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  • Title: Comparison of l-Carnitine and l-Carnitine HCL salt for targeted lung treatment of pulmonary hypertension (PH) as inhalation aerosols: Design, comprehensive characterization, in vitro 2D/3D cell cultures, and in vivo MCT-Rat model of PH.
    Author: Acosta MF, Muralidhran P, Abrahamson MD, Grijalva CL, Carver M, Tang H, Klinger C, Fineman JR, Black SM, Mansour HM.
    Journal: Pulm Pharmacol Ther; 2020 Dec; 65():101998. PubMed ID: 33556627.
    Abstract:
    Disrupted l-Carnitine (L-Car) homeostasis has been implicated in the development of pulmonary hypertension (PH). L-Car has been administered orally and intravenously causing systemic side effects. To the authors' knowledge, there are no reports using L-Car or L-Car HCl as an inhaled aerosol through the respiratory route in a targeted manner either from dry powder inhaler (DPI) or liquid delivery system. The purpose of the comprehensive and systematic comparative study between L-Car and L-Car HCl salt was to design and develop dry powder inhalers (DPIs) of each. This was followed by comprehensive physicochemical characterization, in vitro cell viability as a function of dose on 2D human pulmonary cell lines from different lung regions and in vitro cell viability on 3D small airway epithelia human primary cells at the air-liquid interface (ALI). In addition in vitro transepithelial electrical resistance (TEER) in air-interface culture (AIC) conditions on 2D human pulmonary cell line and 3D small airway epithelia human primary cells was carried out. In vitro aerosol dispersion performance using three FDA-approved human DPI devices with different device properties was also examined. Following advanced spray drying under various conditions, two spray drying pump rates (low and medium) were found to successfully produce spray-dried L-Car powders while four spray drying pump rates (low, medium, medium-high, and high) all resulted in the production of spray-dried L-Car HCl powders. Raw L-Car and L-Car HCl were found to be crystalline. All SD powders retained crystallinity following spray drying and polymorphic interconversion in the solid-state was identified as the mechanism for retaining crystallinity after the advanced spray drying process. All SD powders aerosolized readily with all three human DPI devices. However, the in vitro dispersion parameters for the SD powders was not conducive for in vivo administration to rats in DPIs due to hygroscopicity and nanoaggreation. In vivo rat studies were successfully accomplished using inhaled liquid aerosols. Safety was successfully demonstrated in vivo in healthy Sprague Dawley rats. Furthermore, therapeutic efficacy was successfully demonstrated in vivo in the monocrotaline (MCT)-rat model of PH after two weeks of daily L-Car inhalation aerosol treatment.
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