Abstract
Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil.
Highlights
Treprostinil (TRE), a prostacyclin pulmonary vasodilator, has been approved for the treatment of pulmonary arterial hypertension (PAH) [1,2] and is available as a solution for inhalation (Tyvaso®, United Therapeutics) [3], as an oral tablet (Orenitram®, United Therapeutics) [4], and as an injection (Remodulin®, United Therapeutics) [5]
We have shown that the presence of two novel metered-dose inhaler (MDI) excipients, DSPE-PEG2000 and PEG400, is critical for obtaining the desired in vivo performance of an MDI formulation of Treprostinil palmitil (TP)
Using an iterative evaluation process focused on in vitro performance parameters, such as chemical stability, physical stability, and aerosol performance, we were able to identify a lead formulation, treprostinil palmitil inhalation aerosol (TPIA)-W, which consists of TP, DSPE-PEG2000, and PEG400 at a concentration ratio of 1:0.5:3.0 mg/mL, dissolved in HFA-134a/isopropyl alcohol (IPA) cosolvent-based propellant
Summary
Treprostinil (TRE), a prostacyclin pulmonary vasodilator, has been approved for the treatment of pulmonary arterial hypertension (PAH) [1,2] and is available as a solution for inhalation (Tyvaso®, United Therapeutics) [3], as an oral tablet (Orenitram®, United Therapeutics) [4], and as an injection (Remodulin®, United Therapeutics) [5]. Because of its short elimination half-life (≈ 30 min), inhalation treatment of PAH with TRE requires frequent dosing to sustain pulmonary vasodilation [3,5]. Inhalation of TRE is associated with adverse local and systemic events, including cough, headache, and throat irritation [1]. To overcome these shortcomings researchers, have evaluated numerous strategies to develop alternative therapies, including prodrug chemical modification of TRE [6,7], liposomal encapsulation [8,9], new devices [10], and particle engineering via modern manufacturing techniques [11,12]. We hypothesized that a prodrug formulation of TRE delivered by inhalation and designed to provide prolonged efficacy with potentially reduced adverse events following a simple administration procedure could provide a superior treatment option for PAH patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
