Tags

Type your tag names separated by a space and hit enter

Enhanced Biopharmaceutical Performance of Rivaroxaban through Polymeric Amorphous Solid Dispersion.
Mol Pharm. 2018 02 05; 15(2):652-668.MP

Abstract

Rivaroxaban (RXB) is an orally active direct inhibitor of the activated serine protease Factor Xa, given as monotherapy in the treatment of venous thromboembolism (VTE). It has been characterized in vitro as a substrate for the active, nonsaturable efflux via P-gp transporter, limiting its high permeability. Therefore, the role of P-gp inhibiting polymers in enhancing the biopharmaceutical performance of RXB by preparing polymeric amorphous solid dispersion and subsequent improvement in solubility and permeability was investigated. Initially, solubility parameter and Flory-Huggins interaction parameter were determined for miscibility studies between drug and polymers. Binary dispersions were prepared by dissolving drug with polymers eudragit S100, eudragit L100, and soluplus in common solvent (5% v/v water in tetrahydrofuran) using spray dryer. Prepared binary dispersions were analyzed by differential scanning calorimetry (DSC), microscopy, powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR), dynamic vapor sorption (DVS), and solution nuclear magnetic resonance (NMR) spectroscopy. Superior performance of binary dispersions was observed upon dissolution and solubility studies over micronized active pharmaceutical ingredient. Amorphous solid dispersion (ASD) prepared with soluplus showed 10-fold increase in apparent solubility and maintenance of supersaturation for 24 h compared to the crystalline RXB. Further, pharmacokinetic study performed in animals was in good correlation with the solubility data. Increases of 5.7- and 6.7-fold were observed in AUC and Cmax, respectively, for ASDs prepared with soluplus compared to those with crystalline RXB. FTIR and NMR spectroscopy unveiled the involvement of N-H group of RXB with C═O group of polymers in intermolecular interactions. The decreased drug efflux ratio was observed for ASDs prepared with eudragit S100 and soluplus in Caco-2 transport study suggesting improvement in the absorption of RXB. Hence, the present study demonstrates ASD using soluplus as a promising formulation strategy for enhancing the biopharmaceutical performance of RXB by increasing the solubility and circumventing the P-gp activity.

Authors+Show Affiliations

Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research , Sector-67, S.A.S. Nagar 160062, Punjab, India.Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research , Sector-67, S.A.S. Nagar 160062, Punjab, India.Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research , Sector-67, S.A.S. Nagar 160062, Punjab, India.Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research , Sector-67, S.A.S. Nagar 160062, Punjab, India.Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research , Sector-67, S.A.S. Nagar 160062, Punjab, India.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29287144

Citation

Metre, Sunita, et al. "Enhanced Biopharmaceutical Performance of Rivaroxaban Through Polymeric Amorphous Solid Dispersion." Molecular Pharmaceutics, vol. 15, no. 2, 2018, pp. 652-668.
Metre S, Mukesh S, Samal SK, et al. Enhanced Biopharmaceutical Performance of Rivaroxaban through Polymeric Amorphous Solid Dispersion. Mol Pharm. 2018;15(2):652-668.
Metre, S., Mukesh, S., Samal, S. K., Chand, M., & Sangamwar, A. T. (2018). Enhanced Biopharmaceutical Performance of Rivaroxaban through Polymeric Amorphous Solid Dispersion. Molecular Pharmaceutics, 15(2), 652-668. https://doi.org/10.1021/acs.molpharmaceut.7b01027
Metre S, et al. Enhanced Biopharmaceutical Performance of Rivaroxaban Through Polymeric Amorphous Solid Dispersion. Mol Pharm. 2018 02 5;15(2):652-668. PubMed PMID: 29287144.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced Biopharmaceutical Performance of Rivaroxaban through Polymeric Amorphous Solid Dispersion. AU - Metre,Sunita, AU - Mukesh,Sumit, AU - Samal,Sanjaya K, AU - Chand,Mahesh, AU - Sangamwar,Abhay T, Y1 - 2018/01/16/ PY - 2017/12/30/pubmed PY - 2019/3/5/medline PY - 2017/12/30/entrez KW - Caco-2 permeability KW - P-gp inhibition KW - apparent solubility KW - pharmacokinetics KW - polymeric amorphous solid dispersion KW - rivaroxaban SP - 652 EP - 668 JF - Molecular pharmaceutics JO - Mol Pharm VL - 15 IS - 2 N2 - Rivaroxaban (RXB) is an orally active direct inhibitor of the activated serine protease Factor Xa, given as monotherapy in the treatment of venous thromboembolism (VTE). It has been characterized in vitro as a substrate for the active, nonsaturable efflux via P-gp transporter, limiting its high permeability. Therefore, the role of P-gp inhibiting polymers in enhancing the biopharmaceutical performance of RXB by preparing polymeric amorphous solid dispersion and subsequent improvement in solubility and permeability was investigated. Initially, solubility parameter and Flory-Huggins interaction parameter were determined for miscibility studies between drug and polymers. Binary dispersions were prepared by dissolving drug with polymers eudragit S100, eudragit L100, and soluplus in common solvent (5% v/v water in tetrahydrofuran) using spray dryer. Prepared binary dispersions were analyzed by differential scanning calorimetry (DSC), microscopy, powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR), dynamic vapor sorption (DVS), and solution nuclear magnetic resonance (NMR) spectroscopy. Superior performance of binary dispersions was observed upon dissolution and solubility studies over micronized active pharmaceutical ingredient. Amorphous solid dispersion (ASD) prepared with soluplus showed 10-fold increase in apparent solubility and maintenance of supersaturation for 24 h compared to the crystalline RXB. Further, pharmacokinetic study performed in animals was in good correlation with the solubility data. Increases of 5.7- and 6.7-fold were observed in AUC and Cmax, respectively, for ASDs prepared with soluplus compared to those with crystalline RXB. FTIR and NMR spectroscopy unveiled the involvement of N-H group of RXB with C═O group of polymers in intermolecular interactions. The decreased drug efflux ratio was observed for ASDs prepared with eudragit S100 and soluplus in Caco-2 transport study suggesting improvement in the absorption of RXB. Hence, the present study demonstrates ASD using soluplus as a promising formulation strategy for enhancing the biopharmaceutical performance of RXB by increasing the solubility and circumventing the P-gp activity. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/29287144/Enhanced_Biopharmaceutical_Performance_of_Rivaroxaban_through_Polymeric_Amorphous_Solid_Dispersion_ L2 - https://doi.org/10.1021/acs.molpharmaceut.7b01027 DB - PRIME DP - Unbound Medicine ER -