Hydrophobic ion pairing with cationic derivatives of α-, ß-, and γ-cyclodextrin as a novel approach for development of a self-nano-emulsifying drug delivery system (SNEDDS) for oral delivery of heparin.

To enhance the oral bioavailability of heparin, a self-nano-emulsifying drug delivery system (SNEDDS) was developed using hydrophobic ion-pairing with cationic polymers of α-, ß-, and γ-cyclodextrins (CPCDs). Hydrophobic ion paired complexes were formed, and the recovery of heparin was determined in n-hexane and isopropyl myristate (IPM). The SNEDDSs were prepared and were optimized using D-optimal response surface methodology (RSM). The determination of the recovery of complexes in IPM revealed that in cationic α-cyclodextrin, the highest recovery was achieved at the heparin: CPCD weight ratio of 1:0.5. However, in cationic ß-cyclodextrin the highest recovery was obtained at the weight ratio of 1:4. Similar to CPßCD, for ealed that in c the highest recovery was obtained at 1:4 weight ratio. The size of optimized nano-droplets was found to be 127.00 ± 4.1, 184.00 ± 6.43, and 216.00 ± 5.43 nm; polydispersity index (PdI) values were reported as 0.372 ± 0.005, 0.163 ± 0.008, 0.236 ± 0.003; and calculated loading efficiency (LE%) were 84.60 ± 3.62, 91.06 ± 2.49, and 92.81 ± 0.70% for SNEDDS preparations incorporating cationic derivatives of α-, ß-, and γ-cyclodextrin, respectively. The release study revealed that SNEDDS preparations containing cationic γ-cyclodextrin posed the slowest release rate. Data achieved from cellular uptake study showed that the SNEDDS containing α-cyclodextrin had the highest cumulative uptake percentage after 6 h post-exposure; same results were obtained in the intestinal transport study demonstrating SNEDDS containing α-cyclodextrin posed the highest transport efficiency with Papp of 24.85 × 10 ± 1.06 × 10 cm..