Abstract
Controlling structurally defined properties of drug-bound macromolecules such as surface adhesion and interaction with endogenous proteins in the surrounding environment using prior data from computer-assisted simulation can be of great use in designing controlled release macromolecular therapeutic systems. In this paper, we describe experimental correlation of real-time properties of a polymer with pendant drug molecules, with predicted values obtained from studying in silico molecular interactions of this polymer with ocular surface proteins (mucin) for formulating an ophthalmic in situ gel. Mucoretention of the drug (norfloxacin) within the eye sac is closely associated with binding interactions occurring on the ocular surface, and covalent association of the drug with the mucoadhesive polymer, poly(methylvinyl ether/maleic acid), can largely reduce dosing frequency eliciting prolonged antibacterial action much required in treating conjunctival infections. The physicochemical properties and 3D conformation of the drug-polymer conjugate were predicted by computational studies. Molecular docking of the drug-polymer conjugate with ocular surface mucin (MUC-1) suggested that amino acid residues Arg1095, Asn1091, and Gln1070 of mucin are involved in hydrogen bonding with carboxyl residues in the polymer structure. The orientation of the drug-polymer conjugate in solution profoundly depends on the properties of the drug. The studies further reveal that molecular interactions of MUC-1 with the drug in the drug-polymer conjugate influence the binding orientation of the drug-polymer to mucin. Computationally predicted solvation energies revealed a significant difference in energy values between drug molecule alone (− 113.04 kcal/mol) and the drug-polymer (− 492.44 kcal/mol) suggesting higher aqueous solvation of the drug-polymer conjugate compared with less-soluble drug, and that interactions between polymer chains and ocular aqueous environment dictate the drug-polymer conjugate’s free energy. Our results demonstrate the fabrication of a macromolecular therapeutic gel using drug-polymer with controlled release properties and mucoadhesion guided by information predicted from computational software. Notably, in silico studies reveal that even small variations in molecular composition, in this case, an antibacterial drug that contributes less than half of the entire molecular weight can considerably change the drug’s presentation to the ocular environment.
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Yu K, Li R, Yang Z, Wang F, Wu W, Wang X, et al. Discovery of a potent microtubule-targeting agent: synthesis and biological evaluation of water-soluble amino acid prodrug of combretastatin A-4 derivatives. Bioorg Med Chem Lett. 2015;25:2302–7.
Gund M, Khanna A, Dubash N, Damre A, Singh KS, Satyam A. Water-soluble prodrugs of paclitaxel containing self-immolative disulfide linkers. Bioorg Med Chem Lett. 2015;25:122–7.
Mattarei A, Carraro M, Azzolini M, Paradisi C, Zoratti M, Biasutto L. New water-soluble carbamate ester derivatives of resveratrol. Molecules. 2014;19:15900–17.
Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006;29:278–87.
Wu C, Liu Y, He Z, Sun J. Insight into the development of dissolution media for BCS class II drugs: a review from quality control and prediction of in vivo performance perspectives. Curr Drug Deliv. 2016;13:1004–20.
Vyas S, Kakade P, Chogale M, Disouza J, Patravale V. Multidimensional ophthalmic nanosystems for molecular detection and therapy of eye disorders. Curr Pharm Des. 2015;21:3223–38.
Prabhu P, Patravale V. Dissolution enhancement of atorvastatin calcium by co-grinding technique. Drug Deliv Transl Res. 2015;6:380–91.
Khan A, Iqbal Z, Shah Y, Ahmad L, Ismail, Ullah Z, et al. Enhancement of dissolution rate of class II drugs (hydrochlorothiazide); a comparative study of the two novel approaches; solid dispersion and liquid-solid techniques. Saudi Pharm J. 2015;23:650–7.
Upadhyay P, Trivedi J, Pundarikakshudu K, Sheth N. Comparative study between simple and optimized liposomal dispersion of quetiapine fumarate for diffusion through nasal route. Drug Deliv. 2015;23:1214–21.
Kamble RN, Mehta PP, Kumar A. Efavirenz self-nano-emulsifying drug delivery system: in vitro and in vivo evaluation. AAPS PharmSciTech. 2015;17:1240–7.
Chi L, Wu D, Li Z, Zhang M, Liu H, Wang C, et al. Modified release and improved stability of unstable BCS II drug by using cyclodextrin complex as carrier to remotely load drug into niosomes. Mol Pharm. 2016;13:113–24.
Krull SM, Ma Z, Li M, Dave RN, Bilgili E. Preparation and characterization of fast dissolving Pullulan films containing BCS class II drug nanoparticles for bioavailability enhancement. Drug Dev Ind Pharm. 2015;42:1073–85.
Leonardi A, Bucolo C, Romano GL, Platania CB, Drago F, Puglisi G, et al. Influence of different surfactants on the technological properties and in vivo ocular tolerability of lipid nanoparticles. Int J Pharm. 2014;470:133–40.
Alskar LC, Porter CJ, Bergstrom CA. Tools for early prediction of drug loading in lipid-based formulations. Mol Pharm. 2016;13:251–61.
Van Elssen CH, Clausen H, Germeraad WT, Bennet EP, Menheere PP, Bos GM, et al. Flow cytometry-based assay to evaluate human serum MUC1-Tn antibodies. J Immunol Methods. 2011;365:87–94.
Corrales RM, Narayanan S, Fernandez I, Mayo A, Galarreta DJ, Fuentes-Paez G, et al. Ocular mucin gene expression levels as biomarkers for the diagnosis of dry eye syndrome. Invest Ophthalmol Vis Sci. 2011;52:8363–9.
Cohen S, Lobel E, Trevgoda A, Peled Y. A novel in situ-forming ophthalmic drug delivery system from alginates undergoing gelation in the eye. J Control Release. 1997;44:201–8.
Bernkop-Schnurch A. Chitosan and its derivatives: potential excipients for peroral peptide delivery systems. Int J Pharm. 2000;194:1–13.
Irache JM, Huici M, Konecny M, Espuelas S, Campanero MA, Arbos P. Bioadhesive properties of gantrez nanoparticles. Molecules. 2005;10:126–45.
Prieto E, Puente B, Uixera A, Garcia de Jalon JA, Perez S, Pablo L, et al. Nanoparticles for ocular delivery of memantine: in vitro release evaluation in albino rabbits. Ophthalmic Res. 2012;48:109–17.
Rosenholm JB, Peiponen KE, Gornov E. Materials cohesion and interaction forces. Adv Colloid Interf Sci. 2008;141:48–65.
Elshikh M, Ahmed S, Funston S, Dunlop P, McGaw M, Marchant R, et al. Resazurin-based 96-well plate microdilution method for the determination of minimum inhibitory concentration of biosurfactants. Biotechnol Lett. 2016;38:1015–9.
Tamburic S, Craig DQM. A comparison of different in vitro methods for measuring mucoadhesive performance. Eur J Pharm Biopharm. 1997;44:159–67.
Tang C, Yin C, Pei Y, Zhang M, Wu L. New superporous hydrogels composites based on aqueous Carbopol® solution (SPHCCS): synthesis, characterization and in vitro bioadhesive force studies. Eur Polym J. 2005;41:557–62.
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The authors would like to thank the University Grants Commission, India for Fellowship support and, ISP, India and Pell Tech Healthcare Pvt. Ltd., India for gift samples.
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Vyas, S., Khambete, M., Gudhka, R. et al. In silico modeling of functionalized poly(methylvinyl ether/maleic acid) for controlled drug release in the ocular milieu. Drug Deliv. and Transl. Res. 10, 1085–1094 (2020). https://doi.org/10.1007/s13346-020-00749-w
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DOI: https://doi.org/10.1007/s13346-020-00749-w