｌａｂｅｌ/２０１５/２０７９３２ｓ０００ｌｂｌ.ｐｄｆ. [９] ＦＤＡ.ＢｕｎａｖａｉｌＬａｂｅｌ[ＥＢ/ ＯＬ].(２０１４－０６－０６)[２０２４－０６－２０].ｈｔｔｐｓ:/ / ｗｗｗ.ａｃｃｅｓｓｄａｔａ.ｆｄａ.ｇｏｖ/ ｄｒｕｇｓａｔｆｄａ＿ｄｏｃｓ/ｌａｂｅｌ/２０１４/２０５６３７ｓ０００ｌｂｌ.ｐｄｆ. [１０] ＦＤＡ.ＯｎｓｏｌｉｓＬａｂｅｌ[ＥＢ/ ＯＬ].(２００９－０７－１６) [２０２４－０６－２０].ｈｔｔｐｓ:/ / ｗｗｗ.ａｃｃｅｓｓｄａｔａ.ｆｄａ.ｇｏｖ/ ｄｒｕｇｓａｔｆｄａ＿ｄｏｃｓ/ｌａｂｅｌ/２００９/０２２２６６ｓ０００ｌｂｌ.ｐｄｆ. [１１] ＴｈｅＩｎｔｅｒｎａｔｉｏｎａｌＣｏｕｎｃｉｌｆｏｒＨａｒｍｏｎｉｓａｔｉｏｎｏｆＴｅｃｈｎｉｃａｌＲｅｑｕｉｒｅｍｅｎｔｓｆｏｒＰｈａｒｍａｃｅｕｔｉｃａｌｓｆｏｒＨｕｍａｎＵｓｅ. Ｑ８ＰｈａｒｍａｃｅｕｔｉｃａｌＤｅｖｅｌｏｐｍｅｎｔ[ ＥＢ/ ＯＬ].( ２００９－０８－０１) [２０２４－０６－２０].ｈｔｔｐｓ:/ / ｄａｔａｂａｓｅ.ｉｃｈ.ｏｒｇ/ ｓｉｔｅｓ/ ｄｅｆａｕｌｔ/ｆｉｌｅｓ/ Ｑ８％２８Ｒ２％２９％２０Ｇｕｉｄｅｌｉｎｅ.ｐｄｆ. [１２] 王双庆,左阿龙,郭建鹏.颊黏膜黏附膜的研究进展[Ｊ].中国现代应用药学,２０２２,３９(１):１３４－１４０. [１３] ＬＩＭＨ, ＨＯＡＧＳＷ. Ｐｌａｓｔｉｃｉｚｅｒｅｆｆｅｃｔｓｏｎｐｈｙｓiｃａｌ－ｍｅｃｈａｎｉｃａｌｐｒｏｐｅｒｔｉｅｓｏｆｓｏｌｖｅｎｔｃａｓｔＳｏｌｕｐｌｕｓⒸ ｆｉｌｍｓ[ Ｊ].ＡＡＰＳＰｈａｒｍＳｃｉＴｅｃｈ,２０１３,１４(３):９０３－９１０. [１４] ＳＯＮＡＬＭ,ＮＡＲＥＳＨＰ,ＰＲＡＳＨＡＮＴＨＭ,ｅｔａｌ.ＱｕａｌｉｔｙｂｙＤｅｓｉｇｎａｐｐｒｏａｃｈｆｏｒｓｔｕｄｙｉｎｇｔｈｅｉｍｐａｃｔｏｆｆｏｒｍｕｌａｔｉｏｎａｎｄｐｒｏｃｅｓｓｖａｒｉａｂｌｅｓｏｎｐｒｏｄｕｃｔｑｕａｌｉｔｙｏｆｏｒａｌｄｉｓｉｎｔｅｇｒａｔｉｎｇｆｉｌｍｓ[Ｊ].ＩｎｔＪＰｈａｒｍ,２０１７,５２７(１－２):１５１－１６０. [１５] 国家药品监督管理局药品审评中心.儿童用药( 化学药品)药学开发指导原则[ ＥＢ/ ＯＬ].(２０２０－１２－３１) [２０２４－０６－２０]. ｈｔｔｐｓ:/ / ｗｗｗ. ｃｄｅ. ｏｒｇ. ｃｎ/ ｍａｉｎ/ ｎｅｗｓ/ｖｉｅｗＩｎｆｏＣｏｍｍｏｎ/９５１０２ａ５ｆａｃａｆ８ｆｄ４４３０ｄ０９１６ａ２４ｅａｂ５３. [１６] 杨慧,何东升,李亚楠,等.口腔膜剂制备工艺的研究进展[Ｊ].药学研究,２０１８,３７(７):４１３－４１５. [１７] ＲＵＫＩＹＥＳＯ,ＥＭＲＡＨＯ.ＣｕｒｒｅｎｔＯｖｅｒｖｉｅｗｏｆＯｒａｌＴｈｉｎＦｉｌｍｓ[Ｊ].ＴｕｒｋＪＰｈａｒｍＳｃｉ,２０２１,１８(１):１１１－１２１ [１８] 王璐,胡延臣,王亚敏.口溶膜类新药的开发与评价探讨[Ｊ].药学研究,２０２４,４３(３):３０２－３０７. [１９] ＡＤＡＧＩＯ制药有限公司.舌下阿扑吗啡:２０１０８００３５６４４[Ｐ].２０１２－０５－３０. [２０] ＣＹＮＡＰＳＵＳ疗法有限公司.舌下薄膜:２０１１８００６７６８３[Ｐ].２０１３－１２－２５. [２１] ＳＨＩＦＡＨ,ＳＨＥＥＬＡＹ,ＲＥＥＳＨＡＢ.Ｂｕｃｃａｌｆｉｌｍ:ａｎｏｖｅｌａｐｐｒｏａｃｈｆｏｒｏｒａｌｍｕｃｏｓａｌｄｒｕｇｄｅｌｉｖｅｒｙｓｙｓｔｅｍ[Ｊ].ＡｓｉａｎＪＰｈａｒｍＣｌｉｎＲｅｓ,２０２１,１４(１):２７－３５. [２２] 国家药典委员会.中华人民共和国药典２０２０年版( 四部)[Ｓ].北京:中国医药科技出版社,２０２０. [２３] ＰＡＲＯＤＩＢ, ＲＵＳＳＯＥ, ＢＡＬＤＡＳＳＡＲＩＳ, ｅｔａｌ.Ｄｅｖｅｌｏｐｍｅｎｔａｎｄｃｈａｒａｃｔｅｒｉｚａｔｉｏｎｏｆａｍｕｃｏａｄｈｅｓｉｖｅ sｕｂｌｉｎｇｕａｌｆｏｒｍｕｌａｔｉｏｎｆｏｒｐａｉｎｃｏｎｔｒｏｌ:Ｅｘｔｅｍｐｏｒａｎｅｏｕｓｏｘｙｃｏｄｏｎｅｆｉｌｍｓｉｎｐｅｒｓｏｎａｌｉｚｅｄｔｈｅｒａｐｙ [ Ｊ]. ＤｒｕｇＤｅｖＩｎｄＰｈａｒｍ,２０１７,４３(６):９１７－９２４. [２４] ＦＤＡ.２０５６３７Ｏｒｉｇ１ｓ０００Ｃｈｅｍｉｓｔｒｙｒｅｖｉｅｗ(ｓ) [ＥＢ/ ＯＬ].(２０１４－０６－０６)[２０２４－０６－２０].ｈｔｔｐｓ:/ / ｗｗｗ.ａｃｃｅｓｓｄａｔａ.ｆｄａ.ｇｏｖ/ ｄｒｕｇｓａｔｆｄａ＿ｄｏｃｓ/ ｎｄａ/２０１４/２０５６３７Ｏｒｉｇ１ｓ０００ＣｈｅｍＲ.ｐｄｆ. [２５] ＦＤＡ.０２２２６６ｓ０００Ｃｈｅｍｉｓｔｒｙｒｅｖｉｅｗ(ｓ) [ＥＢ/ ＯＬ].(２００９－０７－１６) [ ２０２４－０６－２０].ｈｔｔｐｓ:/ / ｗｗｗ.ａｃｃｅｓｓｄａｔａ.ｆｄａ.ｇｏｖ/ ｄｒｕｇｓａｔｆｄａ＿ｄｏｃｓ/ ｎｄａ/２００９/０２２２６６ｓ０００＿ＣｈｅｍＲ＿Ｐ１.ｐｄｆ. (收稿日期:２０２４－０６－２９) ------------THE END------------ 内容来源：药学研究 2024 Vol.43,No.9 点击查看：投稿获丰厚稿费（24年6月起执行）关注药研一路同行药研论坛：始终把为药品研发一线人员提供高质量、高性价比培训为第一宗旨。自2017年成立以来，累计举办100余期药品研发、注册领域研讨班。据统计，中国医药工业百强企业和研发百强企业均超过90%参加过药研收费类培训。截至2023年底，包括上海强生、辉瑞、阿斯利康、山德士、日本大冢、大鹏、卫材、小林制药、扬子江、恒瑞、正大天晴、东阳光、科伦、中科院等在内的2800余家企事业单位参加过药研线下收费培训，得到业界普遍认可与好评！药研学院：已同众多企业合作超百期直播课，全网观看突破100万+，药研直播课聚焦药品研发相关主题，平均观看人数行业领先。药研自媒体矩阵20万+：目前药研公众号研发领域关注用户约10万人！双直播平台10万人，微信社群5万人，其中制药企业和研发机构关注量5000+。商务合作：15911172616

免疫疗法上市批准

2024-10-24

·Pharmaceutical Technology

Opioid treatment market set to grow despite expected slump in US sale value

Oxycodone is the generic name for a range of commonly-prescribed opoid pain killing tablets. Credit: Steve Heap / Shutterstock. The opioid addiction treatment market will be worth $2.4bn in eight major world markets by 2033. This is according to GlobalData, Pharmaceutical Technology ’s parent company, which forecasts that the market will grow at a compound annual rate (CAGR) of 1.8% from $2.0bn in 2023 to $2.4bn in 2033. The growth is set to be driven primarily by an increase in diagnosed prevalent opioid use disorder (OUD) cases and an increase in treatment rates across the eight major markets: the US, France, Germany, Italy, Spain, the UK, Canada, and Australia. However, GlobalData’s recent report, Opioid Addiction: Opportunity Assessment and Forecast , points out that market size is likely to see further growth as a result of the introduction of four late-stage pipeline products: cannabidiol, mazindol controlled release (CR), probenecid, and TRV-734. These products could push combined sales in the eight major markets to around $171.4mn by 2033. The biggest market is in the US which, due to its large patient population and expensive medications, constituted 74.1% of sales across the eight major markets in 2023. Jos Opdenakker, neurology analyst at GlobalData, said: “Of the four late-stage pipeline products, three of them (cannabidiol, mazindol CR, and probenecid) are non-opioids. Cannabidiol and mazindol CR are expected to be used as potential adjunctive treatments in addition to the standard of care in the treatment of opioid use disorder, driving an increase in the OUD market. Probenecid is indicated for the treatment of OWS [opioid withdrawal syndrome] and is expected to take market share from existing OWS agents.” See Also: Transforming CML patient monitoring with ICON’s innovative RNA-based NGS assay CPHI Europe: how AI can drive growth in the nutraceutical space The report highlights Trevena ’s TRV-734 as the product to watch: the pipeline product will be used in medication-assisted therapy for the treatment of OWS. Similar to other treatments, it targets the mu receptor, eliciting the partial effects of opioids to limit the side effects of withdrawal, which are often associated with opioid-based treatments. It could generate global sales of approximately $77.6m by 2033. However, Opdenakker added: “While the OUD pipeline agents will bring new mechanisms to market, they are unlikely to become first-line treatments. The need for effective non-opioid treatments that do not target the mu receptor, which could potentially replace opioids as first-line therapies, remains.” GlobalData’s forecast also expects the US market to shrink as a percentage of the overall market, estimating that the percentage of sales attributable to the US market will drop to 70.5% of the eight major markets by 2033. This is due to generic erosion, and the impending expiration of several patents ahead of 2033. Indivior ’s extended-release formulation of buprenorphine, Sublocade, was the top-selling drug in the opioid addiction market in 2023; its patent will expire in June 2031. Also set to expire during the forecast period are Alkermes ’ Vivitrol (naltrexone ER), Braeburn’s long-acting buprenorphine product, Brixadi and Orexo US’ Zubsolv (buprenorphine). Opdenakker concluded: “Although the impending entry of numerous generic products will act as a major barrier to growth and the introduction of the late-stage pipeline products is limited in their potential to generate significant revenues to counter the generic erosion, the increase in diagnosed prevalence, treatment rates, and general awareness surrounding opioid addiction will continue to act as the main drivers of growth across the eight major markets.”

2024-09-26

·FierceHealthcare

Rula Health, focused on measurement-based care, expands virtual therapy to all 50 states

Rula aims to get new patients an appointment within three days or less. Rula Health, a virtual behavioral health company, has expanded its therapy services to all 50 states and Washington, D.C.The announcement comes after the company also scaled its psychiatry services to 31 states. Established in 2019, Rula aims to improve access to personalized, in-network mental healthcare by prioritizing the therapeutic relationship and by taking a measurement-based approach to care.Previously known as Path Mental Health, the company sees all diagnoses in ages over 5. It matches patients to providers based on their preferences, including the therapist's specialty, gender and race, with exact matches found in 97% of searches, according to Rula. It also strives to get new patients an appointment within three days or less. While Rula treats substance use disorder, it does not prescribe Suboxone.“Rula is not just a health tech company, but it’s a technology-enabled provider group. And I use that very carefully and consciously because I think there’s others out there that are kind of just a platform,” Chief Medical Officer Doug Newton, MPH, M.D., told Fierce Healthcare.Every appointment, Rula providers can deploy patient-reported outcome questionnaires that get embedded into the company’s internally built EHR. These ongoing clinical measurements help track where patients are on certain scales, such as the GAD7 or the PHQ9, and enable providers to deliver the highest quality care, Newton explained: “It’s not just about the outcomes. It’s how you get there.” The completion rate for the surveys for at least several sessions is nearly 90%, per Newton. Rula’s current payer partnerships cover more than 120 million lives. It is in-network with major national and regional plans, including Optum, Cigna, Aetna, Anthem and nearly all Blues plans, according to Newton. Rula also currently takes Medicare Advantage but is interested in exploring other government payers. It has a few value-based arrangements. A small portion of Rula providers also offer a private pay option as needed.Beyond coverage, Rula also aims to take its payer and academic relationships further by focusing on quality improvement and research efforts. In the future, Rula hopes to offer additional resources to help patients in between appointments. It also hopes to better tailor the patient-reported outcome surveys to specific patient cases. For instance, Newton suggested, a patient might not need to fill out the GAD7, intended for anxiety disorder, if they have depression. “We want to be smart about it,” Newton said. “The future is going to be about personalized care.”About 50% of Rula patients have shown meaningful improvement by the fourth visit, defined by a four-point gain on the GAD7 or five points on the PHQ9, the company claimed. About 48% of patients enter remission on either the GAD7 or PH19 by the eighth visit. And nearly three-quarters of patients with severe acuity show meaningful improvements by the eighth visit.

100 项与丁丙诺啡纳洛酮相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
-	丁丙诺啡纳洛酮	N07BC51	-

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适应症	国家/地区	公司	日期
未指明的药物依赖	美国	BioDelivery Sciences International, Inc.	2014-06-06
阿片相关性障碍	欧盟	Indivior Europe Ltd.	2006-09-26
阿片相关性障碍	冰岛	Indivior Europe Ltd.	2006-09-26
阿片相关性障碍	列支敦士登	Indivior Europe Ltd.	2006-09-26
阿片相关性障碍	挪威	Indivior Europe Ltd.	2006-09-26
鸦片依赖	美国	Indivior, Inc.	2002-10-08

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适应症	最高研发状态	国家/地区	公司	日期
阿片滥用	申请上市	加拿大	Intelgenx Corp.	2022-01-30
阿片类药物依赖美沙酮	临床3期	美国	Orexo AB	2013-06-01
阿片类药物过量	临床2期	中国	南昌立健药业有限公司	2012-07-20

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04283500 (CTgov)	临床4期	阿片相关性障碍	15	Buprenorphine Naloxone	膚顧餘膚襯蓋鹽艱餘襯(獵積鹹範醖鏇積齋鏇膚) = 醖夢觸願鹹壓觸醖繭艱艱廠鏇醖憲鹹淵積襯廠 (遞構齋壓膚遞築積糧鏇, 繭鑰膚鹽願廠鑰廠簾壓 ~ 衊鹽齋鬱鏇選齋製製鹽) 更多	-	2024-04-15
NCT04521920 (PARTNER UP, Pubmed) 人工标引	N/A	阿片类药物过量 \| HIV感染	17	buprenorphine/naloxone	齋壓廠遞憲積窪蓋窪衊(壓鬱糧獵獵遞積糧鏇夢) = 蓋糧醖觸淵製醖製夢網鏇衊網艱鑰選簾廠艱襯 (艱廠衊餘選餘淵範餘積 )	积极	2024-03-26
				tenofovir disoproxil fumarate/emtricitabine	齋壓廠遞憲積窪蓋窪衊(壓鬱糧獵獵遞積糧鏇夢) = 廠衊憲積構網憲積鏇襯鏇衊網艱鑰選簾廠艱襯 (艱廠衊餘選餘淵範餘積 )
NCT03033732 (Pubmed) 人工标引	临床4期	阿片滥用	268	methadone or buprenorphine/naloxone	-	不佳	2024-03-01
				Methadone	憲積膚廠壓簾鹹構製積(衊齋積膚簾糧艱網蓋鬱) = 選範願鑰憲鏇構構憲願鹹築淵廠蓋簾願夢壓淵 (顧衊遞廠繭糧構齋範淵 ) 更多
NCT03291847 (CTgov)	临床2期	阿片相关性障碍	42	fetal monitoring+Buprenorphine Naloxone	壓醖淵觸觸衊壓糧齋願(壓網壓範選網繭鏇醖鹹) = 獵網鹹願積艱夢壓醖糧構餘淵遞壓衊壓構蓋範 (齋鹽簾願餘膚廠鏇艱衊, 顧製簾鏇蓋獵願鬱鹽選 ~ 艱窪壓醖糧壓糧淵顧網) 更多	-	2023-12-20
NCT04521920 (PARTNER UP \| Providing Suboxone and PrEP Using Telemedicine, CTgov)	N/A	阿片相关性障碍 \| 阿片滥用 \| HIV感染	17	PrEP+Suboxone	築窪鹽積選襯糧願襯廠(積鑰憲淵簾簾鑰鹽築壓) = 艱選淵鹹夢衊淵衊構壓憲齋膚衊繭衊構淵範糧 (膚蓋鏇淵艱選顧鏇繭鹹, 淵憲襯積衊襯鹹鑰夢蓋 ~ 積衊廠窪夢範築蓋淵願) 更多	-	2023-06-08
NCT03711318 (CTgov)	临床3期	海洛因依赖	8	Buprenorphine/naloxone	簾簾衊築築鏇衊鹽構範(選構壓餘窪簾構夢醖繭) = 繭鹽構遞廠鏇獵積選願餘膚鹽襯醖衊淵鑰鑰製 (獵淵網簾製範壓廠觸積, 餘艱積顧鏇鹽憲醖壓壓 ~ 齋衊觸願蓋選願製範網) 更多	-	2022-12-22
NCT00929253 (CAT, CTgov)	N/A	未指明的药物依赖	170	CM+Suboxone (Computer Delivered CRA + CM + Suboxone)	鑰鹽鹽網艱餘築鑰壓鑰(夢網網築壓鏇蓋廠鹹窪) = 顧膚構淵選衊構遞醖夢範鏇鑰襯簾繭鏇構衊鹽 (鑰願窪鏇鏇廠廠鏇範觸, 築積憲壓網遞鑰醖廠製 ~ 鑰獵鑰繭鹽齋繭齋艱艱) 更多	-	2022-05-27
				CM+Suboxone (CM + Suboxone)	鑰鹽鹽網艱餘築鑰壓鑰(夢網網築壓鏇蓋廠鹹窪) = 網衊糧繭願蓋壓網顧餘範鏇鑰襯簾繭鏇構衊鹽 (鑰願窪鏇鏇廠廠鏇範觸, 範築淵衊構積鹽夢鑰糧 ~ 鑰鬱築鏇範餘壓鹽獵襯) 更多
NCT01717963 (Pubmed \| Am J Addict)	临床3期	阿片滥用一线	143	Extended-Release Naltrexone (XR-NTX)	簾鑰繭鹹齋範選醖蓋壓(壓鹽蓋築艱遞襯鏇膚選): HR = 0.46 (95% CI, 0.28 ~ 0.76)	积极	2021-09-01
				Buprenorphine-Naloxone (BP-NLX)
NCT01936857 (BRAVO, CTgov)	临床4期	物质相关疾病 \| HIV感染	281	Buprenorphine/naloxone (Buprenorphine/Naloxone)	願糧蓋襯鑰簾繭鑰範夢(衊窪繭憲繭艱觸憲夢窪) = 蓋廠顧鑰齋築膚願鹽艱齋遞選艱齋鹹膚淵願艱 (顧襯艱獵醖襯膚鹹窪簾, 鬱鑰鬱壓廠積觸憲壓膚 ~ 廠餘顧壓鬱鹹齋蓋製窪) 更多	-	2020-06-24
				Methadone Maintenance Therapy (Methadone Maintenance Therapy)	願糧蓋襯鑰簾繭鑰範夢(衊窪繭憲繭艱觸憲夢窪) = 遞簾鬱遞餘餘鏇憲餘膚齋遞選艱齋鹹膚淵願艱 (顧襯艱獵醖襯膚鹹窪簾, 築遞淵壓夢廠膚鏇夢鹽 ~ 鏇壓簾製遞糧衊積餘鹹) 更多
NCT01550341 (STRIDE, CTgov)	N/A	获得性免疫缺陷综合征 \| 未指明的药物依赖	50	Buprenorphine/naloxone (Buprenorphine)	憲醖餘艱膚憲範廠願範(廠糧鏇衊醖艱膚範衊衊) = 齋製憲顧積顧廠簾餘廠廠構鏇鹽觸醖憲鬱壓網 (構鑰醖鑰鬱糧網蓋鬱網, 廠憲遞夢鏇襯糧築壓衊 ~ 顧簾簾淵蓋鏇淵鬱願網) 更多	-	2020-05-06
				Placebo Oral Tablet (Placebo)	憲醖餘艱膚憲範廠願範(廠糧鏇衊醖艱膚範衊衊) = 鑰餘構願顧製鬱襯艱壓廠構鏇鹽觸醖憲鬱壓網 (構鑰醖鑰鬱糧網蓋鬱網, 蓋膚鏇繭獵鹽獵鹹鹽範 ~ 鑰製醖蓋壓艱夢壓簾蓋) 更多