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

Abstract

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 in vitro 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^−r ± 1.06 × 10^−± cm.s^−m.

Keywords:

• Heparin
• oral delivery
• self-nano-emulsifying drug delivery system (SNEDDS)
• hydrophobic ion paring
• α-cyclodextrin
• ß-cyclodextrin
• γ-cyclodextrin

Acknowledgments

The authors thank the technicians and employees of the laboratory of pharmaceutical technology, School of Pharmacy, Hamadan University of Medical Sciences for their kind collaboration in performing the study. Moreover, the authors thank Institute of Biochemistry and Biophysics (IBB), Tehran University, for their collaboration in staining and microscopic imaging.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The study was made possible by financial supports from the Deputy of Research and Technology, Hamadan University of Medical Sciences, Hamadan, Iran, under a grant [No. 9803212305].