Publicado
Sistemas de liberación modificada para fármacos neurológicos: Avances y desafíos en terapias antiparkinsonianas
Sistemas de liberação modificada para fármacos neurológicos: Avanços e desafios nas terapias antiparkinsonianas
Modified drug delivery systems for neurological drugs: Advances and challenges in antiparkinsonian therapies
DOI:
https://doi.org/10.15446/rcciquifa.v55n3.125818Palabras clave:
liberación modificada, liberación prolongada, antiparkinsonianos, levodopa, dopamina (es)modified-release, extended-release, antiparkinsonian, levodopa, dopamine (en)
liberação modificada, liberação prolongada, antiparkinsonianos, levodopa, dopamina (pt)
Descargas
Introducción: La enfermedad de Parkinson (EP) es un trastorno neurodegenerativo caracterizado por la pérdida progresiva de neuronas dopaminérgicas en la sustancia negra, lo que provoca una deficiencia de dopamina en el sistema nervioso central. Objetivo: analizar los avances en sistemas de liberación modificada y prolongada aplicados al tratamiento de la EP. Métodos: Se realizó una revisión de la literatura centrada en terapias basadas en L-DOPA, agonistas dopaminérgicos e inhibidores de MAO-B y COMT, con énfasis en tecnologías de liberación controlada y vías alternativas de administración. Resultados: La L-DOPA sigue siendo el tratamiento de referencia; sin embargo, su baja biodisponibilidad, limitada llegada al cerebro y fluctuaciones plasmáticas asociadas a discinesias han impulsado el desarrollo de formulaciones de liberación prolongada. Entre las estrategias destacan matrices poliméricas, sistemas osmóticos y formulaciones mucoadhesivas, así como vías alternativas como implantes, parches transdérmicos, infusiones intestinales y formulaciones nasales e inhalatorias. Además, micro y nanopartículas han mostrado potencial para mejorar la estabilidad farmacocinética, reducir efectos adversos y disminuir la frecuencia de administración. Conclusiones: Persisten limitaciones relevantes, incluyendo la imprecisión en la dosificación de sistemas de infusión, la variabilidad en la absorción, el impacto clínico aún limitado de algunas formulaciones y la dificultad para lograr un control sostenido de los síntomas. Estos desafíos resaltan la necesidad de desarrollar sistemas más predecibles, eficaces y clínicamente relevantes.
Introdução: A doença de Parkinson (DP) é um distúrbio neurodegenerativo caracterizado pela perda progressiva de neurônios dopaminérgicos na substância negra, o que leva a uma deficiência de dopamina no sistema nervoso central. Objetivo: Analisar os avanços em sistemas de liberação modificada e prolongada aplicados ao tratamento da DP. Métodos: Foi realizada uma revisão da literatura focada em terapias baseadas em L-DOPA, agonistas dopaminérgicos e inibidores de MAO-B e COMT, com ênfase em tecnologias de liberação controlada e vias alternativas de administração. Resultados: A L-DOPA continua sendo o tratamento de referência; no entanto, sua baixa biodisponibilidade, limitada chegada ao cérebro e flutuações plasmáticas associadas a discinesias têm impulsionado o desenvolvimento de formulações de liberação prolongada. Entre as estratégias, destacam-se matrizes poliméricas, sistemas osmóticos e formulações mucoadesivas, bem como vias alternativas como implantes, adesivos transdérmicos, infusões intestinais e formulações nasais e inalatórias. Além disso, micro e nanopartículas têm demonstrado potencial para melhorar a estabilidade farmacocinética, reduzir efeitos adversos e diminuir a frequência de administração. Conclusões: Persistem limitações relevantes, incluindo a imprecisão na dosagem de sistemas de infusão, a variabilidade na absorção, o impacto clínico ainda limitado de algumas formulações e a dificuldade em alcançar um controle sustentado dos sintomas. Esses desafios ressaltam a necessidade de desenvolver sistemas mais previsíveis, eficazes e clinicamente relevantes.
Introduction: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to a deficiency of dopamine in the central nervous system. Objective: To analyze advances in modified and prolonged-release systems applied to the treatment of PD. Methods: A literature review was conducted focusing on therapies based on L-DOPA, dopaminergic agonists, and MAO-B and COMT inhibitors, with emphasis on controlled-release technologies and alternative routes of administration. Results: L-DOPA remains the gold standard treatment; however, its low bioavailability, limited brain delivery, and plasma fluctuations associated with dyskinesias have driven the development of extended-release formulations. Among the strategies, polymeric matrices, osmotic systems, and mucoadhesive formulations stand out, as well as alternative routes such as implants, transdermal patches, intestinal infusions, and nasal and inhaled formulations. Additionally, micro- and nanoparticles have shown potential to improve pharmacokinetic stability, reduce adverse effects, and decrease dosing frequency. Conclusions: Relevant limitations persist, including imprecision in infusion system dosing, variability in absorption, the still limited clinical impact of some formulations, and the difficulty in achieving sustained symptom control. These challenges highlight the need to develop more predictable, effective, and clinically relevant systems.
Referencias
1. E.F. van Vliet, M.J. Knol, R.M. Schiffelers, M. Caiazzo & M.H.A.M. Fens, Levodopa-loaded na-noparticles for the treatment of Parkinson’s disease. Journal of Controlled Release, 360, 212-224 (2023). https://doi.org/10.1016/j.jconrel.2023.06.026
2. T.K. Lee & E.L. Yankee. A review on Parkinson’s disease treatment. Neurosciences, 8, 222 (2021). https://doi.org/10.20517/2347-8659.2020.58
3. World Health Organization (WHO). Parkinson disease. WHO Report, 2023. URL: https://www.who.int/news-room/fact-sheets/detail/parkinson-disease
4. A. Kouli, K.M. Torsney & W.L. Kuan. Parkinson’s disease: Etiology, neuropathology, and pathogene-sis. Exon Publications, 2018; pp. 3–26. https://doi.org/10.15586/codonpublications.parkinsonsdisease.2018.ch1
5. D.D. Nakmode, C.M. Day, Y. Song & S. Garg. The management of Parkinson's disease: An overview of the current advancements in drug delivery systems. Pharmaceutics, 15(5), 1503 (2023). https://doi.org/10.3390/pharmaceutics15051503
6. W. Oertel, K. Eggert, R. Pahwa, C.M. Tanner, R.A. Hauser, C. Trenkwalder, R. Ehret, J.P. Az-ulay, S. Isaacson, L. Felt & M.J. Stempien. Randomized placebo-controlled trial of ADS-5102. Movement Disorders, 32(12), 1701–1709 (2017). https://doi.org/10.1002/mds.27131
7. O. Rascol, L. Tönges, T. deVries, M. Jaros, A. Quartel & D. Jacobs. Immediate-release/extended-release amantadine (OS320) to treat Parkinson's disease with levodopa-induced dyskinesia: Analysis of the randomized, controlled ALLAY-LID studies. Parkinsonism & Related Disorders, 96, 65–73 (2022). https://doi.org/10.1016/j.parkreldis.2022.01.022
8. D.D. Nakmode, S. Abdella, Y. Song & S. Garg. Development of an in-situ forming implant system for levodopa and carbidopa for the treatment of Parkinson’s disease. Drug Delivery and Translational Research, 15, 4026–4042 (2025). https://doi.org/10.1007/s13346-025-01892-y
9. Z. Mao, A. Hsu, S. Gupta & M. Modi. Population pharmacodynamics of IPX066: An oral ex-tended-release capsule formulation of carbidopa–levodopa, and immediate-release carbidopa–levodopa in patients with advanced Parkinson’s disease. The Journal of Clinical Pharmacology, 53(5), 523–531 (2013). https://doi.org/10.1002/jcph.63
10. R. Pahwa, K.E. Lyons, R.A. Hauser, S. Fahn, J. Jankovic, E. Pourcher, A. Hsu, M. O'Connell, S. Kell & S. Gupta. Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson's disease. Parkinsonism & Related Disorders, 20(2), 142–148 (2014). https://doi.org/10.1016/ j.parkreldis.2013.08.017
11. L. Bazán-Rodríguez, A. Cervantes-Arriaga, R. Llorens-Arenas, H. Calderón-Fajardo & M. Rodríguez-Violante. No difference on adherence between immediate-release versus extended-release dopamine agonists in uninsured subjects with Parkinson's disease. Movement Disorders: Clinical Practice, 3(1), 68–72 (2016). https://doi.org/10.1002/mdc3.12226
12. R. Pahwa, C.M. Tanner, R.A. Hauser, K. Sethi, S. Isaacson, D. Truong, L. Struck, A.E. Ruby, N.L. McClure, G.T. Went & M.J. Stempien. Amantadine extended release for levodopa-induced dyskinesia in Parkinson's disease (EASED Study). Movement Disorders, 30(6), 788–795 (2015). https://doi.org/10.1002/mds.26159
13. C.W. Makumi, A. Asgharian, J. Ellis, S. Shaikh, T. Jimenez & S. VanMeter. Long-term, open-label, safety study of once-daily ropinirole extended/prolonged release in early and advanced Parkinson's disease. International Journal of Neuroscience, 126(1), 30–38 (2016). https://doi.org/10.3109/ 00207454.2014.991924
14. A.J. Espay, F.L. Pagan, B.L. Walter, J.C. Morgan, L.W. Elmer, C.H. Waters, P. Agarwal, R. Dhall, W.G. Ondo, K.J. Klos & D.E. Silver. Optimizing extended-release carbidopa/levodopa in Parkinson disease: Consensus on conversion from standard therapy. Neurology: Clinical Practice, 7(1), 86–93 (2017). https://doi.org/10.1212/cpj.0000000000000316
15. A. Mittur, S. Gupta & N.B. Modi. Pharmacokinetics of Rytary®, an extended-release capsule formulation of carbidopa–levodopa. Clinical Pharmacokinetics, 56, 999–1014 (2017). https://doi.org/ 10.1007/s40262-017-0511-y
16. R. Pahwa, C.M. Tanner, R.A. Hauser, S.H. Isaacson, P.A. Nausieda, D.D. Truong, P. Agarwal, K.L. Hull, K.E. Lyons, R. Johnson & M.J. Stempien. ADS-5102 (Amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson disease (EASE LID Study): A random-ized clinical trial. JAMA Neurology, 74(8), 941–949 (2017). https://doi.org/10.1001/jamaneurol.2017.0943
17. J. Margolesky & C. Singer. Extended-release oral capsule of carbidopa–levodopa in Parkinson disease. Therapeutic Advances in Neurological Disorders, 11, 1–12 (2018). https://doi.org/10.1177/ 1756285617737728
18. T. Müller & J.-D. Möhr. Efficacy of carbidopa-levodopa extended-release capsules (IPX066) in the treatment of Parkinson disease. Expert Opinion on Pharmacotherapy, 19(18), 2063–2071 (2018). https://doi.org/10.1080/14656566.2018.1538355
19. W. Xiang, Y.Q. Sun & H.C. Teoh. Comparison of nocturnal symptoms in advanced Parkinson’s disease patients with sleep disturbances: pramipexole sustained release versus immediate re-lease formulations. Drug Design, Development and Therapy, 12, 2017–2024 (2018). https://doi.org/ 10.2147/dddt.s160300
20. L.W. Elmer, J.L. Juncos, C. Singer, D.D. Truong, S.R. Criswell, S. Parashos, L. Felt, R. Johnson & R. Patni. Pooled analyses of phase III studies of ADS-5102 (Amantadine) extended-release cap-sules for dyskinesia in Parkinson’s disease. CNS Drugs, 32, 387–398 (2018). https://doi.org/10.1007/ s40263-018-0498-4
21. J. Paik & S.J. Keam. Amantadine extended-release (GOCOVRI™): A review in levodopa-induced dyskinesia in Parkinson's disease. CNS Drugs, 32, 797–806 (2018). https://doi.org/10.1007/s40263-018-0552-2
22. L. Brusa, V. Ponzo, A. Stefani, R. Ceravolo, G. Palermo, E. Finazzi-Agrò, et al. Extended release levodopa at bedtime as a treatment for nocturiain Parkinson's disease: An open label study. Journal of the Neurological Sciences, 410, 116625 (2020). https://doi.org/10.1016/j.jns.2019.116625
23. N. Hattori, H. Mochizuki, K. Hasegawa, M. Nomoto, E. Uchida, T. Terahara, K. Okawa & H. Fukuta. Ropinirole patch versus placebo, ropinirole extended-release tablet in advanced Parkin-son's disease. Movement Disorders, 35(9), 1565–1573 (2020). https://doi.org/10.1002/mds.28071
24. A. Rizos, A. Sauerbier, C. Falup-Pecurariu, P. Odin, A. Antonini, P. Martinez-Martin, B. Kessel, T. Henriksen, M. Silverdale, G. Durner & K. Chaudhuri. Tolerability of non-ergot oral and transdermal dopamine agonists in younger and older Parkinson's disease patients: an European multicentre survey. Journal of Neural Transmission, 127, 875–879 (2020). https://doi.org/10.1007/s00702-020-02168-0
25. R.A. Hauser, L. Zeitlin, S. Fisher & R. D'Souza. Duration of benefit per dose: Carbidopa-Levodopa immediate release vs. extended-release capsules (Rytary®). Parkinsonism & Related Disorders, 82, 133–137 (2021). https://doi.org/10.1016/j.parkreldis.2020.12.002
26. T. Kiss, G. Katona, L. Mérai, L. Janovák, Á. Deák, G. Kozma, Z. Kónya & R. Ambrus. Devel-opment of a hydrophobicity-controlled delivery system containing levodopa methyl ester hy-drochloride loaded into a mesoporous silica. Pharmaceutics, 13(7), 1039 (2021). https://doi.org/10.3390/pharmaceutics13071039
27. S.H. Mehta, R. Pahwa, C.M. Tanner, R.A. Hauser & R. Johnson. Effects of Gocovri (Aman-tadine) extended release capsules on non-motor symptoms in patients with Parkinson's disease and dyskinesia. Neurology and Therapy, 10, 307–320 (2021). https://doi.org/10.1007/s40120-021-00246-3
28. R.A. Hauser, S.H. Mehta, D. Kremens, D. Chernick & A.E. Formella. Effects of Gocovri (Aman-tadine) extended-release capsules on motor aspects of experiences of daily living in people with Parkinson's disease and dyskinesia. Neurology and Therapy, 10, 739–751 (2021). https://doi.org/ 10.1007/s40120-021-00256-1
29. K.A. Chan, Y.-C. Hsieh, S.-F. Hsieh & R.-S. Chen. Changes in pramipexole utilization after introduction of the extended-release formulation: A nationwide study in Taiwan. Drugs - Real World Outcomes, 8, 63–71 (2021). https://doi.org/10.1007/s40801-020-00215-6
30. E. Wollmer & S. Klein. Patient-specific in vitro drug release testing coupled with in silico PBPK modeling to forecast the in vivo performance of oral extended-release levodopa formulations in Parkinson's disease patients. European Journal of Pharmaceutics and Biopharmaceutics, 180, 101–118 (2022). https://doi.org/10.1016/j.ejpb.2022.09.015
31. R.A. Hauser, N. Giladi, W. Poewe, J. Brotchie, H. Friedman, S. Oren & P. Litman. P2B001 (Ex-tended release pramipexole and rasagiline): A new treatment option in development for Parkin-son’s disease. Advances in Therapy, 39, 1881–1894 (2022). https://doi.org/10.1007/s12325-022-02097-2
32. R.A. Hauser, J. Lytle, A.E. Formella & C.M. Tanner. Amantadine delayed release/extended release capsules significantly reduce OFF time in Parkinson’s disease. NPJ Parkinson’s Disease, 8, 29 (2022). https://doi.org/10.1038/s41531-022-00291-1
33. P. LeWitt, A. Ellenbogen, D. Burdick, S. Gunzler, R. Gil, R. Dhall, G. Banisadr & R. D'Souza. Improving levodopa delivery: IPX203, a novel extended-release carbidopa-levodopa formula-tion. Clinical Parkinsonism & Related Disorders, 8, 100197 (2023). https://doi.org/10.1016/ j.prdoa.2023.100197
34. A.J. Espay, J.L. Ostrem, A.E. Formella & C.M. Tanner. Extended-release amantadine for OFF-related dystonia in Parkinson's disease. Parkinsonism & Related Disorders, 122, 106088 (2024). https://doi.org/10.1016/j.parkreldis.2024.106088
35. M. Hexy, S.H. Jose, A. Thomas, R. Yedhukrishna, A. Varghese, K.J. Noel-Francis & E. Sheesh. Hardware synthesis of closed loop PID controlled L-DOPA model for automated drug delivery. Biomedical Signal Processing and Control, 100(Part A), 106840 (2025). https://doi.org/10.1016/ j.bspc.2024.106840
36. M. Pravika, J. Jacob & K.P. Joseph. Design of linear electromechanical actuator for automatic ambulatory Duodopa pump. Engineering Science and Technology, 31, 101056 (2022). https://doi.org/ 10.1016/j.jestch.2021.09.002
37. X. Liu, S. Yan, M. Li, S. Zhang, G. Guo, Q. Yin, Z. Tong, X.D. Chen & W.D. Wu. Spray dried levodopa-doped powder potentially for intranasal delivery. Pharmaceutics, 14(7), 1384 (2022). https://doi.org/10.3390/pharmaceutics14071384
38. C. Bartos, E. Pallagi, P. Szabó-Révész, R. Ambrus, G. Katona, T. Kiss, M. Rahimi & I. Csóka. Formulation of levodopa containing dry powder for nasal delivery applying the quality-by-design approach. European Journal of Pharmaceutical Sciences, 123, 475–483 (2018). https://doi.org/10.1016/ j.ejps.2018.07.061
39. Comunidad Autónoma de Castilla y León, Consejería de Sanidad. Especialidades farmacéuticas de liberación modificada y Bienestar Social. Sacylite: Boletín de Información Terapéutica, 4, 1–4 (2004). URL: https://www.saludcastillayleon.es/sanidad/cm/facm/1235427/385209-SACYLITE%202004%204_Especialidades%20Farmac%C3%A9uticas%20de%20liberaci%C3%B3n.PDF
40. A.U. Kura, S.H.H. Ali, M.Z. Hussein, S. Fakurazi & P. Arulselvan. Development of a con-trolled-release anti-parkinsonian nanodelivery system using levodopa as the active agent. Inter-national Journal of Nanomedicine, 8(1), 1103–1110 (2013). https://doi.org/10.2147/ijn.s39740
41. A. Lees, E. Tolosa, F. Stocchi, J.J. Ferreira, O. Rascol, A. Antonini & W. Poewe. Optimizing levodopa therapy, when and how? Perspectives on the importance of delivery and the potential for an early combination approach. Expert Review of Neurotherapeutics, 23(1), 15–24 (2023). https://doi.org/ 10.1080/14737175.2023.2176220
42. F. Stocchi & L. Vacca. A systematic review on the clinical experience with melevodo-pa/carbidopa fixed combination in patients with Parkinson disease. Minerva Medica, 110(6), 575–585 (2019). https://doi.org/10.23736/s0026-4806.19.06330-4
43. R. Zangaglia, F. Stocchi, M. Sciarretta, A. Antonini, F. Mancini, M. Guidi, E. Martignoni & C. Pacchetti. Clinical experiences with levodopa methylester (melevodopa) in patients with Parkin-son disease experiencing motor fluctuations: an open-label observational study. Clinical Neuro-pharmacology, 33(2), 61–66 (2010). https://doi.org/10.1097/wnf.0b013e3181c5e60c
44. Centro Andaluz de Documentación e Información de Medicamentos (Cadime). Tratamiento farmacológico de la enfermedad de Parkinson. Boletín Terapéutico Andaluz, 2023. https://doi.org/ 10.11119/bta2023-38-01
45. L.R.F. Faro, L.A. Justo, M. Alfonso & R. Durán. Possible synergies between isatin, an endoge-nous MAO inhibitor, and antiparkinsonian agents on the dopamine release from striatum of freely moving rats. Neuropharmacology, 171, 108083 (2020). https://doi.org/10.1016/j.neuropharm.2020.108083
Dimensions
PlumX
Visitas a la página del resumen del artículo
Descargas
Cómo citar
Licencia
Derechos de autor 2026 Revista Colombiana de Ciencias Químico-Farmacéuticas
Esta obra está bajo una licencia internacional Creative Commons Atribución 4.0.
El Departamento de Farmacia de la Facultad de Ciencias de la Universidad Nacional de Colombia autoriza la fotocopia de artículos y textos para fines de uso académico o interno de las instituciones citando la fuente. Las ideas emitidas por los autores son responsabilidad expresa de estos y no de la revista.
Todo el contenido de esta revista, excepto dónde está identificado, está bajo una Licencia Creative Commons de Atribución 4.0 aprobada en Colombia. Consulte la normativa en: http://co.creativecommons.org/?page_id=13
