Gauani Helena, Baker Thomas, Li Zhili, Malinin Vladimir S, Perkins Walter R, Sullivan Eugene J, Cipolla David
Insmed Incorporated, Bridgewater, NJ 08807, USA.
Pharmaceutics. 2023 Mar 14;15(3):934. doi: 10.3390/pharmaceutics15030934.
Treprostinil palmitil (TP), a prodrug of treprostinil, is being developed as an inhalation powder (TPIP) for the treatment of patients with pulmonary arterial hypertension (PAH) and pulmonary hypertension due to interstitial lung disease (PH-ILD). In ongoing human clinical trials, TPIP is administered via a commercially available high resistance (HR) RS01 capsule-based dry powder inhaler (DPI) device manufactured by Berry Global (formerly Plastiape), which utilizes the patient's inspiratory flow to provide the required energy to deagglomerate and disperse the powder for delivery to their lungs. In this study, we characterized the aerosol performance of TPIP in response to changes in inhalation profiles to model more realistic use scenarios, i.e., for reduced inspiratory volumes and with inhalation acceleration rates that differ from those described in the compendia. The emitted dose of TP for all combinations of inhalation profiles and volumes ranged narrowly between 79 and 89% for the 16 and 32 mg TPIP capsules at the 60 LPM inspiratory flow rate but was reduced to 72-76% for the 16 mg TPIP capsule under the scenarios at the 30 LPM peak inspiratory flow rate. There were no meaningful differences in the fine particle dose (FPD) at all conditions at 60 LPM with the 4 L inhalation volume. The FPD values for the 16 mg TPIP capsule ranged narrowly between 60 and 65% of the loaded dose for all inhalation ramp rates with a 4 L volume and at both extremes of ramp rates for inhalation volumes down to 1 L, while the FPD values for the 32 mg TPIP capsule ranged between 53 and 65% of the loaded dose for all inhalation ramp rates with a 4 L volume and at both extremes of ramp rates for inhalation volumes down to 1 L for the 60 LPM flow rate. At the 30 LPM peak flow rate, the FPD values for the 16 mg TPIP capsule ranged narrowly between 54 and 58% of the loaded dose at both extremes of the ramp rates for inhalation volumes down to 1 L. Based on these in vitro findings, the TPIP delivery system appears not to be affected by the changes in inspiratory flow profiles or inspiratory volumes that might be expected to occur in patients with PAH or PH associated with underlying lung conditions such as ILD.
曲前列尼尔棕榈酸酯（TP）是曲前列尼尔的前体药物，正被开发为吸入粉雾剂（TPIP），用于治疗肺动脉高压（PAH）和间质性肺疾病所致肺动脉高压（PH-ILD）患者。在正在进行的人体临床试验中，TPIP通过Berry Global（原Plastiape）生产的基于RS01胶囊的市售高阻力（HR）干粉吸入器（DPI）装置给药，该装置利用患者的吸气气流提供所需能量，使粉末解聚并分散，以便输送至肺部。在本研究中，我们对TPIP的气溶胶性能进行了表征，以应对吸入曲线的变化，从而模拟更实际的使用场景，即吸气量减少以及吸气加速率与药典中所述不同的情况。在60升/分钟的吸气流速下，16毫克和32毫克TPIP胶囊在所有吸入曲线和体积组合下的TP发射剂量范围较窄，在79%至89%之间，但在30升/分钟的峰值吸气流速情况下，16毫克TPIP胶囊的发射剂量降至72%-76%。在60升/分钟、4升吸入体积的所有条件下，细颗粒剂量（FPD）没有显著差异。对于16毫克TPIP胶囊，在4升体积的所有吸入斜率速率下以及吸入体积低至1升的斜率速率两端，FPD值范围较窄，为装载剂量的60%至65%；对于32毫克TPIP胶囊，在60升/分钟流速下，4升体积的所有吸入斜率速率下以及吸入体积低至1升的斜率速率两端，FPD值在装载剂量的53%至65%之间。在30升/分钟的峰值流速下，对于16毫克TPIP胶囊，在吸入体积低至1升的斜率速率两端，FPD值范围较窄，为装载剂量的54%至58%。基于这些体外研究结果，TPIP给药系统似乎不受PAH或与潜在肺部疾病（如ILD）相关的PH患者可能出现的吸气气流曲线或吸气量变化的影响。
