Academic Journal
Effect of thin-film freezing process parameters and excipient composition on mRNA lipid nanoparticles in inhalable powders.
| Τίτλος: | Effect of thin-film freezing process parameters and excipient composition on mRNA lipid nanoparticles in inhalable powders. |
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| Συγγραφείς: | Sandoval MA; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, United States., Li Q; University of Pennsylvania, Perelman School of Medicine, Department of Medicine, Philadelphia, PA 19104, United States., Shi R; University of Pennsylvania, Perelman School of Medicine, Department of Medicine, Philadelphia, PA 19104, United States., Giri BR; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, United States., Yanwinitchai S; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, United States., Southard B; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, United States., Ni H; University of Pennsylvania, Perelman School of Medicine, Department of Medicine, Philadelphia, PA 19104, United States., Owens DE 3rd; TFF Pharmaceuticals, Inc., Fort Worth, TX 76107, United States., Williams RO 3rd; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, United States., Weissman D; University of Pennsylvania, Perelman School of Medicine, Department of Medicine, Philadelphia, PA 19104, United States. Electronic address: Dreww@pennmedicine.upenn.edu., Cui Z; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, United States. Electronic address: Zhengrong.Cui@austin.utexas.edu. |
| Πηγή: | International journal of pharmaceutics [Int J Pharm] 2026 Oct 05; Vol. 703, pp. 127318. Date of Electronic Publication: 2026 Aug 18. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier/North-Holland Biomedical Press Country of Publication: Netherlands NLM ID: 7804127 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3476 (Electronic) Linking ISSN: 03785173 NLM ISO Abbreviation: Int J Pharm Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Amsterdam, Elsevier/North-Holland Biomedical Press. |
| Ιατρικοί όροι (MeSH): | RNA, Messenger*/chemistry , RNA, Messenger*/administration & dosage , Nanoparticles*/chemistry , Excipients*/chemistry , Lipids*/chemistry, Chemistry, Pharmaceutical/methods ; Hemagglutinin Glycoproteins, Influenza Virus/chemistry ; Hemagglutinin Glycoproteins, Influenza Virus/genetics ; Powders ; Administration, Inhalation ; Particle Size ; Freeze Drying ; Aerosols ; Freezing ; Dry Powder Inhalers ; Drug Compounding ; Liposomes |
| Περίληψη: | Inhalable messenger RNA (mRNA) therapeutics provide direct access to the respiratory tract but liquid mRNA-lipid nanoparticle (LNP) formulations often require frozen storage and can be destabilized during nebulization. Thin-film freeze-drying (TFFD) offers a viable manufacturing approach to convert mRNA-LNP suspensions into stable dry powders with desirable aerosol performance. Our prior work focused on how LNP composition and excipients affect mRNA-LNPs when they are subject to TFFD. Herein, we evaluated how thin-film freezing (TFF) process parameters in addition to formulation composition influence mRNA-LNPs and the aerosol performance of the resultant powders, using influenza virus Cal07 hemagglutinin (Cal07 HA) mRNA-LNPs. Increasing the lipid-to-mRNA ratio (LPR) improved HA mRNA encapsulation and enabled the selection of two lead HA mRNA-LNP formulation candidates.A 2-level factorial design of experiments (DOE) showed that Tris buffer, HA mRNA-LNP type, excipients, and drum temperature affected mRNA encapsulation efficiency and mRNA-LNP particle size differently after TFFD and reconstitution. Notably, processing at -30 °C better preserved HA mRNA encapsulation efficiency than at -80 °C and this effect was formulation-dependent.The selected mRNA-LNP powders were amorphous, highly porous, and exhibited desirable aerosol performance. The immunogenicity of the HA mRNA-LNPs was maintained after TFFD and reconstitution. Importantly, HA mRNA-LNPs that were destabilized by nebulization did not show significant changes in their particle size and mRNA encapsulation efficiency when actuated as TFFD powders using a dry powder inhaler. These findings highlight the importance of TFF process parameters in developing inhalable mRNA-LNP dry powders using TFFD. (Copyright © 2026 Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Given his role as an Editor, Zhengrong Cui had no involvement in the peer review of this article and had no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to another journal editor. |
| Contributed Indexing: | Keywords: Dry powder; Freeze-drying; Immunogenicity; Inhalation; Lipid nanoparticles; mRNA |
| Substance Nomenclature: | 0 (RNA, Messenger) 0 (Excipients) 0 (Powders) 0 (Lipids) 0 (Aerosols) 0 (Lipid Nanoparticles) 0 (Hemagglutinin Glycoproteins, Influenza Virus) 0 (Liposomes) |
| Entry Date(s): | Date Created: 20260818 Date Completed: 20260919 Latest Revision: 20260919 |
| Update Code: | 20260920 |
| DOI: | 10.1016/j.ijpharm.2026.127318 |
| PMID: | 42612848 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-3476 |
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| DOI: | 10.1016/j.ijpharm.2026.127318 |