Development of Diphenyl carbonate-Crosslinked Cyclodextrin Based Nanosponges for Oral Delivery of Baricitinib: Formulation, Characterization and Pharmacokinetic Studies

Abstract

Background:The aim of the present investigation is to prepare baricitinib (BAR)-loaded diphenyl carbonate (DPC) β-cyclodextrin (βCD) based nanosponges (NSs) to improve the oral bioavailability. Methods: BAR-loaded DPC-crosslinked βCD NSs (B-DCNs) were prepared prepared by varying the molar ratio of βCD: DPC (1:1.5 to 1:6). The developed B-DCNs loaded with BAR were characterized for particle size, polydispersity index (PDI), zeta potential (ZP), % yield and percent entrapment efficiency (%EE). Results: Based on the above evaluations, BAR-loaded DPC βCD NSs (B-CDN3) was optimized with mean size (345.8±4.7 nm), PDI (0.335±0.005), Yield (91.46±7.4%) and EE (79.1±1.6%). The optimized NSs (B-CDN3) was further confirmed by SEM, spectral analysis, BET analysis, in vitro release and pharmacokinetic studies. The optimized NSs (B-CDN3) showed 2.13 times enhancement in bioavailability in comparison to pure BAR suspension. Conclusion: It could be anticipated that NSs loaded with BAR as a promising tool for release and bioavailability for the treatment of rheumatic arthritis and Covid-19.

Exploring Cyclodextrin-Based Nanosponges as Drug Delivery Systems: Understanding the Physicochemical Factors Influencing Drug Loading and Release Kinetics

“…The relationship between EE and 1:n shows four different natures: Increase in EE with 1:n —observed for β-CD:CDI complexes with bortezomib ( 1 ) [ 79 ], flutamide ( 2 ) [ 80 ], piroxicam ( 3 ) [ 81 ], and sulfamethoxazole ( 4 ) [ 82 ], β-CD:DPC complexes with baricitinib ( 5 ) [ 83 ] and febuxostat ( 6 ) [ 84 ], naproxen-loaded β-CD:TDI ( 7 ) [ 85 ], and clotrimazole-loaded 2-HP-β-CD:DMC ( 8 ) [ 86 ]; Maximum EE for specific 1:n —observed for β-CD:DPC complexes with nifedipine (1:4) ( 9 ) [ 87 ] and rilpivirine (1:4) ( 10 ) [ 88 ], and for β-CD:PMDA complexes with acetylsalicylic acid (1:4) ( 11 ) [ 89 ], diclofenac sodium (1:2) ( 12 ) [ 90 ], and rosuvastatin calcium (1:6) ( 13 ) [ 91 ]; Decrease in EE with 1:n —observed for l -DOPA-loaded β-CD:CDI ( 14 ) [ 92 ] and 5-fluorouracil-loaded β-CD:DPC ( 15 ) [ 93 ]; No influence of 1:n on EE —observed for paliperidone-loaded β-CD:CDI ( 16 ) [ 94 ] and ciprofloxacin-loaded 2-HP-β-CD:DPC ( 17 ) [ 95 ]. …”

“…Increase in EE with 1:n —observed for β-CD:CDI complexes with bortezomib ( 1 ) [ 79 ], flutamide ( 2 ) [ 80 ], piroxicam ( 3 ) [ 81 ], and sulfamethoxazole ( 4 ) [ 82 ], β-CD:DPC complexes with baricitinib ( 5 ) [ 83 ] and febuxostat ( 6 ) [ 84 ], naproxen-loaded β-CD:TDI ( 7 ) [ 85 ], and clotrimazole-loaded 2-HP-β-CD:DMC ( 8 ) [ 86 ];…”

“…Lastly, the Brunauer–Emmett–Teller (BET) theory enables the evaluation of the surface area of CDNS particles. This method is implemented via evaluation of the pore volume of CDNS by adsorption of gas molecules, e.g., liquid nitrogen, which can then be used to calculate the pore diameter and, subsequently, the surface area [ 83 , 91 ].…”

“…This phenomenon can be explained depending on the polymerization degree—for lower 1 :n , the CDNS network is uncompleted, resulting in poor drug complexation and poor ability to form dense, organized structures, whereas for higher 1 :n , polymer steric hindrances could lead to branching of the polymer structure. Particle size could also increase with the growth of 1 :n , as shown by the principles of β-CD:CDI complexes with bortezomib ( 1 ) [ 79 ], piroxicam ( 3 ) [ 81 ], and l -DOPA ( 14 ) [ 92 ], and of β-CD:DPC complexes with baricitinib ( 5 ) [ 83 ] and nifedipine ( 9 ) [ 87 ], which are the result of destabilization of the polymer network, as mentioned previously.…”

“…The incorporation of drugs into CDNSs alone can lead to changes in the cumulative drug release observed at the same time, which translates into accelerating or slowing down the drug release rate ( Table 7 ). An increase in cumulative drug release as compared with the pure drug was observed for β-CD:CDI complexes with bortezomib ( 1 ) [ 79 ], flutamide ( 2 ) [ 80 ], atorvastatin calcium ( 23 ) [ 99 ], and rilpivirine ( 34 ) [ 107 ], β-CD:DPC complexes with baricitinib ( 5 ) [ 83 ], rilpivirine ( 10 ) [ 88 ], irbesartan ( 20 ) [ 97 ], dexamethasone ( 24 and 42 ) [ 100 , 113 ], efavirenz ( 31 ) [ 105 ], erlotinib ( 32 ) [ 106 ], and domperidone ( 39 ) [ 110 ], β-CD:PMDA complexes with rosuvastatin calcium ( 13 ) [ 91 ], irbesartan ( 21 ) [ 97 ], rilpivirine ( 35 ) [ 107 ], and imiquimod ( 46 ) [ 117 ], and 2-HP-β-CD:DPC complexes with ibuprofen ( 28 ) [ 102 ], due to increased wettability and improvement of the water solubility of the drug [ 80 , 88 , 97 , 99 , 107 ], reductions in drug crystallinity [ 88 , 97 ] and particle size [ 88 , 97 , 100 , 117 ], and increases in the surface area [ 83 , 88 ] resulting from encapsulation into CDNSs. On the other hand, a decrease in the amount of drug released was observed for β-CD:CDI complexes with paliperidone ( 16 ) [ 94 ], econazole nitrate ( 43 ) [ 114 ], and dexamethasone ( 44 ) [ 115 ], β-CD:DPC complexes with febuxostat ( 6 ) [ 84 ], clobetasol propionate ( 19 ) [ 96 ...…”