{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T18:45:16Z","timestamp":1769453116698,"version":"3.49.0"},"reference-count":32,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T00:00:00Z","timestamp":1769299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea Grant funded by the Korean Government","award":["NRF-2021R1A2C4002746"],"award-info":[{"award-number":["NRF-2021R1A2C4002746"]}]},{"name":"Ministry of Health & Welfare, Republic of Korea","award":["RS-2024-00335798"],"award-info":[{"award-number":["RS-2024-00335798"]}]},{"name":"Korea government","award":["RS-2025-02273102"],"award-info":[{"award-number":["RS-2025-02273102"]}]},{"name":"Ministry of Education(MOE) and the (Chungcheongbuk-do), Republic of Korea","award":["2025-RISE-11-014-03"],"award-info":[{"award-number":["2025-RISE-11-014-03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: This study developed a macitentan (MAC)\u2013tadalafil (TAD) dry powder inhalation preparation using suspension-based spray drying to enhance pulmonary delivery and reduce systemic exposure to oral combination therapy in patients with pulmonary arterial hypertension (PAH). Methods: MAC\u2013TAD composite powders were prepared by physically mixing or spray-drying aqueous ethanol suspensions at various MAC:TAD ratios. The lead M2-T8 was co-spray-dried with 5, 25, or 50% (w\/w) L-leucine. Results: Spray-dried formulations exhibited narrower and more uniform particle size distributions (Dv50 2\u20136 \u00b5m; Dv90~10 \u00b5m) and higher emitted dose values than the physical mixtures. In the M2-T8 spray-dried formulation, TAD exhibited an elevated fine particle dose (FPD) (3073.45 \u00b1 1312.30 \u03bcg), demonstrating improved aerosolization relative to the physical mixture, even outperforming the TAD-higher M1-T9 formulation (2896.83 \u00b1 531.38 \u03bcg), suggesting that favorable interparticle adhesive interactions were developed during co-drying. The incorporation of 25% L-leucine produced the greatest improvement in dispersibility, increasing the FPD by ~31% for MAC and 17% for TAD, whereas excessive L-leucine (50%) reduced the aerosol performance. Powder X-ray diffraction and differential scanning calorimetry confirmed the retention of the MAC and TAD crystallinities, with L-leucine remaining either amorphous or partially crystalline. Conclusions: Suspension-based spray drying yielded MAC\u2013TAD composite formulations with improved uniformity and aerosol performance. The optimized 2:8 formulation containing 25% L-leucine demonstrated the most efficient pulmonary deposition, supporting its potential as an inhaled combination therapy for the treatment of PAH.<\/jats:p>","DOI":"10.3390\/pharmaceutics18020155","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T08:14:23Z","timestamp":1769415263000},"page":"155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Co-Spray-Dried Macitentan\u2013Tadalafil with Leucine Microparticles for Inhalable Delivery in Pulmonary Arterial Hypertension"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5431-9098","authenticated-orcid":false,"given":"Chang-Soo","family":"Han","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5650-2454","authenticated-orcid":false,"given":"Jin-Hyuk","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1072-0921","authenticated-orcid":false,"given":"Hyeon Woo","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea"},{"name":"Dongkook Pharmaceutical Co., Ltd., Gwacheon 13840, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yechan","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5329-8443","authenticated-orcid":false,"given":"Chun-Woong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Chungbuk National University, Cheongju 28644, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1517\/17460441.2016.1153625","article-title":"Novel approaches to pulmonary arterial hypertension drug discovery","volume":"11","author":"Sung","year":"2016","journal-title":"Expert Opin. 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