Amorphous Solid Dispersionbased Dissolving Microneedles for Transdermal Delivery of Ivacaftor
DOI:
https://doi.org/10.22159/ijap.2026v18i5.59390Keywords:
Ivacaftor, Amorphous solid dispersion, Dissolving microneedles, Transdermal delivery, Pediatric formulationAbstract
Objective: Ivacaftor (IVAC) is limited by poor aqueous solubility, extensive first-pass metabolism, and variable oral absorption. This study aimed to develop an amorphous solid dispersion (ASD)based dissolving microneedle (DMN) system for transdermal delivery of IVAC to overcome these limitations.
Methods: IVAC-Soluplus® ASDs were prepared and characterized using differential scanning calorimetry and powder X-ray diffraction. Dissolution and apparent solubility were evaluated. The optimized ASD was incorporated into DMNs, which were assessed for morphology, mechanical strength, insertion capability, in vitro release, ex vivo skin permeation, cytocompatibility, and stability covering four months.
Results: The optimized 1:10 IVAC:Soluplus® ASD increased apparent solubility to 0.25 mg/mL (≈4-fold higher than IVAC). Solid-state characterization confirmed complete amorphization. ASD based DMNs exhibited rapid and complete drug release within 30 min, whereas IVAC-loaded DMNs released only 26.1%. The microneedles were uniform, mechanically robust, and dissolved rapidly upon insertion. Ex vivo studies demonstrated significantly enhanced permeation, with ASD DMNs achieving 64.2% drug permeation over 24 h compared to 10.5% for Raw Material DMNs. Cytotoxicity was reduced in ASD formulations, and four months stability studies showed 98% drug retention with preserved morphology, mechanical integrity, and amorphous state over 4 months.
Conclusion: Direct integration of IVAC ASDs into DMNs significantly improves solubility, release, and transdermal delivery performance. This platform represents a promising, minimally invasive alternative for delivering poorly water-soluble drugs such as IVAC.
References
[1] Galande AD, Khurana NA, Mutalik S. Pediatric dosage forms-challenges and recent developments: A critical review. J Appl Pharm Sci 2020;10(7):155-166.
[2] Baryakova TH, Pogostin BH, Langer R, McHugh KJ. Overcoming barriers to patient adherence: the case for developing innovative drug delivery systems. Nat Rev Drug Discovery 2023;22(5):387-409.
[3] Elzinga FA, Malik PRV, Akkerman OW, Rottier BL, van der Vaart H, Touw DJ, Koppelman GH, Mian P. Pharmacokinetics of Ivacaftor, Tezacaftor, Elexacaftor, and Lumacaftor in Special Cystic Fibrosis Populations: A Systematic Review. Clin Pharmacokinet 2025; 64(7):999-1046.
[4] Fohner AE, McDonagh EM, Clancy JP, Carrillo MW, Altman RB, Klein TE. PharmGKB summary: ivacaftor pathway, pharmacokinetics/pharmacodynamics. Pharmacogenet Genomics 2017;27(1):39-42.
[5] Laffleur F, Keckeis V. Advances in drug delivery systems: Work in progress still needed? Int J Pharm 2020; 590:119912.
[6] Alqahtani MS, Kazi M, Alsenaidy MA, Ahmad MZ . Advances in Oral Drug Delivery. Front Pharmacol 2021;12:618411.
[7] Maqbool T, Ahtesham M, Rabia SM, Ijaz A, Fatima D. Unlocking the potential of transdermal drug delivery for effective diabetes control: a review. Kashf Journal of Multidisciplinary Research 2025;2(03):47-58.
[8] Kaneria NS, Tuleu C, Ernest T. Opportunities for enteral drug delivery for neonates, infants, and toddlers: a critical exploration. Expert Opin Drug Delivery 2022;19(5):475-519.
[9] Almughem FA, Aldossary AM, Tawfik EA, Alomary MN, Alharbi WS, Alshahrani MY, Alshehri AA. Cystic Fibrosis: Overview of the Current Development Trends and Innovative Therapeutic Strategies. Pharmaceutics 2020;12(7):616.
[10] Alruwaili TAM, Alanazi MF, Alruwaili BF, Fayed HK, Elsaeed M, Alnazi TD, Aljared A, Alanazi AM, Alanazi AM, Alsharari SD, Alshammari A. A systematic review and meta-analysis of the treatment modalities available for children afflicted from cystic fibrosis. BMC Pediatr 2025;25(1):753.
[11] Kováčik A, Kopečná M, Vávrová K. Permeation enhancers in transdermal drug delivery: Benefits and limitations. Expert Opin Drug Deliv 2020;17(2):145-55.
[12] Crasta A, Painginkar T, Sreedevi A, Pawar SD, Sathyanarayana MB, Vasantharaju SG, Osmani RA, Ravi G. Transdermal drug delivery system: A comprehensive review of innovative strategies, applications, and regulatory perspectives. OpenNano 2025;24: 100245.
[13] Shah SWA, Li X, Yuan H, et al. Innovative transdermal drug delivery systems: Benefits, challenges, and emerging application. BMEMat 2025; 3:e70001.
[14] Linakis MW, Roberts JK, Lala AC, Spigarelli MG, Medlicott NJ, Reith DM, Ward RM, Sherwin CM. Challenges Associated with Route of Administration in Neonatal Drug Delivery. Clin Pharmacokinet 2016;55(2):185-196.
[15] Iqbal B, Ali J, Baboota S. Recent advances and development in epidermal and dermal drug deposition enhancement technology. Int J Dermatol 2018; 57(6):646-660.
[16] Tapfumaneyi P, Imran M, Mohammed Y, Roberts MS. Recent advances and future prospective of topical and transdermal delivery systems. Front Drug Deliv 2022;2:957732.
[17] Liu F, Kaplan AL, Levring J, Einsiedel J, Tiedt S, Distler K, Omattage NS, Kondratov IS, Moroz YS, Pietz HL, Irwin JJ. Structure-based discovery of CFTR potentiators and inhibitors. Cell 2024;187(14):3712-25.
[18] Gorzelanny C, Mess C, Schneider SW, Huck V, Brandner JM. Skin barriers in dermal drug delivery: which barriers have to be overcome and how can we measure them? Pharmaceutics 2020(7);12:684.
[19] Paredes AJ, McKenna PE, Ramöller IK, Naser YA, Volpe‐Zanutto F, Li M, Abbate MT, Zhao L, Zhang C, Abu‐Ershaid JM, Dai X. Microarray Patches: Poking a Hole in the Challenges Faced When Delivering Poorly Soluble Drugs. Adv Funct Mater 2021;31(1): 2005792.
[20] Rupal D, Umadoss P. Transdermal patches: an emerging mode of drug delivery system in pulmonary arterial hypertension. J Drug Deliv Ther 2021;11:176-86.
[21] Zafar S, Rana SJ, Hamza M, Hussain A, Abbas N, Ghori MU, Arshad MS. Advancements in transdermal drug delivery using microneedles: technological and material perspective. Discov Pharm Sci 2025;1(1):5.
[22] Lyu S, Dong Z, Xu X, Bei HP, Yuen HY, Cheung CW, Wong MS, He Y, Zhao X. Going below and beyond the surface: Microneedle structure, materials, drugs, fabrication, and applications for wound healing and tissue regeneration. Bioact Mater 2023; 27:303-26.
[23] M. N. J, Chandrakala V, Srinivasan S. An overview: recent development in transdermal drug delivery. Int J Pharm Pharm Sci 2022;14(10):1-9.
[24] Nagarkar R, Singh M, Nguyen HX, Jonnalagadda S. A review of recent advances in microneedle technology for transdermal drug delivery. J Drug Deliv Sci Technol 2020; 59: 101923.
[25] Dave R, Shinde S, Kalayil N, Budar A. Engineering microscopic delivery systems: a review of dissolving microneedle design, fabrication, and function. Micro Nano Syst Lett 2024;12(1):14.
[26] Cid AG, Simonazzi A, Palma SD, Bermúdez JM. Solid Dispersion Technology As a Strategy to Improve the Bioavailability of Poorly Soluble Drugs. Ther Deliv 2019;10(6): 363-82.
[27] Guembe-Michel N, Nguewa P, González-Gaitano G. Soluplus®-Based Pharmaceutical Formulations: Recent Advances in Drug Delivery and Biomedical Applications. Int J Mol Sci 2025;26(4):1499.
[28] Patel K, Shah S, Patel J. Solid dispersion technology as a formulation strategy for the fabrication of modified release dosage forms: A comprehensive review. DARU J Pharm Sci 2022;30(1):165-189.
[29] Tekade AR, Yadav JN. A review on solid dispersion and carriers used therein for solubility enhancement of poorly water soluble drugs. Adv Pharm Bull 2020;10(3):359.
[30] Schittny A, Huwyler J, Puchkov M. Mechanisms of increased bioavailability through amorphous solid dispersions: a review. Drug Deliv 2020;27(1):110-27.
[31] Budiman A, Ivana H, Huang KA, Huang SA, Nadhira MS, Rusdin A, Aulifa DL. Biocompatible natural polymer-based amorphous solid dispersion system improving drug physicochemical properties, stability, and efficacy. Polymers 2025;17(15):2059.
[32] Chatterjee B, Reddy A, Santra M, Khamanga S. Amorphization of drugs for transdermal delivery-a recent update. Pharmaceutics 2022;14(5):983.
[33] Nasereddin J, Shakib M. Ira: a free and open-source Fourier transform infrared (FTIR) data analysis widget for pharmaceutical applications. Anal Lett 2023;56(16):2637-48.
[34] Zaid Alkilani A, Abo-Zour H, Basheer HA, Abu-Zour H, Donnelly RF. Development and Evaluation of an Innovative Approach Using Niosomes Based Polymeric Microneedles to Deliver Dual Antioxidant Drugs. Polymers 2023;15(8):1962.
[35] Zaid Alkilani A, Abu-Zour H, Alshishani A, Abu-Huwaij R, Basheer HA, Abo-Zour H. Formulation and Evaluation of Niosomal Alendronate Sodium Encapsulated in Polymeric Microneedles: In Vitro Studies, Stability Study and Cytotoxicity Study. Nanomaterials 2022;12(20):3570.
[36] Cheng Z, Lin H, Wang Z, Yang X, Zhang M, Liu X, Wang B, Wu Z, Chen D. Preparation and characterization of dissolving hyaluronic acid composite microneedles loaded micelles for delivery of curcumin. Drug Deliv Transl Res 2020;10(5):1520-30.
[37] Larrañeta E, Moore J, Vicente-Pérez EM, González-Vázquez P, Lutton R, Woolfson AD, Donnelly RF. A proposed model membrane and test method for microneedle insertion studies. Int J Pharm 2014;472(1-2):65-73.
[38] Jeong S, Jeong S, Chung S, Kim A. Revisiting in vitro release test for topical gel formulations: The effect of osmotic pressure explored for better bio-relevance. Eur J Pharm Sci 2018;112:102-111.
[39] Antonoaea P. Comparative analysis of the release performance of indomethacin from transdermal therapeutic systems. Farmacia 2020;68(6):1029-35.
[40] Lu X, Huang C, Li M, Skomski D, Xu W, Yu L, Byrn SR, Templeton AC, Su Y. Molecular Mechanism of Crystalline-to-Amorphous Conversion of Pharmaceutical Solids from 19 F Magic Angle Spinning NMR. J Phys Chem B 2020;124(25):5271-83.
[41] Wang M, Gong J, Rades T, Martins IC. Amorphization of different furosemide polymorphic forms during ball milling: Tracking solid-to-solid phase transformations. Int J Pharm 2023; 648:123573.
[42] Chen J, Ahmed MU, Zhu C, Yu S, Pan W, Velkov T, Li J, Zhou QT. In vitro evaluation of drug delivery behavior for inhalable amorphous nanoparticle formulations in a human lung epithelial cell model. Int J Pharm 2021;596:120211.
[43] Anjani QK, Sabri AHB, Moreno-Castellanos N, Utomo E, Cárcamo-Martínez Á, Domínguez-Robles J, Wardoyo LA, Donnelly RF. Soluplus®-based dissolving microarray patches loaded with colchicine: towards a minimally invasive treatment and management of gout. Biomater Sci 2022;10(20):5838-55.
[44] Fiume MM, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler D, Marks Jr JG, Shank RC, Slaga TJ, Snyder PW, Andersen FA. Safety Assessment of Propylene Glycol, Tripropylene Glycol, and PPGs as Used in Cosmetics. Int J Toxicol 2012;31:245S-260S.
[45] Patel V, Gaurav V. Role of Polyethylene Glycol in Dermatology. Indian Dermatol Online J 2025;16(2):227-34.
[46] Lee YJ, Ahn YJ, Lee G-J. Cytotoxicity evaluation of sodium lauryl sulfate in a paper-based 3D cell culture system. Anal Methods 2022;14(18):1755-64.
[47] Porsio B, Lentini L, Ungaro F, Di Leonardo A, Quaglia F, Giammona G, Cavallaro G. Inhalable nano into micro dry powders for ivacaftor delivery: The role of mannitol and cysteamine as mucus-active agents. Int J Pharm 2020;582:119304.
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