DEVELOPMENT OF BIOPLASTIC IN-SITU IMPLANT FOR ANTIBIOTIC DRUG LOADING
Bioplastic In-Situ Implant for Antibiotic Drug Loading
DOI:
https://doi.org/10.55766/sujst10491Keywords:
Bioplastic, In-Situ implant, Antibiotic, Drug delivery systeAbstract
Typically, solvent removal-induced in-situ implants start in a solution state and undergo phase inversion to form depot formulations. In this research, the development and evaluation of a bioplastic in-situ implant for antibiotic drug loading were conducted. Two types of cellulose acetate butyrate (CAB) and cellulose acetate propionate (CAP) were used as bioplastic polymers for the in-situ implant. These polymers, at a concentration of 15% w/w, were dissolved in various solvents, including dimethyl sulfoxide (DMSO), glycerol formal (GF), N-methyl pyrrolidone (NMP), 2-pyrrolidone (PYR), and tetraglycol (TG). The polymers did not completely dissolve in TG, whereas all the other solvents were able to dissolve the polymers fully. Notably, the lowest apparent viscosity of these polymeric solutions was achieved when NMP was used as the solvent. The in-situ implants loaded with 1% w/w levofloxacin hemihydrate (Lv) were prepared using these polymers dissolved in NMP. The low viscosity of these solutions, combined with their rapid transformation into a depot matrix, facilitates administration via injection. The use of CAP as a polymer in this drug delivery system enabled self-transformation into a matrix in an aqueous medium due to solvent removal. Nonetheless, its depot hardness and adhesion were slightly lower than some in-situ implant prepared from CAB. Microscopic observations under both stereoscope and microscope confirmed swift phase inversion into a matrix implant of the Lv-loaded CAP-based in-situ implant after exposure to aqueous phase of agarose gel. This implant prolonged the release of the antibiotic drug for five days. Additionally, the developed in-situ implant demonstrated effective antimicrobial activity against Phophyromonas gingivalis, Staphylococcus aureus and Candida albicans. These findings highlight the potential of Lv-loaded CAP-based in-situ implant systems as promising candidates for localized depot delivery systems, particularly after exposure to physiological fluids such as crevicular fluid for the treatment of periodontitis.
References
Brodbeck, K.J., DesNoyer, J.R., and McHugh, A.J. (1999). Phase inversion dynamics of PLGA solutions related to drug delivery part ii the role of solution thermodynamics and bath-side mass transfer. Journal of Controlled Release, 62:333-344.
Chen, S. and Singh, J. (2005). Controlled delivery of testosterone from smart polymer solution based systems: in vitro evaluation. International Journal of Pharmaceutics, 295:183-190. https://doi.org/10.1016/j.ijpharm.2005.02.023
Ghayor, C., Gjoksi, B., Siegenthaler, B., and Weber, F.E. (2015). N-methyl pyrrolidone (NMP) inhibits lipopolysaccharide-induced inflammation by suppressing NF-κB signaling. Inflammation Research, 64:527-536. https://doi.org/10.1007/s00011-015-0833-x
Islam, N.U., Umar, M.N., Khan, E., Al-Joufi, F.A., Abed, S.N., Said, M., Ullah, H., Iftikhar, M., Zahoor, M., and Khan, F.A. (2022). Levofloxacin cocrystal/salt with phthalimide and caffeic acid as promising solid-state approach to improve antimicrobial efficiency. Antibiotics, 11:797. https://doi.org/10.3390/antibiotics11060797
Jain, R.A., Rhodes, C.T., Railkar, A.M., Malick, A.W., and Shah, N.H. (2000). Controlled release of drugs from injectable in situ formed biodegradable PLGA microspheres: effect of various formulation variables. European Journal of Pharmaceutics and Biopharmaceutics, 50:257-262.
Khaing, E.M., Jitrangsri, K., Chomto, P., and Phaechamud, T. (2024). Nitrocellulose for prolonged permeation of levofloxacin HCl-salicylic acid in situ gel. Polymers, 16(7):989. https://doi.org/10.3390/polym16070989
Koppolu, P., Sirisha, S., Penala, S., Reddy, P.K., Alotaibi, D.H., Abusalim, G.S., Lingam, A.S., Mukhtar, A.H., Barakat, A., and AlMokhatieb, A.A. (2022). Correlation of blood and salivary pH levels in healthy, gingivitis, and periodontitis patients before and after non-surgical periodontal therapy. Diagnostics, 12:97. https://doi.org/10.3390/diagnostics12010097
Lertsuphotvanit, N., Sirirak, J., Tamdee, P., Tuntarawongsa, S., Phaechamud, T., and Chantadee, T. (2023). Ways to assess and regulate the performance of a bi-mechanism-induced borneol-based in situ forming matrix. Pharmaceutics, 15:2053. https://doi.org/10.3390/pharmaceutics15082053
Peter, Z. (2008). Crystalline cellulose and derivatives: characterization and structures. Springer Series in Wood Science: Springer-Verlag, p. 175-206.
Phaechamud, T., Mahadlek, J., Charoenteeraboon, J., and Choopun, S. (2013). Characterization and antimicrobial activity of N-methyl-2-pyrrolidone-loaded ethylene oxide-propylene oxide block copolymer thermosensitive gel. Indian Journal Pharmaceutical Sciences, 74(6):498-504.
Phaechamud, T., Praphanwittaya, P., and Laotaweesub, K. (2018). Solvent effect on fluid characteristics of doxycycline hyclate-loaded bleached shellac in situ-forming gel and -microparticle formulations. Journal of Pharmaceutical Investigation, 48:409-419. https://doi.org/10.1007/s40005-017-0338-4
Phaechamud, T., Senarat, S., Puyathorn, N., and Praphanwittaya, P. (2019). Solvent exchange and drug release characteristics of doxycycline hyclate-loaded bleached shellac in situ-forming gel and - microparticle. International Journal of Biological Macromolecules, 135:1,261-1,272. https://doi.org/10.1016/j.ijbiomac.2018.11.098
Poet, T.S., Kirman, C.R., Bader, M., van Thriel, C., Gargas, M.L., and Hinderliter, P.M. (2009). Quantitative risk analysis for N-methyl pyrrolidone using physiologically based pharmacokinetic and benchmark dose modeling. Toxicological Sciences, 113:468-482. https://doi.org/10.1093/toxsci/kfp264
Puyathorn, N., Senarat, S., Lertsuphotvanit, N., and Phaechamud, T. (2023). Physicochemical and bioactivity characteristics of doxycycline hyclate-loaded solvent removal-induced ibuprofen-based in situ forming gel. Gels, 9:128. https://doi.org/10.3390/gels9020128
Ramos, F., Willart, J-F., Neut, C., Agossa, K., Siepmann, J., and Siepmann, F. (2024) In-situ forming PLGA implants: Towards less toxic solvents. International Journal of Pharmaceutics, 657:124121. https://doi.org/10.1016/j.ijpharm.2024.124121
Rein, S.M., Intaraphairot, T., Santimaleeworagun, W., Chantadee, T., Chuenbarn, T., and Phaechamud. T. (2022). Fluid properties of solvents and oils used in in situ forming microparticles. Thai Journal of Pharmaceutical Sciences, 46(1):46-55.
Ritger, P.L., and Peppas, N.A. (1987). A simple equation for description of solute release I. Fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. Journal of Controlled Release, 5:23-36. https://doi.org/10.1016/0168-3659(87)90034-4
Roche-Molina, M., Hardwick, B., Sanchez-Ramos, C., Sanz-Rosa, D., Gewert, D., Cruz, F.M., Gonzalez-Guerra, A., Andres, V., Palma, J.A., Ibanez, B., Mckenzie, G., and Bernal, J.A. (2020). The pharmaceutical solvent N-methyl-2-pyrrolidone (NMP) attenuates inflammation through Krüppel-like factor 2 activation to reduce atherogenesis. Scientific Reports, 10:1-16. https://doi.org/10.1038/s41598-020-68350-2
Senarat, S., Pichayakorn, W., Phaechamud, T., and Tuntarawongsa, S. (2023). Antisolvent Eudragit® polymers based in situ forming gel for periodontal controlled drug delivery. Journal of Drug Delivery Science and Technology, 82:104361. https://doi.org/10.1016/j.jddst.2023.104361
Shefeeq, T., and Ahmad, N. (2012). Mathematical modelling for the diffusional release of a dispersed solute from a cylindrical polymer matrix into finite external volume. Journal of Applied Mathematics, 3(1):34-38. https://doi.org/10.4236/am.2012.31006
Shukla, A.J., and Price, J.C. (1991). Effect of drug loading and molecular weight of cellulose acetate propionate on the release characteristics of theophylline microspheres. Pharmaceutical Research, 8(11):1,396-4,000. https://doi.org/10.1023/A:1015801207091
Sobral, M.C., Sobral, A.J, Guthrie, J.T., and Gil, M.H. (2008). Ketotifen controlled release from cellulose acetate propionate and cellulose acetate butyrate membranes. Journal of Materials Science: Materials in Medicine, 19(2):677-682. https://doi.org/10.1007/s10856-007-0168-4
Sprockel, O.L., and Prapaitrakul, W. (1988). Effect of eluant properties on drug release from cellulose acetate butyrate-coated drug resin complexes. International Journal of Pharmaceutics, 48(1):217-222. https://doi.org/10.1016/0378-5173(88)90266-9
Swain, G.P., Patel, S., Gandhi, J., and Shah, P. (2019). Development of moxifloxacin hydrochloride loaded in-situ gel for the treatment of periodontitis: In-vitro drug release study and antibacterial activity. Journal of Oral Biology and Craniofacial Research, 9(3):190-200. https://doi.org/10.1016/j.jobcr.2019.04.001
Tonetti, M.S., Greenwell, H., and Kornman, K.S. (2018). Staging and grading of periodontitis: Framework and proposal of a new classification and case definition. Journal of Periodontology, 89(1):S159-S72. https://doi.org/10.1002/jper.18-0006
Viglianisi, G., Santonocito, S., Lupi, S.M., Amato, M., Spagnuolo, G., Pesce, P., and Isola, G. (2023). Impact of local drug delivery and natural agents as new target strategies against periodontitis: new challenges for personalized therapeutic approach. Therapeutic Advances in Chronic Disease, 14:1-28. https://doi.org/10.1177/20406223231191043
Voigt, M., Koerber, M., and Bodmeier R. (2012). Improve physical stability and injectability of non-aqueous in situ PLGA microparticle forming emulsions. International Journal of Pharmaceutics, 434:251-256. https://doi.org/10.1016/j.ijpharm.2012.05.029
Weng, J., Tong, H.H., and Chow, S.F. (2020). In vitro release study of the polymeric drug nanoparticles: development and validation of a novel method. Pharmaceutics, 12:732. https://doi.org/10.3390/pharmaceutics12080732
Zhang, X., Yang, L., Zhang, C., Liu, D., Meng, S., Zhang, W., and Meng, S. (2019). Effect of polymer permeability and solvent removal rate on in situ forming implants: drug burst release and microstructure. Pharmaceutics, 11(10):520. https://doi.org/10.3390/pharmaceutics11100520








