Potential of Stimuli-Responsive In Situ Gel System for Sustained Ocular Drug Delivery: Recent Progress and Contemporary Research

Abstract

Eyesight is one of the most well-deserved blessings, amid all the five senses in the human body. It captures the raw signals from the outside world to create detailed visual images, granting the ability to witness and gain knowledge about the world. Eyes are exposed directly to the external environment; they are susceptible to the vicissitudes of diseases. The World Health Organization has predicted that the number of individuals affected by eye diseases will rise enormously in the next decades. However, the physical barriers of the eyes and the problems associated with conventional ocular formulations are significant challenges in ophthalmic drug development. This has generated the demand for a sustained ocular drug delivery system, which serves to deliver effective drug concentration at a reduced frequency for consistent therapeutic effect and better patient treatment adherence. Recent advancement in pharmaceutical dosage design has demonstrated that a stimuli-responsive in situ gel system exhibits the favorable characteristics for providing sustained ocular drug delivery and enhanced ocular bioavailability. Stimuli-responsive in situ gels undergo a phase transition (solution-gelation) in response to the ocular environmental temperature, pH, and ions. These stimuli transform the formulation into a gel at the cul de sac to overcome the shortcomings of conventional eye drops, such as rapid nasolacrimal drainage and short contact time with the ocular surface This review highlights the recent successful research outcomes of stimuli-responsive in situ gelling systems in treating in vivo models with glaucoma and various ocular infections. Additionally, it also presents the mechanism, recent development, and safety considerations of stimuli-sensitive in situ gel as the potential sustained ocular delivery system for treating common eye disorders.

Keywords: in situ ophthalmic gel; ion-responsive; mucoadhesive; multi-stimuli-responsive; novel approaches; ocular drug delivery; pH-responsive; safety; thermo-responsive.

Figure 1

Mucoadhesion involves two steps: a contact stage followed by a consolidation stage. In the contact stage (Step 1), wetting and swelling occur in the mucoadhesive formulation when the polymer spreads over the mucus membrane to develop a deep contact with the mucus layer [13,14]. Subsequently, the consolidation stage (Step 2) involves physicochemical interactions that establish and consolidate the adhesive interaction [15]. In this stage, the mucin chains entangle with the mucoadhesive polymer chains, resulting in mechanical bond formation [16,17]. Then, moisture’s presence promotes the formation of chemical bonds such as hydrogen bonds, covalent bonds, and weak van Der Waals forces that strengthen the system [13,16].

Figure 2

HET-CAM test for optimized formulation. Each of the eggs is treated with 0.9% NaCl (negative control), 1% sodium dodecyl sulfate (SDS) (positive control), and optimized formulation, respectively. The mean irritation score obtained for the negative control, positive control, and the optimized formulation was 0.04 (no irritation), 14.07 (severe irritation), and 0.05 (no irritation), respectively [25].

Figure 3

(a) In vivo fluorescein tracking study/elimination study. Before administration, fluorescein sodium salt was incorporated into the formulations to track the presence of eye drops. One drop of marketed solution eye drop of ciprofloxacin was administered in the lower conjunctival sac. An auto-refractometer visualized and showed that the elimination of the marketed eye drop was within 10 min [31]. (b) In vivo fluorescein tracking study/elimination study. Similarly, fluorescein sodium salt was incorporated into the formulations to track the presence of gel. One drop of in situ gel was administered in the lower conjunctival sac. An auto-refractometer visualized and showed that the elimination of the marketed eye drop was within 60 min [31].

Figure 4

The anti-cataract effect of the blank group, model group, DSF suspensions group, DSF_SD suspensions group, and DSF_SD/in situ gel group were evaluated throughout the 7 days of administration. (Blank control): the lenses were clear; (Model control): the opacity was observed and developed cataracts; (DSF suspension): the cataract was developed faster on day 4 and day 5 compared to the model group; (DSF_SD suspension): the cataract was developed but not as severe as the DSF suspension group; (DSF_SD/in situ gel): the lenses were clear, and no opacity was detected throughout 7 days [39].

Figure 5

Histological cross-section of excised goat cornea stained with hematoxylin–eosin after treated with (a) isopropyl alcohol as the positive control; (b) normal saline as the negative control; and (c) a developed chitosan nanoparticulate in situ gelling system [68]. A noticeable difference comparing both developed formulations with positive control is the widening of intracellular spaces with the distortion of superficial epithelial cells, which highlights that the developed formulation was generally tolerable on the goat cornea.

Figure 6

Ni et al. revealed (A) in vivo dwelling time of marketed bear bile eye drops and advanced formulation displayed by fluorescence-gel formulation, the residence time was remarkably longer in advanced formulation compared to marketed drops; (B) the retention time of marketed bear bile and advanced formulation, where ** p < 0.01 [75].

Figure 7

Ni et al. displayed the morphology of developed bear bile-loaded pH-responsive in situ ocular gels. (A1): G1, pH 5.0; (A2): G1, pH 7.2; (B1): G2, pH 5.0; (B2): G2, pH 7.2; (C1): G3, pH 5.0; (C2): G3, pH 7.2 [75].

Figure 8

Photomicrographs of corneal after the administration of ciprofloxacin solution, methylcellulose (MC)-based preformed gel, CMC pre-formed gel and Pluronic F-127-based in situ gel [32].