Preparation and Characterization of Ion-Sensitive Brimonidine Tartrate In Situ Gel for Ocular Delivery

Abstract

Brimonidine tartrate (BRT) is a highly selective α2 adrenergic receptor agonist as treatment for patients with open angle glaucoma and high intraocular pressure. The objective of this study was to formulate an ophthalmic ion-sensitive in situ gel (ISG) of BRT to increase the retention time of the drug and its bioavailability. The optimum formulation of 2 mg/mL BRT-ISG was obtained with 0.45% gellan gum as the gel matrix. In vitro release results showed that the water-soluble drug bromonidine tartrate in ocular in situ gels exhibited a high burst effect and fast release in solution. The results of dialysis membrane permeation showed that there was a significant difference between the commercially available and BRT-ISG groups after 45 min. The results of the pre-corneal retention study indicated that gellan gum can effectively prolong ocular surface retention. Preliminary stability results showed that it should be stored in a cool and dark place, and the formulation under long-term preservation can be basically stable. The pharmacokinetic study of the BRT-ISG in the anterior chamber of the rabbit eye was studied by microdialysis technique, and microdialysis samples were analyzed by LC-MS/MS. The pharmacokinetic study showed that the BRT-ISG reached Cmax (8.16 mg/L) at 93 min after administration, which was 2.7 times that of the BRT eye drops, and the AUC(0-t) (1397.08 mg·min/L) was 3.4 times that of the BRT eye drops. The optimal prescription can prolong the retention time of BRT in front of the cornea and significantly improve the bioavailability of BRT in the eye. Combined with the results of in vitro release, permeation and pre-corneal retention studies, the improvement of BRT-ISG bioavailability in rabbit eyes was found to be mainly due to the retention effect after the mixture of ISG and tears.

Keywords: brimonidine tartrate; in-situ gel; microdialysis; ocular permeation.

Figure 1

Chemical structure of BRT.

Figure 2

Franz diffusion cell set up for diffusion studies: (a) flat-mouth Franz diffusion cell, (b) arc-mouth Franz diffusion cell.

Figure 3

(a–e) The effect of ion intensity on the viscosity of different formulations ((a) 0.4% gellan gum; (b) 0.45% gellan gum; (c) 0.45% gellan gum and 0.1% HPMC; (d) 0.45% gellan gum and 0.2% HPMC; (e) 0.5% gellan gum). (f) The value of viscosity change of the formulations STF = 40:28 (34 °C, 10 rpm, n = 4).

Figure 4

(a) 0.45% Gellan gum mixed with artificial tears in different ratios (from left to right: 0.45% gellan gum/STF from 40:0, 40:7, 40:14 to 40:84). (b) The effect of ion intensity on the viscosity of the optimal BRT-ISG (34 °C, 10 rpm, n = 4). (c) The effects of shear rate on the viscosity of the 0.45% gellan gum:STF = 40:28 (non-physiological was 25 °C, the other was 34 °C, n = 4).

Figure 5

(a) In vitro release profiles of dialysis bag model (n = 4, $\overline{\mathrm{x}}$ ± s). (b) Dialysis membrane permeation profile (n = 6, $\overline{\mathrm{x}}$ ± s). * p < 0.05 BRT-ISG vs. eye drops at 45 min, ** p < 0.01 BRT-ISG vs. Eye Drops at 60, 90, 120 min. (c) Ex vivo transscleral permeation profile (n = 5, $\overline{\mathrm{x}}$ ± s). * p < 0.05 BRT-ISG vs. eye drops at 15, 30 min, ** p < 0.01 BRT-ISG vs. eye drops at 60 min. (d) Ex vivo transcorneal permeation profile (n = 5, $\overline{\mathrm{x}}$ ± s).

Figure 6

In vivo fluorescence imaging of Fls-gel and Fls-solu at various time points after instillation.

Figure 7

The obtained data of at 0, 1, 2, 4, 24, 48, and 72 h after the instillation of BRT-ISG and commercial product of BRT 14d continuously.

Figure 8

Concentration of Brimonidine in the aqueous humor of rabbits after administration of eye drops and BRT−ISG (n = 10, $\overline{\mathrm{x}}$ ± s). * p < 0.05 and ** p < 0.01 BRT−ISG vs. eye drops.