Fabrication and Characterization of Poly(lactic acid)/Chitosan Biocomposite Films for Controlled Oral Delivery of Lovastatin
Main Article Content
Abstract
Lovastatin (Lov), a lipid-lowering statin, suffers from low oral bioavailability due to poor solubility and extensive first-pass metabolism. The study developed poly(lactic acid)/chitosan (PLA/Cs) composite films incorporating Lov (5 – 20 wt.%) and examined how drug loading influences structural characteristics and release behavior. Films were prepared via a solution-based method. FT-IR analysis confirmed hydrogen bonding and dipole interactions among PLA, Cs, and Lov, while FESEM imaging revealed a morphological shift of Lov from rod-like crystals to spherical particles, with the PLA/Cs ratio of 5/5 and Lov accounting for 10 wt.% the total polymer (PCL5510), sample displaying the most uniform dispersion. Drug release followed a biphasic pattern: an initial burst release from surface-adsorbed drug, followed by sustained release governed by diffusion and polymer matrix degradation. Lov content strongly influenced release kinetics, with PCL5510 achieving slow, stable release at pH 2.0 and accelerated release at pH 7.4, conditions favorable for intestinal absorption. These findings identify PCL5510 as an optimal formulation for controlled oral delivery of statins and highlight the potential of PLA/Cs-based systems in drug delivery applications.
Keywords
Biocomposites, chitosan, drug release, lovastatin, Poly(lactic acid).
Article Details
References
[1] S. Istvan and J. Deisenhofer, Structural mechanism for statin inhibition of HMG-CoA reductase, Science, vol. 292, no. 5519, pp. 1160–1164, May 2001. https://doi.org/10.1126/science.1059344
[2] Endo A., The discovery and development of HMG-CoA reductase inhibitors, Journal of Lipid Research, vol. 33, iss. 11, pp. 1569–1582, Nov. 1992. https://doi.org/10.1016/S0022-2275(20)41379-3
[3] Kazi M., Al-Swairi M., Ahmad A., Raish M., Alanazi F. K., Badran M. M., Khan A. A., Alanazi A. M. and Hussain M. D., Evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for poorly water-soluble talinolol: preparation, in vitro and in vivo assessment, Frontiers in Pharmacology, vol. 10, May 2019, Art. no. 459. https://doi.org/10.3389/fphar.2019.00459
[4] Liu D., Yang F., Xiong F. and Gu N., The smart drug delivery system and its clinical potential, Theranostics, vol. 6, no. 9, pp. 1306–1323, 2016. https://doi.org/10.7150/thno.14858
[5] Rautio J., Meanwell N. A., Di L., and Hageman M. J., The expanding role of prodrugs in contemporary drug design and development, Nature Reviews Drug Discovery, vol. 17, no. 8, pp. 559–587, Apr. 2018. https://doi.org/10.1038/nrd.2018.46
[6] Middleton J. C. and Tipton A. J., Synthetic biodegradable polymers as orthopedic devices, Biomaterials, vol. 21, iss. 23, pp. 2335–2346, Dec. 2000.https://doi.org/10.1016/S0142-9612(00)00101-0
[7] Mawazi S. M., Kumar M., Ahmad N., Ge Y., and Mahmood S., Recent applications of chitosan and its derivatives in antibacterial, anticancer, wound healing, and tissue engineering fields, Polymers, vol. 16, iss. 10, May 2024, Art. no. 1351. https://doi.org/10.3390/polym16101351
[8] Dash M., Chiellini F., Ottenbrite R. M., and Chiellini E., Chitosan - a versatile semi-synthetic polymer in biomedical applications, Progress in Polymer Science, vol. 36, iss. 8, pp. 981–1014, Aug. 2011.
https://doi.org/10.1016/j.progpolymsci.2011.02.001
[9] Moldovan A., Cuc S., Prodan D., Rusu M., Popa D., Taut A. C., Petean I., Bomboş D., Doukeh R., and Nemes O., Development and characterization of polylactic acid (PLA)-based nanocomposites used for food packaging, Polymers, vol. 15, iss. 13, Jun. 2023, Art. no. 2855. https://doi.org/10.3390/polym15132855
[10] Dimzon I. K. D. and Knepper T. P., Degree of deacetylation of chitosan by infrared spectroscopy and partial least squares, International Journal of Biological Macromolecules, vol. 72, no. 1, pp. 939–945, Jan. 2015. https://doi.org/10.1016/j.ijbiomac.2014.09.050
[11] El-Araby A., Janati W., Ullah R., Ercisli S., and Errachidi F., Chitosan, chitosan derivatives, and chitosan-based nanocomposites: eco-friendly materials for advanced applications (a review), Frontier in Chemistry, vol. 11, Jan. 2024, Art. no. 1327426. https://doi.org/10.1089/fchem.2023.1327426
[12] Nguyen L. N., Vu M. Q., La G. C., Nguyen C. T., Hoang D. T., Tran D. T. T., Thai H., and Vu T. Q., Assessment of hemostatic ability of biomaterial based on chitosan and Eclipta prostrata L. extract, Biomedical Materials, vol. 19, 2024, Art. no. 035026. https://doi.org/10.1088/1748-605X/ad386e
[13] Pallipurath A. R., Skelton J. M., Britton A., Willneff E. A., and Schroeder S. L. M., Bulk and surface conformations in solid-state lovastatin: spectroscopic and molecular dynamics studies, Crystals, vol. 11, no. 5, May 2021, Art. no. 509. https://doi.org/10.3390/cryst11050509
[14] Vu T. T. T., Nguyen N. T. H., Vu M. Q., Nguyen L. N., Nguyen V. T. B., and Vu T. Q., Synthesis and characterization of chitosan/carrageenan/polyaniline-based biocomposite as lovastatin carrier and its drug release ability in buffer solutions, HNUE Journal of Science, vol. 68, iss. 3, pp. 46–74, 2023. https://doi.org/10.18173/2354-1059.2023-0061
[15] GhavamiNejad A., Ashammakhi N., Wu X. Y., and Khademhosseini A., Crosslinking strategies for 3D bioprinting of polymeric hydrogels, Small, vol. 16, iss. 35, Jul. 2020, Art. no. 2002931. https://doi.org/10.1002/smll.202002931
[16] Hatcher L. E., Li W., Payne P., Benyahia B., Rielly C. D., and Wilson C. C., Tuning morphology in active pharmaceutical ingredients: controlling the crystal habit of lovastatin through solvent choice and non-size-matched polymer additives, Crystal Growth & Design, vol. 20, iss. 9, pp. 5854–5862, Aug. 2020. https://doi.org/10.1021/acs.cgd.0c00470
[17] Ha H. M., Vu M. Q., Vu T. T. T., Dao T. T. P., Pham D. T., Nguyen V. T. B., Duong L. K., Nguyen L. N., Doan O. T. Y., Nguyen C. T., Thai H., and Vu T. Q., Evaluation of the effect of the chitosan/carrageenan ratio on lovastatin release from chitosan/carrageenan based biomaterials, Vietnam Journal of Chemistry, vol. 60, iss. 1, pp. 72–78, Oct. 2022. https://doi.org/10.1002/vjch.202200078
[18] Thai H., Nguyen C. T., Thach L. T., Tran M. T., Huynh D. M., Nguyen T. T. T., Le G. D., Can M. V., Tran L. D., Bach G. L., Kavitha Ramadass, C. I. Sathish, and Quan Van Le, Characterization of chitosan/alginate/lovastatin nanoparticles and investigation of their toxic effects in vitro and in vivo, Scientific Reports, vol. 10, no. 1, pp. 909, Jan. 2020. https://doi.org/10.1038/s41598-020-57666-8
[19] Shen M., Zheng L., Koole L. H., Polymeric microspheres designed to carry crystalline drugs at their surface or inside cavities and dimples, Pharmaceutics, vol. 15, iss. 8, 2023, Art. no. 2146. https://doi.org/10.3390/pharmaceutics15082146
[20] Sun Y. and Long D., Preparation, characterization and in vitro/in vivo evaluation of lovastatin-loaded PLGA microspheres by local administration for femoral head necrosis, Drug Design, Development and Therapy, vol. 15, pp. 601–610, Feb. 2021. https://doi.org/10.2147/DDDT.S286306
[21] Bhujbal S. V., Mitra B., Jain U., Gong Y., Agrawal A., Karki S., Taylor L. S., Kumar S., and Zhou Q. Pharmaceutical amorphous solid dispersion: a review of manufacturing strategies, Acta Pharmaceutica Sinica B, vol. 11, iss. 8, pp. 2505–2536, Aug. 2021. https://doi.org/10.1016/j.apsb.2021.05.014
[22] Patel R. P. and Mayur M. P., Physicochemical characterization and dissolution study of solid dispersions of lovastatin with polyethylene glycol 4000 and polyvinylpyrrolidone K30, Pharmaceutical Development and Technology, vol. 12, iss. 1, pp. 21–33, Oct. 2008. https://doi.org/10.1080/10837450601166510
[23] Bhujbal S. V., Mitra B., Jain U., Gong Y., Agrawal A., Karki S., Taylor L. S., Kumar S., and Zhou Q., Pharmaceutical amorphous solid dispersion: a review of manufacturing strategies, Acta Pharm. Sin. B, vol. 11, iss. 8, pp. 2505–2536, 2021.
https://doi.org/10.1016/j.apsb.2021.05.014
[24] Li W., Chen J., Zhao S., Huang T., Ying H., Trujillo C., Molinaro G., Zhou Z., Jiang T., Liu W., Li L., Bai Y., Quan P., Ding Y., Hirvonen J., Yin G., Santos H., Fan J., and Liu D., High drug-loaded microspheres enabled by controlled in-droplet precipitation promote functional recovery after spinal cord injury, Nature Communications, vol. 13, no. 1, Mar. 2022, Art. no. 1262. https://doi.org/10.1038/s41467-022-28787-7
[25] Pantani R., Volpe V., Titomanlio G., Foam injection molding of poly(lactic acid) with environmentally friendly physical blowing agents, Journal of Materials Processing Technology, vol. 214, no. 12, pp. 3098–3107, 2014. https://doi.org/10.1016/j.jmatprotec.2014.07.002
[26] Vlachopoulos A., Karlioti G., Balla E., Daniilidis V., Kalamas T., Stefanidou M., Bikiaris N. D., Christodoulou E., Koumentakou I., and Karavas E., and Bikiaris D. N., Poly(lactic acid)-based microparticles for drug delivery applications: an overview of recent advances, Pharmaceutics, vol. 14, iss. 2, Feb. 2022, Art. no. 359. https://doi.org/10.3390/pharmaceutics14020359
[27] Liu C., Zhang D., Li D., Jiang D., and Chen X., Preparation and characterization of biodegradable polylactide (PLA) microspheres encapsulating ginsenoside Rg3, Chemistry Research in Chinese Universities, vol. 24, no.5, pp. 588–591, Sep. 2008. https://doi.org/10.1016/S1005-9040(08)60124-5
[28] Pandey S., Shaikh F., Gupta A., Tripathi P., and Yadav J. S., A recent update: solid lipid nanoparticles for effective drug delivery, Advanced Pharmaceutical Bulletin, vol. 12, iss. 1, 2002, Art. no. 7. https://doi.org/10.34172/apb.2022.007
[2] Endo A., The discovery and development of HMG-CoA reductase inhibitors, Journal of Lipid Research, vol. 33, iss. 11, pp. 1569–1582, Nov. 1992. https://doi.org/10.1016/S0022-2275(20)41379-3
[3] Kazi M., Al-Swairi M., Ahmad A., Raish M., Alanazi F. K., Badran M. M., Khan A. A., Alanazi A. M. and Hussain M. D., Evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for poorly water-soluble talinolol: preparation, in vitro and in vivo assessment, Frontiers in Pharmacology, vol. 10, May 2019, Art. no. 459. https://doi.org/10.3389/fphar.2019.00459
[4] Liu D., Yang F., Xiong F. and Gu N., The smart drug delivery system and its clinical potential, Theranostics, vol. 6, no. 9, pp. 1306–1323, 2016. https://doi.org/10.7150/thno.14858
[5] Rautio J., Meanwell N. A., Di L., and Hageman M. J., The expanding role of prodrugs in contemporary drug design and development, Nature Reviews Drug Discovery, vol. 17, no. 8, pp. 559–587, Apr. 2018. https://doi.org/10.1038/nrd.2018.46
[6] Middleton J. C. and Tipton A. J., Synthetic biodegradable polymers as orthopedic devices, Biomaterials, vol. 21, iss. 23, pp. 2335–2346, Dec. 2000.https://doi.org/10.1016/S0142-9612(00)00101-0
[7] Mawazi S. M., Kumar M., Ahmad N., Ge Y., and Mahmood S., Recent applications of chitosan and its derivatives in antibacterial, anticancer, wound healing, and tissue engineering fields, Polymers, vol. 16, iss. 10, May 2024, Art. no. 1351. https://doi.org/10.3390/polym16101351
[8] Dash M., Chiellini F., Ottenbrite R. M., and Chiellini E., Chitosan - a versatile semi-synthetic polymer in biomedical applications, Progress in Polymer Science, vol. 36, iss. 8, pp. 981–1014, Aug. 2011.
https://doi.org/10.1016/j.progpolymsci.2011.02.001
[9] Moldovan A., Cuc S., Prodan D., Rusu M., Popa D., Taut A. C., Petean I., Bomboş D., Doukeh R., and Nemes O., Development and characterization of polylactic acid (PLA)-based nanocomposites used for food packaging, Polymers, vol. 15, iss. 13, Jun. 2023, Art. no. 2855. https://doi.org/10.3390/polym15132855
[10] Dimzon I. K. D. and Knepper T. P., Degree of deacetylation of chitosan by infrared spectroscopy and partial least squares, International Journal of Biological Macromolecules, vol. 72, no. 1, pp. 939–945, Jan. 2015. https://doi.org/10.1016/j.ijbiomac.2014.09.050
[11] El-Araby A., Janati W., Ullah R., Ercisli S., and Errachidi F., Chitosan, chitosan derivatives, and chitosan-based nanocomposites: eco-friendly materials for advanced applications (a review), Frontier in Chemistry, vol. 11, Jan. 2024, Art. no. 1327426. https://doi.org/10.1089/fchem.2023.1327426
[12] Nguyen L. N., Vu M. Q., La G. C., Nguyen C. T., Hoang D. T., Tran D. T. T., Thai H., and Vu T. Q., Assessment of hemostatic ability of biomaterial based on chitosan and Eclipta prostrata L. extract, Biomedical Materials, vol. 19, 2024, Art. no. 035026. https://doi.org/10.1088/1748-605X/ad386e
[13] Pallipurath A. R., Skelton J. M., Britton A., Willneff E. A., and Schroeder S. L. M., Bulk and surface conformations in solid-state lovastatin: spectroscopic and molecular dynamics studies, Crystals, vol. 11, no. 5, May 2021, Art. no. 509. https://doi.org/10.3390/cryst11050509
[14] Vu T. T. T., Nguyen N. T. H., Vu M. Q., Nguyen L. N., Nguyen V. T. B., and Vu T. Q., Synthesis and characterization of chitosan/carrageenan/polyaniline-based biocomposite as lovastatin carrier and its drug release ability in buffer solutions, HNUE Journal of Science, vol. 68, iss. 3, pp. 46–74, 2023. https://doi.org/10.18173/2354-1059.2023-0061
[15] GhavamiNejad A., Ashammakhi N., Wu X. Y., and Khademhosseini A., Crosslinking strategies for 3D bioprinting of polymeric hydrogels, Small, vol. 16, iss. 35, Jul. 2020, Art. no. 2002931. https://doi.org/10.1002/smll.202002931
[16] Hatcher L. E., Li W., Payne P., Benyahia B., Rielly C. D., and Wilson C. C., Tuning morphology in active pharmaceutical ingredients: controlling the crystal habit of lovastatin through solvent choice and non-size-matched polymer additives, Crystal Growth & Design, vol. 20, iss. 9, pp. 5854–5862, Aug. 2020. https://doi.org/10.1021/acs.cgd.0c00470
[17] Ha H. M., Vu M. Q., Vu T. T. T., Dao T. T. P., Pham D. T., Nguyen V. T. B., Duong L. K., Nguyen L. N., Doan O. T. Y., Nguyen C. T., Thai H., and Vu T. Q., Evaluation of the effect of the chitosan/carrageenan ratio on lovastatin release from chitosan/carrageenan based biomaterials, Vietnam Journal of Chemistry, vol. 60, iss. 1, pp. 72–78, Oct. 2022. https://doi.org/10.1002/vjch.202200078
[18] Thai H., Nguyen C. T., Thach L. T., Tran M. T., Huynh D. M., Nguyen T. T. T., Le G. D., Can M. V., Tran L. D., Bach G. L., Kavitha Ramadass, C. I. Sathish, and Quan Van Le, Characterization of chitosan/alginate/lovastatin nanoparticles and investigation of their toxic effects in vitro and in vivo, Scientific Reports, vol. 10, no. 1, pp. 909, Jan. 2020. https://doi.org/10.1038/s41598-020-57666-8
[19] Shen M., Zheng L., Koole L. H., Polymeric microspheres designed to carry crystalline drugs at their surface or inside cavities and dimples, Pharmaceutics, vol. 15, iss. 8, 2023, Art. no. 2146. https://doi.org/10.3390/pharmaceutics15082146
[20] Sun Y. and Long D., Preparation, characterization and in vitro/in vivo evaluation of lovastatin-loaded PLGA microspheres by local administration for femoral head necrosis, Drug Design, Development and Therapy, vol. 15, pp. 601–610, Feb. 2021. https://doi.org/10.2147/DDDT.S286306
[21] Bhujbal S. V., Mitra B., Jain U., Gong Y., Agrawal A., Karki S., Taylor L. S., Kumar S., and Zhou Q. Pharmaceutical amorphous solid dispersion: a review of manufacturing strategies, Acta Pharmaceutica Sinica B, vol. 11, iss. 8, pp. 2505–2536, Aug. 2021. https://doi.org/10.1016/j.apsb.2021.05.014
[22] Patel R. P. and Mayur M. P., Physicochemical characterization and dissolution study of solid dispersions of lovastatin with polyethylene glycol 4000 and polyvinylpyrrolidone K30, Pharmaceutical Development and Technology, vol. 12, iss. 1, pp. 21–33, Oct. 2008. https://doi.org/10.1080/10837450601166510
[23] Bhujbal S. V., Mitra B., Jain U., Gong Y., Agrawal A., Karki S., Taylor L. S., Kumar S., and Zhou Q., Pharmaceutical amorphous solid dispersion: a review of manufacturing strategies, Acta Pharm. Sin. B, vol. 11, iss. 8, pp. 2505–2536, 2021.
https://doi.org/10.1016/j.apsb.2021.05.014
[24] Li W., Chen J., Zhao S., Huang T., Ying H., Trujillo C., Molinaro G., Zhou Z., Jiang T., Liu W., Li L., Bai Y., Quan P., Ding Y., Hirvonen J., Yin G., Santos H., Fan J., and Liu D., High drug-loaded microspheres enabled by controlled in-droplet precipitation promote functional recovery after spinal cord injury, Nature Communications, vol. 13, no. 1, Mar. 2022, Art. no. 1262. https://doi.org/10.1038/s41467-022-28787-7
[25] Pantani R., Volpe V., Titomanlio G., Foam injection molding of poly(lactic acid) with environmentally friendly physical blowing agents, Journal of Materials Processing Technology, vol. 214, no. 12, pp. 3098–3107, 2014. https://doi.org/10.1016/j.jmatprotec.2014.07.002
[26] Vlachopoulos A., Karlioti G., Balla E., Daniilidis V., Kalamas T., Stefanidou M., Bikiaris N. D., Christodoulou E., Koumentakou I., and Karavas E., and Bikiaris D. N., Poly(lactic acid)-based microparticles for drug delivery applications: an overview of recent advances, Pharmaceutics, vol. 14, iss. 2, Feb. 2022, Art. no. 359. https://doi.org/10.3390/pharmaceutics14020359
[27] Liu C., Zhang D., Li D., Jiang D., and Chen X., Preparation and characterization of biodegradable polylactide (PLA) microspheres encapsulating ginsenoside Rg3, Chemistry Research in Chinese Universities, vol. 24, no.5, pp. 588–591, Sep. 2008. https://doi.org/10.1016/S1005-9040(08)60124-5
[28] Pandey S., Shaikh F., Gupta A., Tripathi P., and Yadav J. S., A recent update: solid lipid nanoparticles for effective drug delivery, Advanced Pharmaceutical Bulletin, vol. 12, iss. 1, 2002, Art. no. 7. https://doi.org/10.34172/apb.2022.007