Novel inhalable powder formulation of pirfenidone with sustained release properties to improve pulmonary deposition

Pirfenidone (PFD) is used as an oral agent to treat idiopathic pulmonary fibrosis (IPF) [[1], [2], [3]]. PFD is known to have anti-fibrotic and anti-inflammatory potential via the regulation and inhibition of various inflammatory and fibrotic pathways [[4], [5], [6], [7], [8], [9]]. Although these beneficial effects for IPF patients, severe and frequent side effects have been reported, such as digestive symptoms and phototoxic dermatitis after oral administration [1,10,11]. The occurrence of these side effects led to a reduction in dosage or discontinuation of PFD in some patients with IPF [11,12]. Therefore, to achieve efficacious PFD treatment with wide safety margins, the avoidance or reduction of the risk of orally-dosed PFD-induced adverse effects is urgently required. Possible onset mechanisms of the adverse effects induced by orally-taken PFD have been reported [13,14], and exposure of the digestive tracts and skin to PFD may be associated with the occurrence of gastrointestinal discomfort and phototoxic skin responses, respectively. In this context, reduction of exposure of non-targeted tissues to PFD may reduce the risk of PFD-induced adverse effects.

To achieve efficacious and safe PFD medication for IPF patients, inhalation systems have been investigated [[15], [16], [17], [18], [19]], and respirable powder formulation of PFD (PFD-RP) has been newly developed to maximize topical efficacy of PFD for the lung and minimize the risk of side effects [20]. Insufflation of PFD-RP (0.3 mg-PFD/rat) could attenuate antigen-evoked lung inflammatory responses and achieve markedly lower systemic exposure to PFD compared with orally-dosed PFD at toxic doses [20,21]. Indeed, intestinal motility attenuation and dermal phototoxic events could not be observed after intratracheal administration of PFD-RP at the pharmacologically-effective dose because of limited exposure of the gastrointestinal tract and skin to PFD. On the other hand, a pharmacokinetic drawback of insufflated PFD-RP was identified in a previous investigation, specifically its rapid elimination from the lung, characterized by an elimination half-life of approximately 0.28 h [20]. Rapid elimination from the lung may necessitate frequent dosing of PFD-RP for IPF patients to achieve sufficient pharmacological efficacy; therefore, pharmacokinetic remediation to prolong retention of PFD in the lung would be required to treat IPF by inhalation systems of PFD. Sustained release techniques have been used to control drug absorption and the plasma concentration [22,23], and sustained release formulations contribute to the duration of efficacy and reduction of the risk of side effects [24,25]. There are limited reports on pharmacokinetic remediation of inhalation systems of PFD using sustained release techniques.

The aim of this study was to develop a new RP system of PFD with sustained release properties to ameliorate the pharmacokinetic drawback, particularly the rapid elimination of PFD from the lung, observed in the previously-developed PFD-RP. Several polymers were employed to fabricate solid dispersion of PFD (SD/PFD), and the dissolution behavior of SD/PFDs was examined. Based on the results of dissolution tests of SD/PFDs, SD/PFD with sustained release properties (SRSD/PFD) was chosen to prepare an RP formulation of SRSD/PFD (SRSD/PFD-RP), and physicochemical characterizations of SRSD/PFD-RP were undertaken to assess crystallinity, particle size, and surface morphology. The anti-inflammatory potential, pharmacokinetic characteristics, and in vivo skin phototoxicity after intratracheal administration of SRSD/PFD-RP were examined.

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Materials

PFD was bought from Tokyo Chemical Industry (Tokyo, Japan). Kollidon® 30,  Kollidon 90 F ,  Kollidon® SR, and Eudragit® E PO were supplied by BASF Japan Ltd. (Tokyo, Japan). Pullulan was provided by Hayashibara Co., Ltd. (Okayama, Japan). Respitose® SV-003 and erythritol were supplied by DFE Pharma (Goch, Germany) and Nikken Chemicals (Tokyo, Japan), respectively. Aluminium hydroxide gel (Alhydrogel® 2%), horseradish peroxidase, and ovalbumin (OVA) were bought from Sigma-Aldrich.

Yoshiki Seto, Gen Suzuki, Masashi Kato, Hideyuki Sato, Satomi Onoue, Novel inhalable powder formulation of pirfenidone with sustained release properties to improve pulmonary deposition, Journal of Drug Delivery Science and Technology, Volume 94, 2024, 105487, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.105487.

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