Formulaciones disuasorias de abuso: descripción de estrategias tecnológicas y su posible influencia en la mitigación del abuso de opioides comerciales

El abuso de opioides de prescripción oral constituye un problema grave de salud pública que puede llevar a consecuencias serias como el aumento de trastornos por consumo de opioides, sobredosis y muertes causadas por opioides. Desde el sector farmacéutico, han surgido formulaciones diseñadas para ev...

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Autores:: Sanchez Alcalá, Camilo Eduardo

Tipo de recurso:: https://purl.org/coar/resource_type/c_7a1f

Fecha de publicación:: 2024

Institución:: Universidad El Bosque

Repositorio:: Repositorio U. El Bosque

Idioma:: spa

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dc.title.none.fl_str_mv	Formulaciones disuasorias de abuso: descripción de estrategias tecnológicas y su posible influencia en la mitigación del abuso de opioides comerciales
dc.title.translated.none.fl_str_mv	Abuse-deterrent formulations: description of technological strategies and their potential influence on mitigating commercial opioid abuse
title	Formulaciones disuasorias de abuso: descripción de estrategias tecnológicas y su posible influencia en la mitigación del abuso de opioides comerciales
spellingShingle	Formulaciones disuasorias de abuso: descripción de estrategias tecnológicas y su posible influencia en la mitigación del abuso de opioides comerciales Opioides Abuso de opioides, Formulaciones disuasorias de abuso 615.19 Opioids Opioid abuse Abuse deterrent formulations
title_short	Formulaciones disuasorias de abuso: descripción de estrategias tecnológicas y su posible influencia en la mitigación del abuso de opioides comerciales
title_full	Formulaciones disuasorias de abuso: descripción de estrategias tecnológicas y su posible influencia en la mitigación del abuso de opioides comerciales
title_fullStr	Formulaciones disuasorias de abuso: descripción de estrategias tecnológicas y su posible influencia en la mitigación del abuso de opioides comerciales
title_full_unstemmed	Formulaciones disuasorias de abuso: descripción de estrategias tecnológicas y su posible influencia en la mitigación del abuso de opioides comerciales
title_sort	Formulaciones disuasorias de abuso: descripción de estrategias tecnológicas y su posible influencia en la mitigación del abuso de opioides comerciales
dc.creator.fl_str_mv	Sanchez Alcalá, Camilo Eduardo
dc.contributor.advisor.none.fl_str_mv	Vargas Mantilla, Jors Steven Velandia Paris, María Angelica
dc.contributor.author.none.fl_str_mv	Sanchez Alcalá, Camilo Eduardo
dc.subject.none.fl_str_mv	Opioides Abuso de opioides, Formulaciones disuasorias de abuso
topic	Opioides Abuso de opioides, Formulaciones disuasorias de abuso 615.19 Opioids Opioid abuse Abuse deterrent formulations
dc.subject.ddc.none.fl_str_mv	615.19
dc.subject.keywords.none.fl_str_mv	Opioids Opioid abuse Abuse deterrent formulations
description	El abuso de opioides de prescripción oral constituye un problema grave de salud pública que puede llevar a consecuencias serias como el aumento de trastornos por consumo de opioides, sobredosis y muertes causadas por opioides. Desde el sector farmacéutico, han surgido formulaciones diseñadas para evitar la manipulación de los analgésicos opioides de receta por administración oral para su consumo por vías alternativas (Intranasal e IV, entre otras), estas se han denominado formulaciones disuasorias de abuso (ADF’s). Los objetivos de esta revisión fueron la construcción de una base de datos efectiva para seleccionar y filtrar la información referente al tema, examinar los aspectos tecnológicos y clínicos de las ADF’s para comprender su funcionamiento y determinar la influencia de estas en la problemática planteada, además de analizar su efectividad y plantear recomendaciones pertinentes. Se construyó de manera satisfactoria la base de datos, que fue útil para analizar las investigaciones seleccionadas. Se encontraron las herramientas tecnológicas más empleadas en este tipo de formulaciones y se determinó la disminución de parámetros relacionados con el abuso de opioides causados por la implementación de estos diseños al mercado. Se concluyó que, la base de datos permitió una extracción efectiva de la información; se identificaron las tendencias tecnológicas en cuanto a materiales, métodos, formas farmacéuticas y mecanismos de disuasión más empleados y eficientes, además, se encontró la reducción satisfactoria en el abuso de opioides de prescripción por administración oral causada por las ADF’s
publishDate	2024
dc.date.accessioned.none.fl_str_mv	2024-11-20T13:14:55Z
dc.date.available.none.fl_str_mv	2024-11-20T13:14:55Z
dc.date.issued.none.fl_str_mv	2024-10
dc.type.coar.fl_str_mv	http://purl.org/coar/resource_type/c_7a1f
dc.type.local.none.fl_str_mv	Tesis/Trabajo de grado - Monografía - Pregrado
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dc.identifier.instname.spa.fl_str_mv	Universidad El Bosque
dc.identifier.reponame.spa.fl_str_mv	reponame:Repositorio Institucional Universidad El Bosque
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identifier_str_mv	Universidad El Bosque reponame:Repositorio Institucional Universidad El Bosque repourl:https://repositorio.unbosque.edu.co
dc.language.iso.fl_str_mv	spa
language	spa
dc.relation.references.none.fl_str_mv	[1] M. L. Meldrum, “The ongoing opioid prescription epidemic: Historical context,” Aug. 01, 2016, American Public Health Association Inc. doi: 10.2105/AJPH.2016.303297 [2] S. Calcaterra, J. Glanz, and I. A. Binswanger, “National trends in pharmaceutical opioid related overdose deaths compared to other substance related overdose deaths: 1999-2009,” Drug Alcohol Depend, vol. 131, no. 3, pp. 263–270, Aug. 2013, doi: 10.1016/j.drugalcdep.2012.11.018. [3] J. Lyden and I. A. Binswanger, “The United States opioid epidemic,” Semin Perinatol, vol. 43, no. 3, pp. 123–131, 2019, doi: 10.1053/j.semperi.2019.01.001. [4] R. L. Rauck, “Mitigation of IV Abuse Through the Use of Abuse-Deterrent Opioid Formulations: An Overview of Current Technologies,” Apr. 01, 2019, Blackwell Publishing Inc. doi: 10.1111/papr.12760. [5] J. V. Pergolizzi, R. B. Raffa, R. Taylor, and S. Vacalis, “Abuse-deterrent opioids: an update on current approaches and considerations,” https://doi.org/10.1080/03007995.2017.1419171, vol. 34, no. 4, pp. 711–723, Apr. 2018, doi: 10.1080/03007995.2017.1419171 [6] M. Murshed, M. Salim, and B. J. Boyd, “Existing and emerging mitigation strategies for the prevention of accidental overdose from oral pharmaceutical products,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 180, pp. 201–211, Nov. 2022, doi: 10.1016/J.EJPB.2022.10.002 [7] X. Xu et al., “Evaluation of Abuse-Deterrent Characteristics of Tablets Prepared via Hot-Melt Extrusion,” AAPS PharmSciTech, vol. 20, no. 6, Aug. 2019, doi: 10.1208/s12249-019-1448-2. [8] A. Soni, A. Paprikar, and S. Lin, “Effect of alkalizing agent on abuse deterrent potential of multiple-unit ingestion of bilayer abuse-deterrent extended-release tablets using propranolol as model drug for opioids overdose crisis,” Int J Pharm, vol. 600, May 2021, doi: 10.1016/j.ijpharm.2021.120480. [9] P. K. Nukala, S. Palekar, M. Patki, and K. Patel, “Abuse Deterrent Immediate Release Egg-Shaped Tablet (Egglets) Using 3D Printing Technology: Quality by Design to Optimize Drug Release and Extraction,” AAPS PharmSciTech, vol. 20, no. 2, Feb. 2019, doi: 10.1208/s12249-019-1298-y. [10] S. Ram Munnangi, N. Narala, P. Lakkala, S. Kumar Vemula, and M. Repka, “Assessing Abuse-Deterrent formulations utilizing Ion-Exchange resin complexation processed via Twin-Screw granulation for improved safety and effectiveness,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 197, Apr. 2024, doi: 10.1016/j.ejpb.2024.114230 [11] Z. Rahman et al., “Assessing impact of formulation and process variables on in-vitro performance of directly compressed abuse deterrent formulations,” Int J Pharm, vol. 502, no. 1–2, pp. 138–150, Apr. 2016, doi: 10.1016/j.ijpharm.2016.02.029. [12] P. Jayendrakumar and P. Rakesh, “Self-regulated Anti-Overdose Crush and Extraction-Resistant Drug Delivery System to Combat Opioid Overdose Crisis,” AAPS PharmSciTech, vol. 23, no. 7, Oct. 2022, doi: 10.1208/s12249-022-02423-5. [13] S. Palekar, P. K. Nukala, and K. Patel, “Aversion liquid-filled drug releasing capsule (3D-RECAL): A novel technology for the development of immediate release abuse deterrent formulations using a fused deposition modelling (FDM) 3D printer,” Int J Pharm, vol. 621, Jun. 2022, doi: 10.1016/j.ijpharm.2022.121804. [14] L. Rezaei, S. Meruva, and M. D. Donovan, “Effect of Manufacturing Process on the Retention of Abuse-Deterrent Properties of PEO-Matrix Tablets,” AAPS PharmSciTech, vol. 23, no. 1, Jan. 2022, doi: 10.1208/s12249-021-02169-6. [15] N. Jedinger, S. Schrank, J. M. Fischer, K. Breinhälter, J. Khinast, and E. Roblegg, “Development of an Abuse- and Alcohol Resistant Formulation Based on Hot-Melt Extrusion and Film Coating,” AAPS PharmSciTech, vol. 17, no. 1, pp. 68–77, Feb. 2016, doi: 10.1208/s12249-015-0373-2. [16] X. Feng, K. W. Wu, V. Balajee, J. Leissa, M. Ashraf, and X. Xu, “Understanding syringeability and injectability of high molecular weight PEO solution through time-dependent force-distance profiles,” Int J Pharm, vol. 631, Jan. 2023, doi: 10.1016/j.ijpharm.2022.122486. [17] E. R. Kinzler, C. Pantaleon, M. S. Iverson, and S. Aigner, “Syringeability of morphine ARER, a novel, abuse-deterrent, extended-release morphine formulation,” American Journal of Drug and Alcohol Abuse, vol. 45, no. 4, pp. 377–384, Jul. 2019, doi: 10.1080/00952990.2019.1599383. [18] G. Kibria, B. Bandaranayake, J. Zheng, S. Lee, and C. Cruz, “Stability of Abuse-deterrent properties of PEO-based Abuse deterrent formulation,” Int J Pharm, vol. 631, Jan. 2023, doi: 10.1016/j.ijpharm.2022.2430. [19] S. Meruva and M. D. Donovan, “Polyethylene Oxide (PEO) Molecular Weight Effects on Abuse-Deterrent Properties of Matrix Tablets,” AAPS PharmSciTech, vol. 21, no. 1, Jan. 2020, doi: 10.1208/s12249-019-1565-y. [20] S. Palekar, P. Kumar Nukala, R. Vartak, and K. Patel, “Abuse deterrent immediate release film technology (ADRIFT): A novel bilayer film technology for limiting intentional drug abuse,” Int J Pharm, vol. 590, Nov. 2020, doi: 10.1016/j.ijpharm.2020.119944. [21] P. K. Nukala, S. Palekar, M. Patki, Y. Fu, and K. Patel, “Multi-dose oral abuse deterrent formulation of loperamide using hot melt extrusion,” Int J Pharm, vol. 569, Oct. 2019, doi: 10.1016/j.ijpharm.2019.118629. [22] S. Meruva and M. D. Donovan, “Effects of Drug-Polymer Interactions on Tablet Properties During the Development of Abuse-Deterrent Dosage Forms,” AAPS PharmSciTech, vol. 20, no. 3, Apr. 2019, doi: 10.1208/s12249-018-1221-y. [23] S. Meruva, L. Rezaei, P. Thool, and M. D. Donovan, “Use of Drug Release Testing to Evaluate the Retention of Abuse Deterrent Properties of Polyethylene Oxide Matrix Tablets,” AAPS PharmSciTech, vol. 21, no. 7, Oct. 2020, doi: 10.1208/s12249- 020-01804-y. [24] H. Qu et al., “Asymmetrical Flow Field Flow Fractionation for Molar Mass Characterization of Polyethylene Oxide in Abuse Deterrent Formulations,” J Chromatogr A, vol. 1705, Aug. 2023, doi: 10.1016/j.chroma.2023.464186 [25] R. Ahmad and H. Omidian, “Development and in vitro evaluation of an abuse-deterrent formulation based on a crosslinked starch derivative,” Int J Pharm, vol. 569, Oct. 2019, doi: 10.1016/j.ijpharm.2019.118602. [26] H. G. Cheng and P. M. Coplan, “Incidence of nonmedical use of OxyContin and other prescription opioid pain relievers before and after the introduction of OxyContin with abuse deterrent properties,” Postgrad Med, vol. 130, no. 6, pp. 568–574, Aug. 2018, doi: 10.1080/00325481.2018.1495541. [27] C. Wolff et al., “The impact of the abuse-deterrent reformulation of extended-release OxyContin on prescription pain reliever misuse and heroin initiation,” Addictive Behaviors, vol. 105, Jun. 2020, doi: 10.1016/j.addbeh.2019.106268. [28] M. DiNardi, “The release of abuse-deterrent OxyContin and adolescent heroin use,” Drug Alcohol Depend, vol. 229, Dec. 2021, doi: 10.1016/j.drugalcdep.2021.109114. [29] L. Degenhardt, R. Bruno, R. Ali, N. Lintzeris, M. Farrell, and B. Larance, “The introduction of a potentially abuse deterrent oxycodone formulation: Early findings from the Australian National Opioid Medications Abuse Deterrence (NOMAD) study,” Drug Alcohol Depend, vol. 151, pp. 56–67, Jun. 2015, doi: 10.1016/j.drugalcdep.2015.02.038. [30] T. Paljarvi, J. Strang, P. D. Quinn, S. Luciano, and S. Fazel, “Abuse-deterrent extended-release oxycodone and risk of opioid related harm,” Addiction, vol. 116, no. 9, pp. 2409–2415, Sep. 2021, doi: 10.1111/add.15392 [31] S. G. Severtson et al., “Sustained reduction of diversion and abuse after introduction of an abuse deterrent formulation of extended release oxycodone,” Drug Alcohol Depend, vol. 168, pp. 219–229, Nov. 2016, doi: 10.1016/j.drugalcdep.2016.09.018. [32] T. J. Cicero and M. S. Ellis, “Abuse-deterrent formulations and the prescription opioid abuse epidemic in the United States: Lessons learned from OxyContin,” JAMA Psychiatry, vol. 72, no. 5, pp. 424–429, May 2015, doi: 10.1001/jamapsychiatry.2014.3043. [33] S. G. Severtson, S. E. D. Kreider, E. C. Amioka, Z. R. Margolin, J. L. Iwanicki, and R. C. Dart, “Postmarketing analysis of misuse, abuse, and diversion of Xtampza ER,” Pain Medicine (United States), vol. 21, no. 12, pp. 3660–3668, 2020, doi:10.1093/PM/PNAA272
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spelling	Vargas Mantilla, Jors StevenVelandia Paris, María AngelicaSanchez Alcalá, Camilo Eduardo2024-11-20T13:14:55Z2024-11-20T13:14:55Z2024-10https://hdl.handle.net/20.500.12495/13263Universidad El Bosquereponame:Repositorio Institucional Universidad El Bosquerepourl:https://repositorio.unbosque.edu.coEl abuso de opioides de prescripción oral constituye un problema grave de salud pública que puede llevar a consecuencias serias como el aumento de trastornos por consumo de opioides, sobredosis y muertes causadas por opioides. Desde el sector farmacéutico, han surgido formulaciones diseñadas para evitar la manipulación de los analgésicos opioides de receta por administración oral para su consumo por vías alternativas (Intranasal e IV, entre otras), estas se han denominado formulaciones disuasorias de abuso (ADF’s). Los objetivos de esta revisión fueron la construcción de una base de datos efectiva para seleccionar y filtrar la información referente al tema, examinar los aspectos tecnológicos y clínicos de las ADF’s para comprender su funcionamiento y determinar la influencia de estas en la problemática planteada, además de analizar su efectividad y plantear recomendaciones pertinentes. Se construyó de manera satisfactoria la base de datos, que fue útil para analizar las investigaciones seleccionadas. Se encontraron las herramientas tecnológicas más empleadas en este tipo de formulaciones y se determinó la disminución de parámetros relacionados con el abuso de opioides causados por la implementación de estos diseños al mercado. Se concluyó que, la base de datos permitió una extracción efectiva de la información; se identificaron las tendencias tecnológicas en cuanto a materiales, métodos, formas farmacéuticas y mecanismos de disuasión más empleados y eficientes, además, se encontró la reducción satisfactoria en el abuso de opioides de prescripción por administración oral causada por las ADF’sPregradoQuímico FarmacéuticoThe abuse of oral prescription opioids is a serious public health problem that can lead to serious consequences such as increased opioid use disorders, overdoses and opioid-related deaths. From the pharmaceutical sector, formulations designed to prevent the manipulation of orally administered prescription opioid analgesics for consumption by alternative routes (Intranasal and IV, among others) have emerged, these have been termed abuse deterrent formulations (ADF's). The objectives of this review were to build an effective database to select and filter the information on the subject, to examine the technological and clinical aspects of ADFs to understand how they work and to determine their influence on the problems raised, as well as to analyze their effectiveness and make pertinent recommendations. The database was constructed in a satisfactory manner, which was useful to analyze the selected research. The technological tools most used in this type of formulations were found and the decrease of parameters related to opioid abuse caused by the implementation of these designs in the market was determined. It was concluded that the database allowed an effective extraction of information; technological trends were identified in terms of materials, methods, pharmaceutical forms and the most used and efficient deterrent mechanisms, and a satisfactory reduction in the abuse of prescription opioids by oral administration caused by ADF's was found.application/pdfAttribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/Acceso abiertohttps://purl.org/coar/access_right/c_abf2http://purl.org/coar/access_right/c_abf2OpioidesAbuso de opioides,Formulaciones disuasorias de abuso615.19OpioidsOpioid abuseAbuse deterrent formulationsFormulaciones disuasorias de abuso: descripción de estrategias tecnológicas y su posible influencia en la mitigación del abuso de opioides comercialesAbuse-deterrent formulations: description of technological strategies and their potential influence on mitigating commercial opioid abuseQuímica FarmacéuticaUniversidad El BosqueFacultad de CienciasTesis/Trabajo de grado - Monografía - Pregradohttps://purl.org/coar/resource_type/c_7a1fhttp://purl.org/coar/resource_type/c_7a1finfo:eu-repo/semantics/bachelorThesishttps://purl.org/coar/version/c_ab4af688f83e57aa[1] M. L. Meldrum, “The ongoing opioid prescription epidemic: Historical context,” Aug. 01, 2016, American Public Health Association Inc. doi: 10.2105/AJPH.2016.303297[2] S. Calcaterra, J. Glanz, and I. A. Binswanger, “National trends in pharmaceutical opioid related overdose deaths compared to other substance related overdose deaths: 1999-2009,” Drug Alcohol Depend, vol. 131, no. 3, pp. 263–270, Aug. 2013, doi: 10.1016/j.drugalcdep.2012.11.018.[3] J. Lyden and I. A. Binswanger, “The United States opioid epidemic,” Semin Perinatol, vol. 43, no. 3, pp. 123–131, 2019, doi: 10.1053/j.semperi.2019.01.001.[4] R. L. Rauck, “Mitigation of IV Abuse Through the Use of Abuse-Deterrent Opioid Formulations: An Overview of Current Technologies,” Apr. 01, 2019, Blackwell Publishing Inc. doi: 10.1111/papr.12760.[5] J. V. Pergolizzi, R. B. Raffa, R. Taylor, and S. Vacalis, “Abuse-deterrent opioids: an update on current approaches and considerations,” https://doi.org/10.1080/03007995.2017.1419171, vol. 34, no. 4, pp. 711–723, Apr. 2018, doi: 10.1080/03007995.2017.1419171[6] M. Murshed, M. Salim, and B. J. Boyd, “Existing and emerging mitigation strategies for the prevention of accidental overdose from oral pharmaceutical products,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 180, pp. 201–211, Nov. 2022, doi: 10.1016/J.EJPB.2022.10.002[7] X. Xu et al., “Evaluation of Abuse-Deterrent Characteristics of Tablets Prepared via Hot-Melt Extrusion,” AAPS PharmSciTech, vol. 20, no. 6, Aug. 2019, doi: 10.1208/s12249-019-1448-2.[8] A. Soni, A. Paprikar, and S. Lin, “Effect of alkalizing agent on abuse deterrent potential of multiple-unit ingestion of bilayer abuse-deterrent extended-release tablets using propranolol as model drug for opioids overdose crisis,” Int J Pharm, vol. 600, May 2021, doi: 10.1016/j.ijpharm.2021.120480.[9] P. K. Nukala, S. Palekar, M. Patki, and K. Patel, “Abuse Deterrent Immediate Release Egg-Shaped Tablet (Egglets) Using 3D Printing Technology: Quality by Design to Optimize Drug Release and Extraction,” AAPS PharmSciTech, vol. 20, no. 2, Feb. 2019, doi: 10.1208/s12249-019-1298-y.[10] S. Ram Munnangi, N. Narala, P. Lakkala, S. Kumar Vemula, and M. Repka, “Assessing Abuse-Deterrent formulations utilizing Ion-Exchange resin complexation processed via Twin-Screw granulation for improved safety and effectiveness,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 197, Apr. 2024, doi: 10.1016/j.ejpb.2024.114230[11] Z. Rahman et al., “Assessing impact of formulation and process variables on in-vitro performance of directly compressed abuse deterrent formulations,” Int J Pharm, vol. 502, no. 1–2, pp. 138–150, Apr. 2016, doi: 10.1016/j.ijpharm.2016.02.029.[12] P. Jayendrakumar and P. Rakesh, “Self-regulated Anti-Overdose Crush and Extraction-Resistant Drug Delivery System to Combat Opioid Overdose Crisis,” AAPS PharmSciTech, vol. 23, no. 7, Oct. 2022, doi: 10.1208/s12249-022-02423-5.[13] S. Palekar, P. K. Nukala, and K. Patel, “Aversion liquid-filled drug releasing capsule (3D-RECAL): A novel technology for the development of immediate release abuse deterrent formulations using a fused deposition modelling (FDM) 3D printer,” Int J Pharm, vol. 621, Jun. 2022, doi: 10.1016/j.ijpharm.2022.121804.[14] L. Rezaei, S. Meruva, and M. D. Donovan, “Effect of Manufacturing Process on the Retention of Abuse-Deterrent Properties of PEO-Matrix Tablets,” AAPS PharmSciTech, vol. 23, no. 1, Jan. 2022, doi: 10.1208/s12249-021-02169-6.[15] N. Jedinger, S. Schrank, J. M. Fischer, K. Breinhälter, J. Khinast, and E. 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Dart, “Postmarketing analysis of misuse, abuse, and diversion of Xtampza ER,” Pain Medicine (United States), vol. 21, no. 12, pp. 3660–3668, 2020, doi:10.1093/PM/PNAA272spaORIGINALTrabajo de grado.pdfTrabajo de grado.pdfapplication/pdf880681https://repositorio.unbosque.edu.co/bitstreams/f8266152-ee16-4282-9dfa-4e54387dbdc7/download2831c10a4a45e9e9210b6749ff9ed806MD57LICENSElicense.txtlicense.txttext/plain; charset=utf-82000https://repositorio.unbosque.edu.co/bitstreams/ce0e9d74-f9a3-47fb-8848-4d4a681f3215/download17cc15b951e7cc6b3728a574117320f9MD53Acta de sustentacion.pdfapplication/pdf1057948https://repositorio.unbosque.edu.co/bitstreams/03a1893e-6161-4241-a839-7e2983ea241b/downloade0fcc5fc603529b2ff0c93ffbf0702d4MD59Carta de autorizacion.pdfapplication/pdf112571https://repositorio.unbosque.edu.co/bitstreams/e59ef5b6-5c6f-4658-aa35-0a9d6c8c4b7d/downloadd380081e49aad09216a902ba81f9f8a4MD510CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-81025https://repositorio.unbosque.edu.co/bitstreams/c91c85f3-dc40-43dc-ac56-5b426f71bbcc/downloadd93f5db78fcf73cec9795c8fea744a8bMD58TEXTTrabajo de grado.pdf.txtTrabajo de grado.pdf.txtExtracted texttext/plain93052https://repositorio.unbosque.edu.co/bitstreams/a7d79356-3e72-4aae-88e8-63032bba6d85/download2937c0159cf676186dcf6d589d91477eMD511THUMBNAILTrabajo de grado.pdf.jpgTrabajo de grado.pdf.jpgGenerated Thumbnailimage/jpeg5155https://repositorio.unbosque.edu.co/bitstreams/1ca271e1-3302-4aa5-bf03-3d722c1ee755/download8065ee319e51c039b19b0c8f0bad33eaMD51220.500.12495/13263oai:repositorio.unbosque.edu.co:20.500.12495/132632024-11-21 03:04:45.005http://creativecommons.org/licenses/by-nc/4.0/Attribution-NonCommercial 4.0 Internationalopen.accesshttps://repositorio.unbosque.edu.coRepositorio Institucional Universidad El Bosquebibliotecas@biteca.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