Evaluación de la permeación de cafeína a partir de productos cosméticos comerciales con acción lipolítica empleando ensayos in vitro en celdas de difusión de Franz

ilustraciones, diagramas

Autores:
Leon Merchan, Heinny Estefania
Tipo de recurso:
Fecha de publicación:
2022
Institución:
Universidad Nacional de Colombia
Repositorio:
Universidad Nacional de Colombia
Idioma:
spa
OAI Identifier:
oai:repositorio.unal.edu.co:unal/84496
Acceso en línea:
https://repositorio.unal.edu.co/handle/unal/84496
https://repositorio.unal.edu.co/
Palabra clave:
610 - Medicina y salud::615 - Farmacología y terapéutica
Cafeína
Cosméticos lipolíticos
Celdas de difusión de Franz
Caracterización fisicoquímica
Gel
Emulgel
Validación analítica
Caffeine
Lipolytic cosmetics
Franz diffusion cells
Physicochemical characterization
Gel
Emulgel
Analytical validation
Permeation
Permeación
Hipodermis
Rights
openAccess
License
Reconocimiento 4.0 Internacional
id UNACIONAL2_6082c85a1a035de118a494f5ddc470c7
oai_identifier_str oai:repositorio.unal.edu.co:unal/84496
network_acronym_str UNACIONAL2
network_name_str Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv Evaluación de la permeación de cafeína a partir de productos cosméticos comerciales con acción lipolítica empleando ensayos in vitro en celdas de difusión de Franz
dc.title.translated.eng.fl_str_mv Evaluation of caffeine permeation from commercial cosmetic products with lipolytic action using in vitro assays in Franz diffusion cells
title Evaluación de la permeación de cafeína a partir de productos cosméticos comerciales con acción lipolítica empleando ensayos in vitro en celdas de difusión de Franz
spellingShingle Evaluación de la permeación de cafeína a partir de productos cosméticos comerciales con acción lipolítica empleando ensayos in vitro en celdas de difusión de Franz
610 - Medicina y salud::615 - Farmacología y terapéutica
Cafeína
Cosméticos lipolíticos
Celdas de difusión de Franz
Caracterización fisicoquímica
Gel
Emulgel
Validación analítica
Caffeine
Lipolytic cosmetics
Franz diffusion cells
Physicochemical characterization
Gel
Emulgel
Analytical validation
Permeation
Permeación
Hipodermis
title_short Evaluación de la permeación de cafeína a partir de productos cosméticos comerciales con acción lipolítica empleando ensayos in vitro en celdas de difusión de Franz
title_full Evaluación de la permeación de cafeína a partir de productos cosméticos comerciales con acción lipolítica empleando ensayos in vitro en celdas de difusión de Franz
title_fullStr Evaluación de la permeación de cafeína a partir de productos cosméticos comerciales con acción lipolítica empleando ensayos in vitro en celdas de difusión de Franz
title_full_unstemmed Evaluación de la permeación de cafeína a partir de productos cosméticos comerciales con acción lipolítica empleando ensayos in vitro en celdas de difusión de Franz
title_sort Evaluación de la permeación de cafeína a partir de productos cosméticos comerciales con acción lipolítica empleando ensayos in vitro en celdas de difusión de Franz
dc.creator.fl_str_mv Leon Merchan, Heinny Estefania
dc.contributor.advisor.none.fl_str_mv Baena Aristizabal, Yolima
Martín Reyes, Liliana Astrid
dc.contributor.author.none.fl_str_mv Leon Merchan, Heinny Estefania
dc.contributor.researchgroup.spa.fl_str_mv Sistemas Para Liberación Controlada de Moléculas Biológicamente Activas
dc.subject.ddc.spa.fl_str_mv 610 - Medicina y salud::615 - Farmacología y terapéutica
topic 610 - Medicina y salud::615 - Farmacología y terapéutica
Cafeína
Cosméticos lipolíticos
Celdas de difusión de Franz
Caracterización fisicoquímica
Gel
Emulgel
Validación analítica
Caffeine
Lipolytic cosmetics
Franz diffusion cells
Physicochemical characterization
Gel
Emulgel
Analytical validation
Permeation
Permeación
Hipodermis
dc.subject.proposal.spa.fl_str_mv Cafeína
Cosméticos lipolíticos
Celdas de difusión de Franz
Caracterización fisicoquímica
Gel
Emulgel
Validación analítica
dc.subject.proposal.eng.fl_str_mv Caffeine
Lipolytic cosmetics
Franz diffusion cells
Physicochemical characterization
Gel
Emulgel
Analytical validation
dc.subject.wikidata.eng.fl_str_mv Permeation
dc.subject.wikidata.spa.fl_str_mv Permeación
dc.subject.wikidata.none.fl_str_mv Hipodermis
description ilustraciones, diagramas
publishDate 2022
dc.date.issued.none.fl_str_mv 2022
dc.date.accessioned.none.fl_str_mv 2023-08-08T19:47:02Z
dc.date.available.none.fl_str_mv 2023-08-08T19:47:02Z
dc.type.spa.fl_str_mv Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv Text
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/TM
status_str acceptedVersion
dc.identifier.uri.none.fl_str_mv https://repositorio.unal.edu.co/handle/unal/84496
dc.identifier.instname.spa.fl_str_mv Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv https://repositorio.unal.edu.co/
url https://repositorio.unal.edu.co/handle/unal/84496
https://repositorio.unal.edu.co/
identifier_str_mv Universidad Nacional de Colombia
Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv spa
language spa
dc.relation.references.spa.fl_str_mv 1. H. I. M. Raja K Sivamani, Jared R. Jagdeo, Peter Elsner, Cosmeceuticals and Active Cosmetics. 2016.
2. A. Benaiges, “Concepto, clasificación y tratamiento de la celulitis,” Dermofarmacia, vol. 22. pp. 78–88, May 2003, Accessed: Nov. 09, 2020. [Online]. Available: https://www.elsevier.es/es-revista-offarm-4-pdf-13047748.
3. A. Herman and A. P. Herman, “Caffeine’s mechanisms of action and its cosmetic use,” Skin Pharmacology and Physiology, vol. 26, no. 1. pp. 8–14, Dec. 2012, doi: 10.1159/000343174
4. N. Hasegawa; and M. Mori, “Effect of Powdered Green Tea and Its Caffeine Content on Lipogenesis and Lipolysis in 3T3-L1 Cell,” Chem. Pharm. Bull., vol. 40, no. 6, pp. 1569–1572, 2000.
5. Comunidad Andina, “DECISIÓN 833. Actualización de la Decisión 516 ‘Armonización de Legislaciones en materia de Productos Cosméticos,’” Gac. Of., 2018.
6. República de colombia, “DECRETO NÚMERO 677 DE 1995 Por el cual se reglamenta parcialmente el Régimen de Registros y Licencias, el Control de Calidad, así como el Régimen de Vigilancia Sanitaria de Medicamentos, Cosméticos, Preparaciones Farmacéuticas a base de Recursos Naturales,” vol. 246, no. abril 26, pp. 1–70, 1995.
7. G. Beauchamp, A. Amaducci, and M. Cook, “Caffeine Toxicity: A Brief Review and Update,” Clin. Pediatr. Emerg. Med., vol. 18, no. 3, pp. 197–202, 2017, doi: 10.1016/j.cpem.2017.07.002.
8. C. Willson, “The clinical toxicology of caffeine: A review and case study,” Toxicol. Reports, vol. 5, no. November, pp. 1140–1152, 2018, doi: 10.1016/j.toxrep.2018.11.002.
9. A. S. Tolley, “Caffeine: Consumption, side effects and impact on performance and mood,” Caffeine Consum. Side Eff. Impact Perform. Mood, no. January, pp. 1–217, 2014.
10. M. Gajewska et al., “In vitro-to-in vivo correlation of the skin penetration, liver clearance and hepatotoxicity of caffeine,” Food Chem. Toxicol., vol. 75, pp. 39–49, 2015, doi: 10.1016/j.fct.2014.10.017.
11. J. Michael, V. Nadine, K. Maike, and B. Adolf, “Erratum: Caffeine and Its Pharmacological Benefits in the Management of Androgenetic Alopecia: A Review (Skin Pharmacol Physiol (2020) 33 (93-109) DOI: 10.1159/000508228),” Skin Pharmacol. Physiol., pp. 153–169, 2020, doi: 10.1159/000511410.
12. M. Visconti, W. Haidari, and S. Feldman, “Therapeutic use of caffeine in dermatology: A literature review,” J. Dermatology Dermatologic Surg., vol. 24, no. 1, p. 18, 2020, doi: 10.4103/jdds.jdds_52_19.
13. C. L. Petersen, V. Kalil, and V. Campos, Drug Delivery in Dermatology. Rio de Janeiro: Springer, 2021.
14. J. B. Wilkinson and R. J. Moore, Cosmetología de Harry, vol. 53, no. 9. 1990.
15. M. A. Bolzinger, S. Briançon, J. Pelletier, and Y. Chevalier, “Penetration of drugs through skin, a complex rate-controlling membrane,” Curr. Opin. Colloid Interface Sci., vol. 17, no. 3, pp. 156–165, 2012, doi: 10.1016/j.cocis.2012.02.001.
16. D. T. Ginat, Neuroradiological imaging of skin diseases and related conditions. Chicago: Springer, 2018.
17. K. S. Saladin, Human Anatomy - Kenneth S. Saladin. Mc Graw Hill, 2007.
18. W. Montagna, A. M. Kligman, K. S. Carlisle, W. Montagna, A. M. Kligman, and K. S. Carlisle, “Hypodermis,” in Atlas of Normal Human Skin, Springer New York, 1992, pp. 367–377.
19. J. A. Bouwstra and M. Ponec, “The skin barrier in healthy and diseased state,” Biochim. Biophys. Acta, vol. 1758, no. 12, pp. 2080–2095, Dec. 2006, doi: 10.1016/j.bbamem.2006.06.021.
20. T. Agner, Skin Barrier Function. current problems in dermatology, 2016.
21. S. Singh and J. Singh, “Transdermal drug delivery by passive diffusion and iontophoresis: A review,” Med. Res. Rev., vol. 13, no. 5, pp. 569–621, Sep. 1993, doi: 10.1002/med.2610130504.
22. SCCP, “SCCP/0970/06 Basic Criteria for the in vitro assessment of dermal absorption of cosmetic ingredients-update March 2006, European Commission,” no. March, 2006, [Online]. Available: https://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_s_03.pdf.
23. J. Kielhorn, S. Melching-Kollmuß, I. Mangelsdorf, and World Health Organization, “Environmental health criteria 235 for dermal absorption,” Environ. Heal. Criteria, 2006.
24. A. Z. Alkilani, M. T. C. McCrudden, and R. F. Donnelly, “Transdermal drug delivery: Innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum,” Pharmaceutics, vol. 7, no. 4, pp. 438–470, 2015, doi: 10.3390/pharmaceutics7040438.
25. S. Trauer et al., “Permeation of topically applied caffeine through human skin - A comparison of in vivo and in vitro data,” Br. J. Clin. Pharmacol., vol. 68, no. 2, pp. 181–186, Aug. 2009, doi: 10.1111/j.1365-2125.2009.03463.x.
26. B. J. Thomas and B. C. Finnin, “The transdermal revolution,” Drug Discov. Today, vol. 9, no. 16, pp. 697–703, 2004, doi: 10.1016/S1359-6446(04)03180-0.
27. R. Gutiérrez Fernández de Molina, “Estudios De Difusión A Través De Piel De Formulaciones Liposómicas De Aciclovir,” Universidad Computense de Madrid, 2011.
28. C. Ehrhardt and K.-J. Kim, Drug Absorption Studies. New York: Springer, 2008.
29. OECD, “OECD Test Guideline 428: Skin Absorption: in vitro method,” no. April. 2004.
30. V. Rogiers and M. Pauwels, “Critical Analysis of the Safety Assessment of Cosmetic Ingredients Performed at the European Level: the in vitro delmal absorption study,” in Safety assesment of cosmetics in Europe, KARGER, 2008, pp. 74–81.
31. D. Selzer, M. M. A. Abdel-Mottaleb, T. Hahn, U. F. Schaefer, and D. Neumann, “Finite and infinite dosing: Difficulties in measurements, evaluations and predictions,” Adv. Drug Deliv. Rev., vol. 65, no. 2, pp. 278–294, 2013, doi: 10.1016/j.addr.2012.06.010.
32. L. Luo and M. E. Lane, “Topical and transdermal delivery of caffeine,” International Journal of Pharmaceutics, vol. 490, no. 1–2. Elsevier B.V., pp. 155–164, May 31, 2015, doi: 10.1016/j.ijpharm.2015.05.050.
33. M. O’Neil, The Merck index : an encyclopedia of chemicals, drugs, and biologicals., Fifteenth edition /. Cambridge UK: Royal Society of Chemistry, 2013.
34. “Caffeine C8H10N4O2 | ChemSpider.” http://www.chemspider.com/Chemical-Structure.2424.html (accessed Aug. 10, 2020).
35. European Food Safety Authority, “Scientific Opinion on the safety of caffeine,” EFSA J., vol. 13, no. 5, 2015, doi: 10.2903/j.efsa.2015.4102.
36. A. Murray and J. Traylor, Caffeine Toxicity. StatPearls Publishing, 2018.
37. A. Bolsoni-Lopes and M. I. C. Alonso-Vale, “Lipolysis and lipases in white adipose tissue – An update,” Archives of Endocrinology and Metabolism, vol. 59, no. 4. Sociedade Brasileira de Endocrinologia e Metabologia, pp. 335–342, 2015, doi: 10.1590/2359-3997000000067.
38. A. Lass, R. Zimmermann, M. Oberer, and R. Zechner, “Lipolysis - A highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores,” Progress in Lipid Research, vol. 50, no. 1. Elsevier Ltd, pp. 14–27, 2011, doi: 10.1016/j.plipres.2010.10.004.
39. M. V. Velasco Robles, C. Tano Nakamura, G. M. Machado-Santelli, C. Vladi Olga, T. M. Kaneko, and A. Rolim Baby, “Effects of caffeine and siloxanetriol alginate caffeine, as anticellulite agents, on fatty tissue: histological evaluation,” 2008.
40. E. Dupont et al., “An integral topical gel for cellulite reduction: Results from a double-blind, randomized, placebo-controlled evaluation of efficacy,” Clin. Cosmet. Investig. Dermatol., vol. 7, pp. 73–88, Feb. 2014, doi: 10.2147/CCID.S53580.
41. B. Vogelgesang, I. Bonnet, N. Godard, B. Sohm, and E. Perrier, “In vitro and in vivo efficacy of sulfo-carrabiose, a sugar-based cosmetic ingredient with anti-cellulite properties,” Int. J. Cosmet. Sci., vol. 33, no. 2, pp. 120–125, Apr. 2011, doi: 10.1111/j.1468-2494.2010.00593.x.
42. F. Turati et al., “Efficacy of cosmetic products in cellulite reduction: systematic review and meta-analysis,” J. Eur. Acad. Dermatology Venereol., vol. 28, no. 1, pp. 1–15, Jan. 2014, doi: 10.1111/jdv.12193.
43. R. Roure, T. Oddos, A. Rossi, F. Vial, and C. Bertin, “Evaluation of the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol, in vitro, ex vivo and in vivo studies,” Int. J. Cosmet. Sci., vol. 33, no. 6, pp. 519–526, Dec. 2011, doi: 10.1111/j.1468-2494.2011.00665.x.
44. C. Dray, D. Daviaud, C. Guigné, P. Valet, and I. Castan-Laurell, “Caffeine reduces TNFα up-regulation in human adipose tissue primary culture,” J. Physiol. Biochem., vol. 63, no. 4, pp. 329–336, 2007, doi: 10.1007/BF03165764.
45. H. Hamishehkar, J. Shokri, S. Fallahi, A. Jahangiri, S. Ghanbarzadeh, and M. Kouhsoltani, “Histopathological evaluation of caffeine-loaded solid lipid nanoparticles in efficient treatment of cellulite,” Drug Dev. Ind. Pharm., vol. 41, no. 10, pp. 1640–1646, 2015, doi: 10.3109/03639045.2014.980426.
46. S. Murosaki et al., “A combination of caffeine, arginine, soy isoflavones, and L-carnitine enhances both lipolysis and fatty acid oxidation in 3T3-L1 and HepG2 cells in vitro and in KK mice in vivo,” J. Nutr., vol. 137, no. 10, pp. 2252–2257, 2007, doi: 10.1093/jn/137.10.2252.
47. C. Sugiura, G. Zheng, L. Liu, and K. Sayama, “Catechins and Caffeine Promote Lipid Metabolism and Heat Production Through the Transformation of Differentiated 3T3-L1 Adipocytes from White to Beige Adipocytes,” J. Food Sci., vol. 85, no. 1, pp. 192–200, 2020, doi: 10.1111/1750-3841.14811.
48. J. Stanek and M. Wochner, “Current and Future ‘ Body-sculpting ’ Cosmetics The Science of Fat,” vol. 130, no. 9, pp. 20–28, 2015.
49. D. Hexsel and M. Soirefmann, “Cosmeceuticals for Cellulite,” Seminars in Cutaneous Medicine and Surgery, vol. 30, no. 3. pp. 167–170, Sep. 2011, doi: 10.1016/j.sder.2011.06.005.
50. N. Otberg et al., “The role of hair follicles in the percutaneous absorption of caffeine,” Br. J. Clin. Pharmacol., vol. 65, no. 4, pp. 488–492, 2008, doi: 10.1111/j.1365-2125.2007.03065.x.
51. M. A. Bolzinger, S. Briançon, J. Pelletier, H. Fessi, and Y. Chevalier, “Percutaneous release of caffeine from microemulsion, emulsion and gel dosage forms,” Eur. J. Pharm. Biopharm., vol. 68, no. 2, pp. 446–451, 2008, doi: 10.1016/j.ejpb.2007.10.018.
52. “Caffeine - Registration Dossier - ECHA,” Dermal absorption. https://echa.europa.eu/registration-dossier/-/registered-dossier/10085/7/2/3 (accessed Nov. 10, 2020).
53. J. Frelichowska, M. A. Bolzinger, J. P. Valour, H. Mouaziz, J. Pelletier, and Y. Chevalier, “Pickering w/o emulsions: Drug release and topical delivery,” Int. J. Pharm., vol. 368, no. 1–2, pp. 7–15, Feb. 2009, doi: 10.1016/j.ijpharm.2008.09.057.
54. M. V Debandi, N. J. François, and M. E. Daraio, “Evaluación De Distintas Membranas Para Liberación in Vitro De Principios Activos Anticelulíticos.,” Aci, vol. 2, no. 2, pp. 97–105, 2011.
55. S. Meesen, “In vitro percutaneus absorption of caffeine from cosmetic formulations,” no. thesis Msc.Cosmetic Sciences, 2011.
56. R. Mustapha, C. Lafforgue, N. Fenina, and J. Marty, “Influence of drug concentration on the diffusion parameters of caffeine,” Indian J. Pharmacol., vol. 43, no. 2, pp. 157–162, Apr. 2011, doi: 10.4103/0253-7613.77351.
57. J. Djajadisastra, Sutriyo, and Hadyanti, “Percutane transport profile of caffeine and aminophyllin as anticellulite and the influences of other substances on in vitro penetration,” Int. J. Pharm. Pharm. Sci., vol. 6, no. 5, pp. 532–538, 2014.
58. E. Abd et al., “Deformable liposomes as enhancer of caffeine penetration through human skin in a Franz diffusion cell test,” Int. J. Cosmet. Sci., pp. 1–10, 2020, doi: 10.1111/ics.12659.
59. N. H. C. S. Silva et al., “Topical caffeine delivery using biocellulose membranes: A potential innovative system for cellulite treatment,” Cellulose, vol. 21, no. 1, pp. 665–674, Feb. 2014, doi: 10.1007/s10570-013-0114-1.
60. I. Iskandarsyah, A. W. Puteri, and E. Ernysagita, “Penetration test of caffeine in ethosome and desmosome gel using an in vitro method,” Int. J. Appl. Pharm., vol. 9, pp. 120–123, 2017, doi: 10.22159/ijap.2017.v9s1.69_76.
61. F. Farner, L. Bors, Á. Bajza, G. Karvaly, I. Antal, and F. Erdő, “Validation of an In vitro-in vivo Assay System for Evaluation of Transdermal Delivery of Caffeine,” Drug Deliv. Lett., vol. 9, no. 1, pp. 15–20, Sep. 2018, doi: 10.2174/2210303108666180903102107.
62. J. Pavlačková et al., “Transdermal absorption of active substances from cosmetic vehicles,” J. Cosmet. Dermatol., vol. 18, no. 5, pp. 1410–1415, 2019, doi: 10.1111/jocd.12873.
63. J. Ageis, H. Suryadi, and M. Jufri, “Formulation and in vitro skin penetration of a solid lipid nanoparticle gel containing coffea arabica extract,” Int. J. Appl. Pharm., vol. 12, no. Special Issue 1, pp. 177–181, 2020, doi: 10.22159/ijap.2020.v12s1.FF040.
64. Y. de Lafuente, A. Ochoa-Andrade, M. E. Parente, M. C. Palena, and A. F. Jimenez-Kairuz, “Preparation and evaluation of caffeine bioadhesive emulgels for cosmetic applications based on formulation design using QbD tools,” Int. J. Cosmet. Sci., pp. 548–556, 2020, doi: 10.1111/ics.12638.
65. M. Dias, A. Farinha, E. Faustino, J. Hadgraft, J. Pais, and C. Toscano, “Topical delivery of caffeine from some commercial formulations,” 1999.
66. A. Smith, A. Chadha, R. Homan, and G. Baki, “Skin Penetration of Caffeine from Marketed Eye Creams,” New York, 2017. [Online]. Available: http://permegear.com/wp-.
67. MINISTERIO DE SALUD, “RESOLUCION NUMERO 8430 DE 1993 ‘Por la cual se establecen las normas científicas, técnicas y administrativas para la investigación en salud,’” 1993.
68. República de Colombia, “Estatuto nacional de proteccion de los animales Ley 84 de 1989,” El Congr. Colomb., vol. 5, no. Diciembre 27, p. 14, 1989, [Online]. Available: http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:No+Title#0.
69. Congreso de Colombia, “Ley 2047 de 2020 "por el cual se prohíbe en colombia la experimentación, importación, fabricación y comercialización de productos cosméticos, sus ingredientes o combinaciones de ellos que sean objeto de pruebas con animales y se dictan otras disposiciones,” 2020.
70. J. Y. Kim, J. Y. Song, E. J. Lee, and S. K. Park, “Rheological properties and microstructures of Carbopol gel network system,” Colloid Polym. Sci., vol. 281, no. 7, pp. 614–623, 2003, doi: 10.1007/s00396-002-0808-7.
71. R. Injac, B. Srdjenovic, M. Prijatelj, M. Boskovic, K. Karljikovic-Rajic, and B. Strukelj, “Determination of caffeine and associated compounds in food, beverages, natural products, pharmaceuticals, and cosmetics by micellar electrokinetic capillary chromatography,” J. Chromatogr. Sci., vol. 46, no. 2, pp. 137–143, 2008, doi: 10.1093/chromsci/46.2.137.
72. E. Marchei, D. De Orsi, C. Guarino, S. Dorato, R. Pacifici, and S. Pichini, “Measurement of iodide and caffeine content in cellulite reduction cosmetic products sold in the European market,” Anal. Methods, vol. 5, no. 2, pp. 376–383, Jan. 2013, doi: 10.1039/c2ay25761k.
73. K. Mladenov and S. SunariĆ, “Caffeine in Hair Care and Anticellulite Cosmetics: Sample Preparation, Solid-Phase Extraction, and HPLC Determination,” J. Cosmet. Sci., vol. 71, no. 5, pp. 251–262, 2020.
74. L. M. Sanabria, J. A. Martínez, and Y. Baena, “Validación de una metodología analítica por HPLC-DAD para la cuantificación de cafeína en un ensayo de permeación in vitro empleando mucosa oral porcina,” Rev. Colomb. Ciencias Químico-Farmacéuticas, vol. 46, no. 2, May 2017, doi: 10.15446/rcciquifa.v46n2.67956.
75. A. M. A. Hasan and M. E.-S. Abdel-Raouf, Cellulose-Based Superabsorbent Hydrogels. 2019.
76. L. A. Martínez, L. M. Sanabria, and Y. Baena, “Safety assessment of complex benzoic acid using in vitro permeation assays with pig skin in Franz cells,” pp. 1–17, 2020.
77. Y. Baena, L. Dallos, R. Manzo, and L. Ponce D’León, “Estandarización de celdas de Franz para la realización de ensayos de liberación de fármacos a partir de complejos con polielectrolitos,” Rev. Colomb. Ciencias Químico-Farmacéuticas, vol. 40, no. 2, pp. 174–188, 2011.
78. L. Sanabria, “Contribución a la implementación de un ensayo de permeación bucal, in vitro, empleano cafeína como compuesto modelo.,” Universidad Nacional de Colombia, 2017.
79. European Medicines Agency, “ICH Guideline M10 on Bioanalytical Method Validation,” Sci. Med. Heal., vol. 44, no. March, p. 57, 2019.
80. Food and Drug Administration -Guidance for Industry, “Bioanalytical method validation,” in Guidance for Industry, 2018, pp. 1–41, doi: 10.5958/2231-5675.2015.00035.6.
81. E. A. Fernández-montes, “Control de calidad Fórmulas dermatológicas,” Farm. Prof., vol. 17, pp. 70–75, 2003, [Online]. Available: https://www.elsevier.es/es-revista-farmacia-profesional-3-pdf-13044489.
82. K. Welin-Berger, J. A. M. Neelissen, and B. Bergenståhl, “The effect of rheological behaviour of a topical anaesthetic formulation on the release and permeation rates of the active compound,” Eur. J. Pharm. Sci., vol. 13, no. 3, pp. 309–318, 2001, doi: 10.1016/S0928-0987(01)00118-X.
83. L. Binder, J. Mazál, R. Petz, V. Klang, and C. Valenta, “The role of viscosity on skin penetration from cellulose ether-based hydrogels,” Ski. Res. Technol., vol. 25, no. 5, pp. 725–734, 2019, doi: 10.1111/srt.12709.
84. C. Wibowo and K. M. Ng, “Product-oriented process synthesis and development: Creams and pastes,” AIChE J., vol. 47, no. 12, pp. 2746–2767, 2001, doi: 10.1002/aic.690471214.
85. D. Saha and S. Bhattacharya, “Hydrocolloids as thickening and gelling agents in food: A critical review,” J. Food Sci. Technol., vol. 47, no. 6, pp. 587–597, 2010, doi: 10.1007/s13197-010-0162-6.
86. H. Iwata and K. Shimada, Formula Ingredients and production in cosmetics, Springer., vol. 53, no. 9. Japan, 2013.
87. D. W. Lachenmeier, “Safety evaluation of topical applications of ethanol on the skin and inside the oral cavity,” J. Occup. Med. Toxicol., vol. 3, no. 1, pp. 1–16, 2008, doi: 10.1186/1745-6673-3-26.
88. L. C. Becker et al., “Safety Assessment of Glycerin as Used in Cosmetics,” Int. J. Toxicol., vol. 38, no. 3_suppl, pp. 6S-22S, Nov. 2019, doi: 10.1177/1091581819883820.
89. S. Björklund, J. Engblom, K. Thuresson, and E. Sparr, “Glycerol and urea can be used to increase skin permeability in reduced hydration conditions,” Eur. J. Pharm. Sci., vol. 50, no. 5, pp. 638–645, 2013, doi: 10.1016/j.ejps.2013.04.022.
90. “Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 31 Hazardous Substances Data Bank (HSDB).” .
91. “Flick, E.W. (ed.). Industrial Solvents Handbook 4 th ed. Noyes Data Corporation., Park Ridge, NJ., 1991., p. 394 Hazardous Substances Data Bank (HSDB).” .
92. C. Reichardt and T. Welton, “Solvents and Solvent Effects in Organic Chemistry: Fourth Edition,” Solvents Solvent Eff. Org. Chem. Fourth Ed., Nov. 2010, doi: 10.1002/9783527632220.
93. “Liquids - Dielectric Constants.” https://www.engineeringtoolbox.com/liquid-dielectric-constants-d_1263.html (accessed Sep. 04, 2022).
94. “Solvent Polarity Table - Miller’s Home.” https://sites.google.com/site/miller00828/in/solvent-polarity-table (accessed Sep. 04, 2022).
95. INVIMA, “Validación de Métodos Analíticos,” pp. 1–92, 2014, [Online]. Available: https://www.invima.gov.co/documents/20143/1433858/Validación+Medicamentos.pdf.
96. Food and Drug Administration, “Methods, Method Verification and Validation,” ORA Lab. Proced., vol. II, pp. 1–19, 2014.
97. M. Akdeniz, S. Gabriel, A. Lichterfeld-Kottner, U. Blume-Peytavi, and J. Kottner, “Transepidermal water loss in healthy adults: a systematic review and meta-analysis update,” Br. J. Dermatol., vol. 179, no. 5, pp. 1049–1055, 2018, doi: 10.1111/bjd.17025.
98. C. Jacques-Jamin, C. Jeanjean-Miquel, A. Domergue, S. Bessou-Touya, and H. Duplan, “Standardization of an in vitro model for evaluating the bioavailability of topically applied compounds on damaged skin: Application to sunscreen analysis,” Skin Pharmacol. Physiol., vol. 30, no. 2, pp. 55–65, 2017, doi: 10.1159/000455196.
99. L. Kong et al., “Chlorogenic acid and caffeine combination attenuates adipogenesis by regulating fat metabolism and inhibiting adipocyte differentiation in 3T3-L1 cells,” J. Food Biochem., no. January, pp. 1–11, 2021, doi: 10.1111/jfbc.13795.
100. H. Nakabayashi, T. Hashimoto, H. Ashida, S. Nishiumi, and K. Kanazawa, “Inhibitory effects of caffeine and its metabolites on intracellular lipid accumulation in murine 3T3-L1 adipocytes,” BioFactors, vol. 34, no. 4, pp. 293–302, 2008, doi: 10.1002/biof.5520340405.
101. S. H. Su, H. W. Shyu, Y. T. Yeh, K. M. Chen, H. Yeh, and S. J. Su, “Caffeine inhibits adipogenic differentiation of primary adipose-derived stem cells and bone marrow stromal cells,” Toxicol. Vitr., vol. 27, no. 6, pp. 1830–1837, 2013, doi: 10.1016/j.tiv.2013.05.011.
102. FOOD AND DRUG ADMINISTRATION (FDA), “Thigh Creams (Cellulite Creams) | FDA.” https://www.fda.gov/cosmetics/cosmetic-products/thigh-creams-cellulite-creams (accessed Sep. 06, 2022).
103. M. Nomura et al., “Inhibition of epidermal growth factor-induced cell transformation and Akt activation by caffeine,” Mol. Carcinog., vol. 44, no. 1, pp. 67–76, Sep. 2005, doi: 10.1002/MC.20120.
104. J. V. Forrester, A. D. Dick, P. G. McMenamin, F. Roberts, and E. Pearlman, “General and ocular pharmacology,” Eye, pp. 338-369.e1, Jan. 2016, doi: 10.1016/B978-0-7020-5554-6.00006-X.
105. K. Al-Khamis, S. S. Davis, and J. Hadgraft, “In vitro-in vivo correlations for the percutaneous absorption of salicylates,” Int. J. Pharm., vol. 40, no. 1–2, pp. 111–118, 1987, doi: 10.1016/0378-5173(87)90055-X.
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_abf2
dc.rights.license.spa.fl_str_mv Reconocimiento 4.0 Internacional
dc.rights.uri.spa.fl_str_mv http://creativecommons.org/licenses/by/4.0/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv Reconocimiento 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.extent.spa.fl_str_mv xxi, 159 páginas
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Universidad Nacional de Colombia
dc.publisher.program.spa.fl_str_mv Bogotá - Ciencias - Maestría en Ciencias Farmacéuticas
dc.publisher.faculty.spa.fl_str_mv Facultad de Ciencias
dc.publisher.place.spa.fl_str_mv Bogotá, Colombia
dc.publisher.branch.spa.fl_str_mv Universidad Nacional de Colombia - Sede Bogotá
institution Universidad Nacional de Colombia
bitstream.url.fl_str_mv https://repositorio.unal.edu.co/bitstream/unal/84496/4/1057599911.2023.pdf
https://repositorio.unal.edu.co/bitstream/unal/84496/3/license.txt
https://repositorio.unal.edu.co/bitstream/unal/84496/5/1057599911.2023.pdf.jpg
bitstream.checksum.fl_str_mv 0611f6b64c941537e74b33194b313704
eb34b1cf90b7e1103fc9dfd26be24b4a
47061bd3ebb6654c5d8ed84abaabfccc
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
repository.name.fl_str_mv Repositorio Institucional Universidad Nacional de Colombia
repository.mail.fl_str_mv repositorio_nal@unal.edu.co
_version_ 1806886661437521920
spelling Reconocimiento 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Baena Aristizabal, Yolimacbb04b44a5caeaeb5dd9836726b0278dMartín Reyes, Liliana Astridee690fc24e2cb588f8ab60f8c67ab375Leon Merchan, Heinny Estefania557851cb0e466da081eea5bc3aaa07a5Sistemas Para Liberación Controlada de Moléculas Biológicamente Activas2023-08-08T19:47:02Z2023-08-08T19:47:02Z2022https://repositorio.unal.edu.co/handle/unal/84496Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, diagramasEn el mercado colombiano se comercializan cosméticos con proclamas lipolíticas que presentan en sus ingredientes cafeína, un compuesto ampliamente utilizado por su acción sobre los mecanismos de acumulación de grasa en el adipocito. Para cumplir con el efecto cosmético prometido, el ingrediente debería poder permear a la hipodermis donde se encuentran las células adiposas, no obstante, esto también implicaría que la cafeína presente en estos productos podría alcanzar el fluido sistémico, causando contravención con la definición de cosméticos según la legislación nacional. En este sentido, se seleccionaron siete productos del mercado colombiano con proclamas lipolíticas que contienen cafeína, con el objetivo de recolectar información sobre la concentración de ésta que podría alcanzar la hipodermis y/o el fluido sistémico al ser aplicados sobre la piel. El desarrollo metodológico incluyó, la realización de ensayos in vitro en celdas de difusión de Franz con dos espesores diferentes de membrana, una con tejido hipodérmico y otra sin éste, determinando la concentración permeada bajo una aplicación de dosis en condiciones de uso. Así mismo, se realizó la caracterización fisicoquímica de los productos elegidos en términos de pH, parámetros reológicos, microestructura, percepción sensorial y fórmula cualicuantitativa, para establecer una correlación entre el comportamiento de permeación y las características propias del vehículo. El estudio de caracterización de la fórmula de los productos evidenció que tres ellos no presentan un contenido de cafeína superior al 0,009 [%w/w] bajo el método de extracción desarrollado. Los demás productos presentaron concentraciones de cafeína superiores al 0,39 [%w/w] y fueron evaluados en ensayos de liberación y permeación, demostrando que la cafeína efectivamente se libera del producto, pero la que logra alcanzar la capa hipodérmica con respecto a la dosis aplicada es inferior al 1%, excepto para un producto que obtuvo un porcentaje del 10 probablemente a causa de sus propiedades fisicoquímicas. No obstante, la concentración de cafeína que se encontró en la capa hipodérmica es menor a la concentración estudiada en los reportes encontrados en la literatura que puede causar un efecto del tipo lipolítico, por lo que no es seguro que pudiese generar el efecto proclamado. Por otro lado, se determinó que la cafeína de estas formulaciones tópicas podría alcanzar el fluido sistémico. En conjunto, los resultados demuestran la importancia de formular adecuadamente un producto que permita la entrega del ingrediente funcional en la capa objetivo, y el valor de implementar este tipo de herramientas in vitro para contribuir con información relacionada con la seguridad y eficacia, con miras a fortalecer los programas de cosmetovigilancia. (Texto tomado de la fuente)Cosmetics with lipolytic claims that contain caffeine in their ingredients are commercialized in the Colombian market. Caffeine is a compound widely used for its action on the mechanisms of fat accumulation in the adipocyte. To fulfill the promised cosmetic effect, the ingredient should be able to permeate the hypodermis where the adipose cells are, however, this would also imply that the caffeine present in these products could reach the systemic fluid, causing contravention with the definition of cosmetics under national legislation. In this context, seven products from the Colombian market with lipolytic claims containing caffeine were selected, with the aim of collecting information on the concentration of caffeine that could reach the hypodermis and/or the systemic fluid when the product is applied to the skin. The methodological development includes in vitro testing in Franz diffusion cells with two different membrane thicknesses, one with hypodermic tissue and the other without it, determining the permeated concentration under a dose application under conditions of use. It also includes the physicochemical characterization of the products chosen in terms of pH, rheological parameters, microstructure, sensory perception and qualitative-quantitative formula, to establish a correlation between permeation behavior and vehicle characteristics. The characterization study of the formula of the products evidence that three of them do not present a caffeine content greater than 0,009 [%w/w] under the extraction method developed. The other products had caffeine concentrations higher than 0,39 [%w/w] and were evaluated in release and permeation trials, showing that caffeine is effectively released from the product, but that the caffeine that reaches the hypodermic layer with respect to the applied dose is less than 1%, except for a product which obtained a percentage of 10 because of its physicochemical properties. However, the concentration of caffeine found in the hypodermic layer is lower than the concentration studied in the reports found in the literature that can cause a lipolytic-type effect, so it is not certain that it could generate the proclaimed effect. On the other hand, it was determined that the caffeine of these topical formulations could reach the systemic fluid. All these results demonstrate the importance of formulating a suitable product that allows the delivery of the functional ingredient in the target layer, and the value of implementing such in vitro tools to contribute information related to safety and efficacy to strengthen cosmetovigilance programs.MaestríaMagíster en Ciencias Farmacéuticasxxi, 159 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Maestría en Ciencias FarmacéuticasFacultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::615 - Farmacología y terapéuticaCafeínaCosméticos lipolíticosCeldas de difusión de FranzCaracterización fisicoquímicaGelEmulgelValidación analíticaCaffeineLipolytic cosmeticsFranz diffusion cellsPhysicochemical characterizationGelEmulgelAnalytical validationPermeationPermeaciónHipodermisEvaluación de la permeación de cafeína a partir de productos cosméticos comerciales con acción lipolítica empleando ensayos in vitro en celdas de difusión de FranzEvaluation of caffeine permeation from commercial cosmetic products with lipolytic action using in vitro assays in Franz diffusion cellsTrabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TM1. H. I. M. Raja K Sivamani, Jared R. Jagdeo, Peter Elsner, Cosmeceuticals and Active Cosmetics. 2016.2. A. Benaiges, “Concepto, clasificación y tratamiento de la celulitis,” Dermofarmacia, vol. 22. pp. 78–88, May 2003, Accessed: Nov. 09, 2020. [Online]. Available: https://www.elsevier.es/es-revista-offarm-4-pdf-13047748.3. A. Herman and A. P. Herman, “Caffeine’s mechanisms of action and its cosmetic use,” Skin Pharmacology and Physiology, vol. 26, no. 1. pp. 8–14, Dec. 2012, doi: 10.1159/0003431744. N. Hasegawa; and M. Mori, “Effect of Powdered Green Tea and Its Caffeine Content on Lipogenesis and Lipolysis in 3T3-L1 Cell,” Chem. Pharm. Bull., vol. 40, no. 6, pp. 1569–1572, 2000.5. Comunidad Andina, “DECISIÓN 833. Actualización de la Decisión 516 ‘Armonización de Legislaciones en materia de Productos Cosméticos,’” Gac. Of., 2018.6. República de colombia, “DECRETO NÚMERO 677 DE 1995 Por el cual se reglamenta parcialmente el Régimen de Registros y Licencias, el Control de Calidad, así como el Régimen de Vigilancia Sanitaria de Medicamentos, Cosméticos, Preparaciones Farmacéuticas a base de Recursos Naturales,” vol. 246, no. abril 26, pp. 1–70, 1995.7. G. Beauchamp, A. Amaducci, and M. Cook, “Caffeine Toxicity: A Brief Review and Update,” Clin. Pediatr. Emerg. Med., vol. 18, no. 3, pp. 197–202, 2017, doi: 10.1016/j.cpem.2017.07.002.8. C. Willson, “The clinical toxicology of caffeine: A review and case study,” Toxicol. Reports, vol. 5, no. November, pp. 1140–1152, 2018, doi: 10.1016/j.toxrep.2018.11.002.9. A. S. Tolley, “Caffeine: Consumption, side effects and impact on performance and mood,” Caffeine Consum. Side Eff. Impact Perform. Mood, no. January, pp. 1–217, 2014.10. M. Gajewska et al., “In vitro-to-in vivo correlation of the skin penetration, liver clearance and hepatotoxicity of caffeine,” Food Chem. Toxicol., vol. 75, pp. 39–49, 2015, doi: 10.1016/j.fct.2014.10.017.11. J. Michael, V. Nadine, K. Maike, and B. Adolf, “Erratum: Caffeine and Its Pharmacological Benefits in the Management of Androgenetic Alopecia: A Review (Skin Pharmacol Physiol (2020) 33 (93-109) DOI: 10.1159/000508228),” Skin Pharmacol. Physiol., pp. 153–169, 2020, doi: 10.1159/000511410.12. M. Visconti, W. Haidari, and S. Feldman, “Therapeutic use of caffeine in dermatology: A literature review,” J. Dermatology Dermatologic Surg., vol. 24, no. 1, p. 18, 2020, doi: 10.4103/jdds.jdds_52_19.13. C. L. Petersen, V. Kalil, and V. Campos, Drug Delivery in Dermatology. Rio de Janeiro: Springer, 2021.14. J. B. Wilkinson and R. J. Moore, Cosmetología de Harry, vol. 53, no. 9. 1990.15. M. A. Bolzinger, S. Briançon, J. Pelletier, and Y. Chevalier, “Penetration of drugs through skin, a complex rate-controlling membrane,” Curr. Opin. Colloid Interface Sci., vol. 17, no. 3, pp. 156–165, 2012, doi: 10.1016/j.cocis.2012.02.001.16. D. T. Ginat, Neuroradiological imaging of skin diseases and related conditions. Chicago: Springer, 2018.17. K. S. Saladin, Human Anatomy - Kenneth S. Saladin. Mc Graw Hill, 2007.18. W. Montagna, A. M. Kligman, K. S. Carlisle, W. Montagna, A. M. Kligman, and K. S. Carlisle, “Hypodermis,” in Atlas of Normal Human Skin, Springer New York, 1992, pp. 367–377.19. J. A. Bouwstra and M. Ponec, “The skin barrier in healthy and diseased state,” Biochim. Biophys. Acta, vol. 1758, no. 12, pp. 2080–2095, Dec. 2006, doi: 10.1016/j.bbamem.2006.06.021.20. T. Agner, Skin Barrier Function. current problems in dermatology, 2016.21. S. Singh and J. Singh, “Transdermal drug delivery by passive diffusion and iontophoresis: A review,” Med. Res. Rev., vol. 13, no. 5, pp. 569–621, Sep. 1993, doi: 10.1002/med.2610130504.22. SCCP, “SCCP/0970/06 Basic Criteria for the in vitro assessment of dermal absorption of cosmetic ingredients-update March 2006, European Commission,” no. March, 2006, [Online]. Available: https://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_s_03.pdf.23. J. Kielhorn, S. Melching-Kollmuß, I. Mangelsdorf, and World Health Organization, “Environmental health criteria 235 for dermal absorption,” Environ. Heal. Criteria, 2006.24. A. Z. Alkilani, M. T. C. McCrudden, and R. F. Donnelly, “Transdermal drug delivery: Innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum,” Pharmaceutics, vol. 7, no. 4, pp. 438–470, 2015, doi: 10.3390/pharmaceutics7040438.25. S. Trauer et al., “Permeation of topically applied caffeine through human skin - A comparison of in vivo and in vitro data,” Br. J. Clin. Pharmacol., vol. 68, no. 2, pp. 181–186, Aug. 2009, doi: 10.1111/j.1365-2125.2009.03463.x.26. B. J. Thomas and B. C. Finnin, “The transdermal revolution,” Drug Discov. Today, vol. 9, no. 16, pp. 697–703, 2004, doi: 10.1016/S1359-6446(04)03180-0.27. R. Gutiérrez Fernández de Molina, “Estudios De Difusión A Través De Piel De Formulaciones Liposómicas De Aciclovir,” Universidad Computense de Madrid, 2011.28. C. Ehrhardt and K.-J. Kim, Drug Absorption Studies. New York: Springer, 2008.29. OECD, “OECD Test Guideline 428: Skin Absorption: in vitro method,” no. April. 2004.30. V. Rogiers and M. Pauwels, “Critical Analysis of the Safety Assessment of Cosmetic Ingredients Performed at the European Level: the in vitro delmal absorption study,” in Safety assesment of cosmetics in Europe, KARGER, 2008, pp. 74–81.31. D. Selzer, M. M. A. Abdel-Mottaleb, T. Hahn, U. F. Schaefer, and D. Neumann, “Finite and infinite dosing: Difficulties in measurements, evaluations and predictions,” Adv. Drug Deliv. Rev., vol. 65, no. 2, pp. 278–294, 2013, doi: 10.1016/j.addr.2012.06.010.32. L. Luo and M. E. Lane, “Topical and transdermal delivery of caffeine,” International Journal of Pharmaceutics, vol. 490, no. 1–2. Elsevier B.V., pp. 155–164, May 31, 2015, doi: 10.1016/j.ijpharm.2015.05.050.33. M. O’Neil, The Merck index : an encyclopedia of chemicals, drugs, and biologicals., Fifteenth edition /. Cambridge UK: Royal Society of Chemistry, 2013.34. “Caffeine C8H10N4O2 | ChemSpider.” http://www.chemspider.com/Chemical-Structure.2424.html (accessed Aug. 10, 2020).35. European Food Safety Authority, “Scientific Opinion on the safety of caffeine,” EFSA J., vol. 13, no. 5, 2015, doi: 10.2903/j.efsa.2015.4102.36. A. Murray and J. Traylor, Caffeine Toxicity. StatPearls Publishing, 2018.37. A. Bolsoni-Lopes and M. I. C. Alonso-Vale, “Lipolysis and lipases in white adipose tissue – An update,” Archives of Endocrinology and Metabolism, vol. 59, no. 4. Sociedade Brasileira de Endocrinologia e Metabologia, pp. 335–342, 2015, doi: 10.1590/2359-3997000000067.38. A. Lass, R. Zimmermann, M. Oberer, and R. Zechner, “Lipolysis - A highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores,” Progress in Lipid Research, vol. 50, no. 1. Elsevier Ltd, pp. 14–27, 2011, doi: 10.1016/j.plipres.2010.10.004.39. M. V. Velasco Robles, C. Tano Nakamura, G. M. Machado-Santelli, C. Vladi Olga, T. M. Kaneko, and A. Rolim Baby, “Effects of caffeine and siloxanetriol alginate caffeine, as anticellulite agents, on fatty tissue: histological evaluation,” 2008.40. E. Dupont et al., “An integral topical gel for cellulite reduction: Results from a double-blind, randomized, placebo-controlled evaluation of efficacy,” Clin. Cosmet. Investig. Dermatol., vol. 7, pp. 73–88, Feb. 2014, doi: 10.2147/CCID.S53580.41. B. Vogelgesang, I. Bonnet, N. Godard, B. Sohm, and E. Perrier, “In vitro and in vivo efficacy of sulfo-carrabiose, a sugar-based cosmetic ingredient with anti-cellulite properties,” Int. J. Cosmet. Sci., vol. 33, no. 2, pp. 120–125, Apr. 2011, doi: 10.1111/j.1468-2494.2010.00593.x.42. F. Turati et al., “Efficacy of cosmetic products in cellulite reduction: systematic review and meta-analysis,” J. Eur. Acad. Dermatology Venereol., vol. 28, no. 1, pp. 1–15, Jan. 2014, doi: 10.1111/jdv.12193.43. R. Roure, T. Oddos, A. Rossi, F. Vial, and C. Bertin, “Evaluation of the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol, in vitro, ex vivo and in vivo studies,” Int. J. Cosmet. Sci., vol. 33, no. 6, pp. 519–526, Dec. 2011, doi: 10.1111/j.1468-2494.2011.00665.x.44. C. Dray, D. Daviaud, C. Guigné, P. Valet, and I. Castan-Laurell, “Caffeine reduces TNFα up-regulation in human adipose tissue primary culture,” J. Physiol. Biochem., vol. 63, no. 4, pp. 329–336, 2007, doi: 10.1007/BF03165764.45. H. Hamishehkar, J. Shokri, S. Fallahi, A. Jahangiri, S. Ghanbarzadeh, and M. Kouhsoltani, “Histopathological evaluation of caffeine-loaded solid lipid nanoparticles in efficient treatment of cellulite,” Drug Dev. Ind. Pharm., vol. 41, no. 10, pp. 1640–1646, 2015, doi: 10.3109/03639045.2014.980426.46. S. Murosaki et al., “A combination of caffeine, arginine, soy isoflavones, and L-carnitine enhances both lipolysis and fatty acid oxidation in 3T3-L1 and HepG2 cells in vitro and in KK mice in vivo,” J. Nutr., vol. 137, no. 10, pp. 2252–2257, 2007, doi: 10.1093/jn/137.10.2252.47. C. Sugiura, G. Zheng, L. Liu, and K. Sayama, “Catechins and Caffeine Promote Lipid Metabolism and Heat Production Through the Transformation of Differentiated 3T3-L1 Adipocytes from White to Beige Adipocytes,” J. Food Sci., vol. 85, no. 1, pp. 192–200, 2020, doi: 10.1111/1750-3841.14811.48. J. Stanek and M. Wochner, “Current and Future ‘ Body-sculpting ’ Cosmetics The Science of Fat,” vol. 130, no. 9, pp. 20–28, 2015.49. D. Hexsel and M. Soirefmann, “Cosmeceuticals for Cellulite,” Seminars in Cutaneous Medicine and Surgery, vol. 30, no. 3. pp. 167–170, Sep. 2011, doi: 10.1016/j.sder.2011.06.005.50. N. Otberg et al., “The role of hair follicles in the percutaneous absorption of caffeine,” Br. J. Clin. Pharmacol., vol. 65, no. 4, pp. 488–492, 2008, doi: 10.1111/j.1365-2125.2007.03065.x.51. M. A. Bolzinger, S. Briançon, J. Pelletier, H. Fessi, and Y. Chevalier, “Percutaneous release of caffeine from microemulsion, emulsion and gel dosage forms,” Eur. J. Pharm. Biopharm., vol. 68, no. 2, pp. 446–451, 2008, doi: 10.1016/j.ejpb.2007.10.018.52. “Caffeine - Registration Dossier - ECHA,” Dermal absorption. https://echa.europa.eu/registration-dossier/-/registered-dossier/10085/7/2/3 (accessed Nov. 10, 2020).53. J. Frelichowska, M. A. Bolzinger, J. P. Valour, H. Mouaziz, J. Pelletier, and Y. Chevalier, “Pickering w/o emulsions: Drug release and topical delivery,” Int. J. Pharm., vol. 368, no. 1–2, pp. 7–15, Feb. 2009, doi: 10.1016/j.ijpharm.2008.09.057.54. M. V Debandi, N. J. François, and M. E. Daraio, “Evaluación De Distintas Membranas Para Liberación in Vitro De Principios Activos Anticelulíticos.,” Aci, vol. 2, no. 2, pp. 97–105, 2011.55. S. Meesen, “In vitro percutaneus absorption of caffeine from cosmetic formulations,” no. thesis Msc.Cosmetic Sciences, 2011.56. R. Mustapha, C. Lafforgue, N. Fenina, and J. Marty, “Influence of drug concentration on the diffusion parameters of caffeine,” Indian J. Pharmacol., vol. 43, no. 2, pp. 157–162, Apr. 2011, doi: 10.4103/0253-7613.77351.57. J. Djajadisastra, Sutriyo, and Hadyanti, “Percutane transport profile of caffeine and aminophyllin as anticellulite and the influences of other substances on in vitro penetration,” Int. J. Pharm. Pharm. Sci., vol. 6, no. 5, pp. 532–538, 2014.58. E. Abd et al., “Deformable liposomes as enhancer of caffeine penetration through human skin in a Franz diffusion cell test,” Int. J. Cosmet. Sci., pp. 1–10, 2020, doi: 10.1111/ics.12659.59. N. H. C. S. Silva et al., “Topical caffeine delivery using biocellulose membranes: A potential innovative system for cellulite treatment,” Cellulose, vol. 21, no. 1, pp. 665–674, Feb. 2014, doi: 10.1007/s10570-013-0114-1.60. I. Iskandarsyah, A. W. Puteri, and E. Ernysagita, “Penetration test of caffeine in ethosome and desmosome gel using an in vitro method,” Int. J. Appl. Pharm., vol. 9, pp. 120–123, 2017, doi: 10.22159/ijap.2017.v9s1.69_76.61. F. Farner, L. Bors, Á. Bajza, G. Karvaly, I. Antal, and F. Erdő, “Validation of an In vitro-in vivo Assay System for Evaluation of Transdermal Delivery of Caffeine,” Drug Deliv. Lett., vol. 9, no. 1, pp. 15–20, Sep. 2018, doi: 10.2174/2210303108666180903102107.62. J. Pavlačková et al., “Transdermal absorption of active substances from cosmetic vehicles,” J. Cosmet. Dermatol., vol. 18, no. 5, pp. 1410–1415, 2019, doi: 10.1111/jocd.12873.63. J. Ageis, H. Suryadi, and M. Jufri, “Formulation and in vitro skin penetration of a solid lipid nanoparticle gel containing coffea arabica extract,” Int. J. Appl. Pharm., vol. 12, no. Special Issue 1, pp. 177–181, 2020, doi: 10.22159/ijap.2020.v12s1.FF040.64. Y. de Lafuente, A. Ochoa-Andrade, M. E. Parente, M. C. Palena, and A. F. Jimenez-Kairuz, “Preparation and evaluation of caffeine bioadhesive emulgels for cosmetic applications based on formulation design using QbD tools,” Int. J. Cosmet. Sci., pp. 548–556, 2020, doi: 10.1111/ics.12638.65. M. Dias, A. Farinha, E. Faustino, J. Hadgraft, J. Pais, and C. Toscano, “Topical delivery of caffeine from some commercial formulations,” 1999.66. A. Smith, A. Chadha, R. Homan, and G. Baki, “Skin Penetration of Caffeine from Marketed Eye Creams,” New York, 2017. [Online]. Available: http://permegear.com/wp-.67. MINISTERIO DE SALUD, “RESOLUCION NUMERO 8430 DE 1993 ‘Por la cual se establecen las normas científicas, técnicas y administrativas para la investigación en salud,’” 1993.68. República de Colombia, “Estatuto nacional de proteccion de los animales Ley 84 de 1989,” El Congr. Colomb., vol. 5, no. Diciembre 27, p. 14, 1989, [Online]. Available: http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:No+Title#0.69. Congreso de Colombia, “Ley 2047 de 2020 "por el cual se prohíbe en colombia la experimentación, importación, fabricación y comercialización de productos cosméticos, sus ingredientes o combinaciones de ellos que sean objeto de pruebas con animales y se dictan otras disposiciones,” 2020.70. J. Y. Kim, J. Y. Song, E. J. Lee, and S. K. Park, “Rheological properties and microstructures of Carbopol gel network system,” Colloid Polym. Sci., vol. 281, no. 7, pp. 614–623, 2003, doi: 10.1007/s00396-002-0808-7.71. R. Injac, B. Srdjenovic, M. Prijatelj, M. Boskovic, K. Karljikovic-Rajic, and B. Strukelj, “Determination of caffeine and associated compounds in food, beverages, natural products, pharmaceuticals, and cosmetics by micellar electrokinetic capillary chromatography,” J. Chromatogr. Sci., vol. 46, no. 2, pp. 137–143, 2008, doi: 10.1093/chromsci/46.2.137.72. E. Marchei, D. De Orsi, C. Guarino, S. Dorato, R. Pacifici, and S. Pichini, “Measurement of iodide and caffeine content in cellulite reduction cosmetic products sold in the European market,” Anal. Methods, vol. 5, no. 2, pp. 376–383, Jan. 2013, doi: 10.1039/c2ay25761k.73. K. Mladenov and S. SunariĆ, “Caffeine in Hair Care and Anticellulite Cosmetics: Sample Preparation, Solid-Phase Extraction, and HPLC Determination,” J. Cosmet. Sci., vol. 71, no. 5, pp. 251–262, 2020.74. L. M. Sanabria, J. A. Martínez, and Y. Baena, “Validación de una metodología analítica por HPLC-DAD para la cuantificación de cafeína en un ensayo de permeación in vitro empleando mucosa oral porcina,” Rev. Colomb. Ciencias Químico-Farmacéuticas, vol. 46, no. 2, May 2017, doi: 10.15446/rcciquifa.v46n2.67956.75. A. M. A. Hasan and M. E.-S. Abdel-Raouf, Cellulose-Based Superabsorbent Hydrogels. 2019.76. L. A. Martínez, L. M. Sanabria, and Y. Baena, “Safety assessment of complex benzoic acid using in vitro permeation assays with pig skin in Franz cells,” pp. 1–17, 2020.77. Y. Baena, L. Dallos, R. Manzo, and L. Ponce D’León, “Estandarización de celdas de Franz para la realización de ensayos de liberación de fármacos a partir de complejos con polielectrolitos,” Rev. Colomb. Ciencias Químico-Farmacéuticas, vol. 40, no. 2, pp. 174–188, 2011.78. L. Sanabria, “Contribución a la implementación de un ensayo de permeación bucal, in vitro, empleano cafeína como compuesto modelo.,” Universidad Nacional de Colombia, 2017.79. European Medicines Agency, “ICH Guideline M10 on Bioanalytical Method Validation,” Sci. Med. Heal., vol. 44, no. March, p. 57, 2019.80. Food and Drug Administration -Guidance for Industry, “Bioanalytical method validation,” in Guidance for Industry, 2018, pp. 1–41, doi: 10.5958/2231-5675.2015.00035.6.81. E. A. Fernández-montes, “Control de calidad Fórmulas dermatológicas,” Farm. Prof., vol. 17, pp. 70–75, 2003, [Online]. Available: https://www.elsevier.es/es-revista-farmacia-profesional-3-pdf-13044489.82. K. Welin-Berger, J. A. M. Neelissen, and B. Bergenståhl, “The effect of rheological behaviour of a topical anaesthetic formulation on the release and permeation rates of the active compound,” Eur. J. Pharm. Sci., vol. 13, no. 3, pp. 309–318, 2001, doi: 10.1016/S0928-0987(01)00118-X.83. L. Binder, J. Mazál, R. Petz, V. Klang, and C. Valenta, “The role of viscosity on skin penetration from cellulose ether-based hydrogels,” Ski. Res. Technol., vol. 25, no. 5, pp. 725–734, 2019, doi: 10.1111/srt.12709.84. C. Wibowo and K. M. Ng, “Product-oriented process synthesis and development: Creams and pastes,” AIChE J., vol. 47, no. 12, pp. 2746–2767, 2001, doi: 10.1002/aic.690471214.85. D. Saha and S. Bhattacharya, “Hydrocolloids as thickening and gelling agents in food: A critical review,” J. Food Sci. Technol., vol. 47, no. 6, pp. 587–597, 2010, doi: 10.1007/s13197-010-0162-6.86. H. Iwata and K. Shimada, Formula Ingredients and production in cosmetics, Springer., vol. 53, no. 9. Japan, 2013.87. D. W. Lachenmeier, “Safety evaluation of topical applications of ethanol on the skin and inside the oral cavity,” J. Occup. Med. Toxicol., vol. 3, no. 1, pp. 1–16, 2008, doi: 10.1186/1745-6673-3-26.88. L. C. Becker et al., “Safety Assessment of Glycerin as Used in Cosmetics,” Int. J. Toxicol., vol. 38, no. 3_suppl, pp. 6S-22S, Nov. 2019, doi: 10.1177/1091581819883820.89. S. Björklund, J. Engblom, K. Thuresson, and E. Sparr, “Glycerol and urea can be used to increase skin permeability in reduced hydration conditions,” Eur. J. Pharm. Sci., vol. 50, no. 5, pp. 638–645, 2013, doi: 10.1016/j.ejps.2013.04.022.90. “Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 31 Hazardous Substances Data Bank (HSDB).” .91. “Flick, E.W. (ed.). Industrial Solvents Handbook 4 th ed. Noyes Data Corporation., Park Ridge, NJ., 1991., p. 394 Hazardous Substances Data Bank (HSDB).” .92. C. Reichardt and T. Welton, “Solvents and Solvent Effects in Organic Chemistry: Fourth Edition,” Solvents Solvent Eff. Org. Chem. Fourth Ed., Nov. 2010, doi: 10.1002/9783527632220.93. “Liquids - Dielectric Constants.” https://www.engineeringtoolbox.com/liquid-dielectric-constants-d_1263.html (accessed Sep. 04, 2022).94. “Solvent Polarity Table - Miller’s Home.” https://sites.google.com/site/miller00828/in/solvent-polarity-table (accessed Sep. 04, 2022).95. INVIMA, “Validación de Métodos Analíticos,” pp. 1–92, 2014, [Online]. Available: https://www.invima.gov.co/documents/20143/1433858/Validación+Medicamentos.pdf.96. Food and Drug Administration, “Methods, Method Verification and Validation,” ORA Lab. Proced., vol. II, pp. 1–19, 2014.97. M. Akdeniz, S. Gabriel, A. Lichterfeld-Kottner, U. Blume-Peytavi, and J. Kottner, “Transepidermal water loss in healthy adults: a systematic review and meta-analysis update,” Br. J. Dermatol., vol. 179, no. 5, pp. 1049–1055, 2018, doi: 10.1111/bjd.17025.98. C. Jacques-Jamin, C. Jeanjean-Miquel, A. Domergue, S. Bessou-Touya, and H. Duplan, “Standardization of an in vitro model for evaluating the bioavailability of topically applied compounds on damaged skin: Application to sunscreen analysis,” Skin Pharmacol. Physiol., vol. 30, no. 2, pp. 55–65, 2017, doi: 10.1159/000455196.99. L. Kong et al., “Chlorogenic acid and caffeine combination attenuates adipogenesis by regulating fat metabolism and inhibiting adipocyte differentiation in 3T3-L1 cells,” J. Food Biochem., no. January, pp. 1–11, 2021, doi: 10.1111/jfbc.13795.100. H. Nakabayashi, T. Hashimoto, H. Ashida, S. Nishiumi, and K. Kanazawa, “Inhibitory effects of caffeine and its metabolites on intracellular lipid accumulation in murine 3T3-L1 adipocytes,” BioFactors, vol. 34, no. 4, pp. 293–302, 2008, doi: 10.1002/biof.5520340405.101. S. H. Su, H. W. Shyu, Y. T. Yeh, K. M. Chen, H. Yeh, and S. J. Su, “Caffeine inhibits adipogenic differentiation of primary adipose-derived stem cells and bone marrow stromal cells,” Toxicol. Vitr., vol. 27, no. 6, pp. 1830–1837, 2013, doi: 10.1016/j.tiv.2013.05.011.102. FOOD AND DRUG ADMINISTRATION (FDA), “Thigh Creams (Cellulite Creams) | FDA.” https://www.fda.gov/cosmetics/cosmetic-products/thigh-creams-cellulite-creams (accessed Sep. 06, 2022).103. M. Nomura et al., “Inhibition of epidermal growth factor-induced cell transformation and Akt activation by caffeine,” Mol. Carcinog., vol. 44, no. 1, pp. 67–76, Sep. 2005, doi: 10.1002/MC.20120.104. J. V. Forrester, A. D. Dick, P. G. McMenamin, F. Roberts, and E. Pearlman, “General and ocular pharmacology,” Eye, pp. 338-369.e1, Jan. 2016, doi: 10.1016/B978-0-7020-5554-6.00006-X.105. K. Al-Khamis, S. S. Davis, and J. Hadgraft, “In vitro-in vivo correlations for the percutaneous absorption of salicylates,” Int. J. Pharm., vol. 40, no. 1–2, pp. 111–118, 1987, doi: 10.1016/0378-5173(87)90055-X.EstudiantesInvestigadoresMaestrosPúblico generalORIGINAL1057599911.2023.pdf1057599911.2023.pdfTesis de Maestría en Ciencias Farmacéuticasapplication/pdf4421126https://repositorio.unal.edu.co/bitstream/unal/84496/4/1057599911.2023.pdf0611f6b64c941537e74b33194b313704MD54LICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/84496/3/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD53THUMBNAIL1057599911.2023.pdf.jpg1057599911.2023.pdf.jpgGenerated Thumbnailimage/jpeg5671https://repositorio.unal.edu.co/bitstream/unal/84496/5/1057599911.2023.pdf.jpg47061bd3ebb6654c5d8ed84abaabfcccMD55unal/84496oai:repositorio.unal.edu.co:unal/844962023-08-08 23:03:20.219Repositorio Institucional Universidad Nacional de Colombiarepositorio_nal@unal.edu.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

Publicaciones similares