Design and Comprehensive Characterization of Dry Powder Inhalation Aerosols of Simvastatin DPPC/DPPG Lung Surfactant-mimic Nanoparticles/microparticles for Pulmonary Nanomedicine

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2024 Sep 17

PMID 39285876

Authors

David Encinas-Basurto

Maria F Acosta

Basanth Babu Eedara

Jeffrey R Fineman

Stephen M Black

Heidi M Mansour

Affiliations

Soon will be listed here.

Abstract

The Rho Kinase (ROCK) pathway is recognized to be involved in changes that lead to remodeling in pulmonary hypertension (PH), particularly cellular processes including signaling, contraction, migration, proliferation, differentiation, and apoptosis. Simvastatin (Sim) has a potent anti-proliferative and pro-apoptotic effect on vasculature smooth muscle cells through the inhibition of the synthesis of isoprenoids intermediates which are essential for the post-translational isoprenylation of Rho, Rac, and Ras family GTPases. Sim targets the underlying mechanism in vascular remodeling. Using bionanomaterials and particle engineering design, this innovative study reports on the advanced inhalable dry powders composed of sim with synthetic phospholipid bionanomaterials, DPPC/DPPG, as a lung surfactant-mimic. These were successfully designed and produced as co-spray dried (Co-SD) nanoparticles and microparticles for nanomedicine delivery as dry powder inhalers (DPIs). Different techniques were used to comprehensively characterize the physicochemical properties of the resulting Co-SD particles. The Next Generation ImpactorTM (NGI™) was used with three different FDA-approved human DPI devices with varying shear stress which were the HandiHaler®, Neohaler®, Aerolizer® DPI devices for aerosol dispersion performance. The formulation-device interactions were examined and correlated. Using human lung cells from different lung regions, cell viability and transepithelial electrical resistance (TEER) at the air-liquid interface showed biocompatibility of the formulations as a function of dose.

References

Hoeper M, McLaughlin V, Dalaan A, Satoh T, Galie N . Treatment of pulmonary hypertension. Lancet Respir Med. 2016; 4(4):323-36. DOI: 10.1016/S2213-2600(15)00542-1. View

Acosta M, Muralidharan P, Grijalva C, Abrahamson M, Hayes Jr D, Fineman J . Advanced therapeutic inhalation aerosols of a Nrf2 activator and RhoA/Rho kinase (ROCK) inhibitor for targeted pulmonary drug delivery in pulmonary hypertension: design, characterization, aerosolization, 2D/3D human lung cell cultures, and efficacy. Ther Adv Respir Dis. 2021; 15:1753466621998245. PMC: 7968029. DOI: 10.1177/1753466621998245. View

Meenach S, Anderson K, Hilt J, McGarry R, Mansour H . High-performing dry powder inhalers of paclitaxel DPPC/DPPG lung surfactant-mimic multifunctional particles in lung cancer: physicochemical characterization, in vitro aerosol dispersion, and cellular studies. AAPS PharmSciTech. 2014; 15(6):1574-87. PMC: 4245438. DOI: 10.1208/s12249-014-0182-z. View

Ren H, Birch N, Suresh V . An Optimised Human Cell Culture Model for Alveolar Epithelial Transport. PLoS One. 2016; 11(10):e0165225. PMC: 5079558. DOI: 10.1371/journal.pone.0165225. View

Russo P, Stigliani M, Prota L, Auriemma G, Crescenzi C, Porta A . Gentamicin and leucine inhalable powder: what about antipseudomonal activity and permeation through cystic fibrosis mucus?. Int J Pharm. 2012; 440(2):250-5. DOI: 10.1016/j.ijpharm.2012.05.077. View

Muralidharan P, Acosta M, Gomez A, Grijalva C, Tang H, Yuan J . Design and Comprehensive Characterization of Tetramethylpyrazine (TMP) for Targeted Lung Delivery as Inhalation Aerosols in Pulmonary Hypertension (PH): In Vitro Human Lung Cell Culture and In Vivo Efficacy. Antioxidants (Basel). 2021; 10(3). PMC: 7998162. DOI: 10.3390/antiox10030427. View

Loirand G, Pacaud P . The role of Rho protein signaling in hypertension. Nat Rev Cardiol. 2010; 7(11):637-47. DOI: 10.1038/nrcardio.2010.136. View

Acosta M, Muralidhran P, Abrahamson M, Grijalva C, Carver M, Tang H . 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. Pulm Pharmacol Ther. 2021; 65:101998. PMC: 8985976. DOI: 10.1016/j.pupt.2021.101998. View

Choudhary M, Chaurawal N, Abul Barkat M, Raza K . Proliposome-Based Nanostrategies: Challenges and Development as Drug Delivery Systems. AAPS PharmSciTech. 2022; 23(8):293. DOI: 10.1208/s12249-022-02443-1. View

10.

Roscigno R, Vaughn T, Parsley E, Hunt T, Eldon M, Rubin L . Comparative bioavailability of inhaled treprostinil administered as LIQ861 and Tyvaso® in healthy subjects. Vascul Pharmacol. 2021; 138:106840. DOI: 10.1016/j.vph.2021.106840. View

11.

Awad K, West J, De Jesus Perez V, MacLean M . Novel signaling pathways in pulmonary arterial hypertension (2015 Grover Conference Series). Pulm Circ. 2016; 6(3):285-94. PMC: 5019081. DOI: 10.1086/688034. View

12.

Humbert M, Lau E, Montani D, Jais X, Sitbon O, Simonneau G . Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2015; 130(24):2189-208. DOI: 10.1161/CIRCULATIONAHA.114.006974. View

13.

Alabsi W, Al-Obeidi F, Polt R, Mansour H . Organic Solution Advanced Spray-Dried Microparticulate/Nanoparticulate Dry Powders of Lactomorphin for Respiratory Delivery: Physicochemical Characterization, In Vitro Aerosol Dispersion, and Cellular Studies. Pharmaceutics. 2020; 13(1). PMC: 7824383. DOI: 10.3390/pharmaceutics13010026. View

14.

Gomez A, Acosta M, Muralidharan P, Yuan J, Black S, Hayes Jr D . Advanced spray dried proliposomes of amphotericin B lung surfactant-mimic phospholipid microparticles/nanoparticles as dry powder inhalers for targeted pulmonary drug delivery. Pulm Pharmacol Ther. 2020; 64:101975. PMC: 8923534. DOI: 10.1016/j.pupt.2020.101975. View

15.

Courrier H, Butz N, Vandamme T . Pulmonary drug delivery systems: recent developments and prospects. Crit Rev Ther Drug Carrier Syst. 2003; 19(4-5):425-98. DOI: 10.1615/critrevtherdrugcarriersyst.v19.i45.40. View

16.

Eedara B, Alabsi W, Encinas-Basurto D, Polt R, Mansour H . Spray-Dried Inhalable Powder Formulations of Therapeutic Proteins and Peptides. AAPS PharmSciTech. 2021; 22(5):185. DOI: 10.1208/s12249-021-02043-5. View

17.

Alhazmi H, Alnami A, Arishi M, Alameer R, Al Bratty M, Rehman Z . A Fast and Validated Reversed-Phase HPLC Method for Simultaneous Determination of Simvastatin, Atorvastatin, Telmisartan and Irbesartan in Bulk Drugs and Tablet Formulations. Sci Pharm. 2017; 86(1). PMC: 5874531. DOI: 10.3390/scipharm86010001. View

18.

Mandegar M, Fung Y, Huang W, Remillard C, Rubin L, Yuan J . Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvasc Res. 2004; 68(2):75-103. DOI: 10.1016/j.mvr.2004.06.001. View

19.

Hitzman C, Elmquist W, Wattenberg L, Wiedmann T . Development of a respirable, sustained release microcarrier for 5-fluorouracil I: In vitro assessment of liposomes, microspheres, and lipid coated nanoparticles. J Pharm Sci. 2006; 95(5):1114-26. DOI: 10.1002/jps.20591. View

20.

Barbalata C, Porfire A, Ambrus R, Mukhtar M, Farkas A, Tomuta I . Process development of inhalation powders containing simvastatin loaded liposomes using spray drying technology. J Liposome Res. 2023; 34(3):421-434. DOI: 10.1080/08982104.2023.2287588. View