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. 2017 Mar 2:12:1731-1745.
doi: 10.2147/IJN.S122747. eCollection 2017.

A novel ion-exchange carrier based upon liposome-encapsulated montmorillonite for ophthalmic delivery of betaxolol hydrochloride

Yi Huang  1 , Qi Tao  2 , Dongzhi Hou  1 , Sheng Hu  1 , Shuangyan Tian  1 , Yanzhong Chen  3 , Ruyi Gui  1 , Lingling Yang  4 , Yao Wang  5
Affiliations

A novel ion-exchange carrier based upon liposome-encapsulated montmorillonite for ophthalmic delivery of betaxolol hydrochloride

Yi Huang et al. Int J Nanomedicine. .

Abstract

As a novel ion-exchange carrier with high surface area and excellent exchangeability, montmorillonite (Mt) was intercalated with betaxolol hydrochloride (BH) to form a nanocomposite and then encapsulated by liposomes (Mt-BH-LPs) for an ophthalmic drug-delivery system. The Mt-BH and Mt-BH-LPs were prepared by an acidification process and ethanol injection combined with ammonium sulfate gradient methods. The successful formation of Mt-BH and Mt-BH-LPs was verified by thermogravimetric analysis, X-ray diffraction, Fourier-transform infrared spectra, and transmission electron microscopy. Mt-BH-LPs possessed the favorable physical characteristics of encapsulation efficiency, drug loading, mean particle size, and ζ-potential. In vitro release studies indicated Mt-BH-LPs effectively maintained a relatively sustained slow release. Immortalized human corneal epithelial cell cytotoxicity, in vivo rabbit eye-irritation tests, and chorioallantoic membrane-trypan blue staining all revealed that Mt-BH-LPs had no obvious irritation on ocular tissues. A new in vitro tear-turnover model, including inserts containing human corneal epithelial cells, was designed to evaluate the precorneal retention time of Mt-BH-LPs. The results showed that Mt-BH-LPs maintained a certain BH concentration in tear fluid for a longer period than the BH solution. In vivo precorneal retention studies also indicated Mt-BH-LPs prolonged drug retention on the ocular surface more than the BH solution. Furthermore, pharmacodynamic studies showed that Mt-BH-LPs had a prolonged effect on decreasing intraocular optical pressure in rabbits. Our results demonstrated that Mt-BH-LPs have potential as an ophthalmic delivery system.

Keywords: intraocular optical pressure; irritation; liposome; montmorillonite; precorneal retention time.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Schematic of the preparation process of Mt-BH-LPs. Abbreviations: Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride; Mt, montmorillonite.
Figure 2
Figure 2
Schematic diagram of the in vitro tear-turnover apparatus. Notes: The model incorporated an insert containing cultured corneal tissue as a turnover chamber; the external basal side of the insert was sealed to avoid a downward diffusion of material. The system was temperature-controlled at human tear-film temperature (34°C). Constant in- and outflow of simulated tears in the chamber were controlled by peristaltic pumps. Abbreviations: STF, simulated tear fluid; iHCEC, immortalized human corneal epithelial cell.
Figure 3
Figure 3
Time to dialysis equilibrium of Mt-BH-LPs Abbreviation: Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes.
Figure 4
Figure 4
Particle-size distribution of (A) BH-LPs and (B) Mt-BH-LPs. Note: The red line indicates cumulative distribution. The black line inidates the percentage of the particle size. f, differential intensity. Abbreviation: Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes.
Figure 5
Figure 5
TEM images of (A, B) BH-LPs and (C, D) Mt-BH-LPs. Note: (B and D) show magnification of red squares in (A and C), respectively. Abbreviations: TEM, transmission electron microscopy; Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes.
Figure 6
Figure 6
(A) XRD patterns of BH, acid-Mt, Mt-BH, acid-Mt + BH BH-LPs, and Mt-BH-LPs; (B) enlarged XRD patterns of acid-Mt and Mt-BH. Abbreviations: XRD, X-ray diffraction; Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride; Mt, montmorillonite.
Figure 7
Figure 7
(A) TGA and (B) DSC pattern of BH, acid-Mt, Mt-BH, BH-LPs, and Mt-BH-LPs. Abbreviations: TGA, thermogravimetric analysis; DSC, differential scanning calorimetry; Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride; Mt, montmorillonite.
Figure 8
Figure 8
FTIR spectra of acid-Mt, BH, Mt-BH, and Mt-BH-LPs. Abbreviations: FTIR, Fourier-transform infrared; Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride; Mt, montmorillonite.
Figure 9
Figure 9
In vitro release curves of BH solution, BH-LPs, and Mt-BH-LPs. Abbreviations: Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride.
Figure 10
Figure 10
Cell viability of (A) Betoptic, (B) BH solution, (C) blank LPs, and (D) Mt-BH-LPs at different exposure times and amounts. Abbreviations: Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride.
Figure 11
Figure 11
Viability of iHCECs with differing amounts of Betoptic, BH solution, blank LPs, and Mt-BH-LPs exposure for 2 hours. Abbreviations: iHCECs, immortalized human corneal epithelial cells; Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride.
Figure 12
Figure 12
Cornea histopathology by microscopy. Notes: (A) Normal cornea, (B) treated with saline, (C) treated with Betoptic, (D) treated with BH solution, and (E) treated with Mt-BH-LPs. Abbreviations: Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride.
Figure 13
Figure 13
Conjunctival histopathology by microscopy. Notes: (A) Normal cornea, (B) treated with saline, (C) treated with Betoptic, (D) treated with BH solution, and (E) treated with Mt-BH-LPs. Abbreviations: Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride.
Figure 14
Figure 14
(A) Hemorrhage situation and (B) trypan blue absorption of CAM. Abbreviations: NS, normal saline; Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride; CAM, chorioallantoic membrane.
Figure 15
Figure 15
Frozen section of stratified immortalized human cornea epithelial cells. Note: Fluorescence microscope image (magnification 400×).
Figure 16
Figure 16
Concentration–time curve in the cornea/tear-film compartment after topical application of BH solution and Mt-BH-LPs. Abbreviations: Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride.
Figure 17
Figure 17
Mean tear-fluid concentration–time curve after topical application of BH solution and Mt-BH-LPs in rabbit eyes. Abbreviations: Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride.
Figure 18
Figure 18
Change in IOP for rabbits with saline, BH solution, and Mt-BH-LPs. Abbreviations: IOP, intraocular pressure; Mt-BH-LPs, montmorillonite–betaxolol hydrochloride liposomes; BH, betaxolol hydrochloride.
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