Thiolated Hydroxypropyl-β-cyclodextrin: A Potential Multifunctional Excipient for Ocular Drug Delivery

Abstract

The goal of this study was the design and evaluation of a thiolated cyclodextrin providing high drug solubilizing and mucoadhesive properties for ocular drug delivery. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was thiolated via a microwave-assisted method, resulting in a degree of thiolation of 33%. Mucoadhesive properties of thiolated HP-β-CD (HP-β-CD-SH) were determined via rheological measurements and ex vivo studies on isolated porcine cornea. Due to thiolation of HP-β-CD, a 2-fold increase of mucus viscosity and a 1.4-fold increase in residence time on isolated corneal tissue were achieved. After instillation, the mean precorneal residence time and AUC of dexamethasone (DMS) eye drops were 4-fold and 11.7-fold enhanced by HP-β-CD-SH, respectively. Furthermore, in the presence of HP-β-CD-SH, a constant high level of DMS in aqueous humour between 30 and 150 min after administration was observed. These results suggest that HP-β-CD-SH is an excellent excipient for ocular formulations of poorly soluble drugs in order to prolong their ocular residence time and bioavailability.

Keywords: aqueous humour; dexamethasone; drug delivery; hydroxypropyl-β-cyclodextrin; mucoadhesive; ocular; thiolation.

Figure 1

Viscosity of HP-β-CD or HP-β-CD-SH (0.1% w/v) with mucus measured on a plate-plate viscometer (1 Hz frequency). Each point is the mean ± standard deviation (SD) of at least three values (*** p < 0.001).

Figure 2

(a) Elastic modulus (G′), (b) viscous modulus (G″), (c) complex viscosity (η*) of HP-β-CD and HP-β-CD-SH with respect to the mucin dispersion at time 0. (d) Elastic modulus (G′), (e) viscous modulus (G″), (f) complex viscosity (η*) of HP-β-CD and HP-β-CD-SH with respect to the dispersion of mucin after 1 h.

Figure 3

Time course of percentage of FDA incorporated in HP-β-SH or HP-β-CD remaining on corneal mucosa continuously rinsed with 100 mM phosphate buffer at 37 °C and 100% relative humidity. Each point is the mean ± SD of three values.

Figure 4

DMS solubility profiles in the presence of HP-β-CD or HP-β-CD-SH. Each point is the mean ± SD of 3 values.

Figure 5

Cell viability screening performed on BALB/3T3 cell line clone A31, exposed for 4 h to HP-β-CD or HP-β-CD-SH in the 1–50 mg/mL concentration range. Untreated cells were used as control. The values indicated in the figure are means ± SD of 6 replicates.

Figure 6

Modified Draize test representation. (A) Left untreated eye of rabbit used as reference; (B–E) the same rabbit right eye after instillation of one drop of eye drops containing 0.3% (m/V) DMS at times: 30 min, 1 h, 2 h and 6 h, respectively. (F) Left untreated eye of rabbit used as reference; (G–L) the same rabbit right eye after instillation of one drop of eye drops containing 0.3% (m/V) DMS and 12.5% HP-β-CD at the time: 30 min, 1 h, 2 h and 6 h, respectively. (M) Left untreated eye of rabbit used as reference; (N–Q) the same right rabbit eye after instillation of one drop of eye drops containing 0.3% (m/V) DMS and 12.5% HP-β-CD-SH at times: 30 min, 1 h, 2 h and 6 h, respectively.

Figure 7

Profiles of DMS elimination from tear fluid of rabbits following instillation of one eye drop (50 μL) containing 0.3% w/v DMS alone or DMS and 12.5% w/v of different CDs. Each point is the mean ± SD of at least 6 values.

Figure 8

Profiles of DMS pharmacokinetics in the aqueous humour of rabbits following instillation of one eye drop (50 μL) containing 0.3% w/v DMS alone or DMS and 12.5% w/v of different CDs. Each point is the mean ± SD of at least six values.