Abstract：
Breast cancer is the most frequently diagnosed cancer in women worldwide, and non-adherence to adjuvant hormonotherapy can negatively impact cancer recurrence and relapse. Non-adherence is associated with side effects of hormonotherapy. Pharmacological strategies to mitigate the side effects include coadministration of antidepressants, however patients remain non-adherent. The aim of this work was to develop medicines containing both hormonotherapy, tamoxifen (20 mg), along with anti-depressants, either venlafaxine (37.5 or 75 mg) or duloxetine (30 or 60 mg), to assess the acceptability and efficacy of this personalised approach for mitigating tamoxifen side effects in a clinical trial. A major criterion for the developed medicines was the production rate, specified at minimum 200 dosage units per hour to produce more than 40,000 units required for the clinical trial. A novel capsule filling approach enabled by the pharmaceutical 3D printer M3DIMAKER 2 was developed for this purpose. Firstly, semi-solid extrusion 3D printing enabled the filling of tamoxifen pharma-ink prepared according to French compounding regulation, followed by filling of commercial venlafaxine or duloxetine pellets enabled by the development of an innovative pellet dispensing printhead. The medicines were successfully developed and produced in the clinical pharmacy department of the cancer hospital Gustave Roussy, located in Paris, France. The developed medicines satisfied quality and production rate requirements and were stable for storage up to one year to cover the duration of the trial. This work demonstrates the feasibility of developing and producing combined tamoxifen medicines in a hospital setting through a pharmaceutical 3D printer to enable a clinical trial with a high medicines production rate requirement.
摘要：
乳腺癌是全球女性中最常见的癌症，不坚持激素辅助治疗会对癌症的复发和复发产生负面影响。不依从性与激素疗法的副作用有关。减轻副作用的药理学策略包括抗抑郁药的共同给药，然而，患者保持非粘附性。这项工作的目的是开发含有两种激素疗法的药物，他莫昔芬（20毫克），连同抗抑郁药,文拉法辛（37.5或75毫克）或度洛西汀（30或60毫克），在临床试验中评估这种个性化方法减轻他莫昔芬副作用的可接受性和有效性。开发药物的主要标准是生产率，规定每小时至少200个剂量单位，以产生临床试验所需的40,000多个单位。为此，开发了一种由制药3D打印机M3DIMAKER2启用的新型胶囊填充方法。首先,半固体挤出3D打印能够填充根据法国复合法规制备的他莫昔芬制药墨水，然后通过开发创新的颗粒分配打印头来填充商业文拉法辛或度洛西汀颗粒。这些药物在肿瘤医院GustaveRoussy的临床药学部门成功开发和生产，位于巴黎,法国。所开发的药物满足质量和生产率要求，并且可以稳定存储长达一年，以覆盖试验的持续时间。这项工作证明了通过制药3D打印机在医院环境中开发和生产联合他莫昔芬药物的可行性，以实现具有高药物生产率要求的临床试验。
