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. 2018 Jun;8(3):484-495.
doi: 10.1007/s13346-018-0504-x.

A stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for ocular drug delivery

Maryam Kabiri #  1   2 , Syed H Kamal #  1 , Sandip V Pawar  1 , Protiva R Roy  1 , Maziar Derakhshandeh  1   3 , Ujendra Kumar  4 , Savvas G Hatzikiriakos  1 , Sazzad Hossain  5 , Vikramaditya G Yadav  6   7
Affiliations

A stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for ocular drug delivery

Maryam Kabiri et al. Drug Deliv Transl Res. 2018 Jun.

Abstract

Most medications targeting optic neuropathies are administered as eye drops. However, their corneal penetration efficiencies are typically < 5%. There is a clear, unmet need for novel transcorneal drug delivery vehicles. To this end, we have developed a stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for controlled release of poorly bioavailable drugs into the aqueous humor of the eye. The hydrogel is formulated as a composite of hyaluronic acid (HA) and methylcellulose (MC). The amphiphilic nanoparticles are composed of poly(ethylene oxide) (PEO) and poly(lactic acid) (PLA). Experimental design aided the identification of hydrogel composition and nanoparticle content in the formulation, and the formulation reliably switched between thixotropy and temperature-dependent rheopexy when it was tested in a rheometer under conditions that simulate the ocular surface, including blinking. These properties should ensure that the formulation coats the cornea through blinking of the eyelid and facilitate application of the medication as an eye drop immediately prior to the patient's bedtime. We subsequently tested the efficacy of our formulation in whole-eye experiments by loading the nanoparticles with cannabigerolic acid (CBGA). Our formulation exhibits over a 300% increase in transcorneal penetration over control formulations. This work paves the way for the introduction of novel products targeting ocular diseases to the market.

Keywords: Cannabinoids; Glaucoma; Hydrogel; Nanoparticles; Switchable rheology; Synthetic biology.

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Conflict of interest statement

Sazzad Hossain is the Chief Scientific Officer of InMed Pharmaceuticals Inc., a biopharmaceutical company that is commercializing an anti-glaucoma treatment that employs the formulation described in this study.

Figures

Fig. 1
Fig. 1
Storage and loss moduli as a function of temperature for hydrogels with different weight percent of HA and MC. All experiments were performed at 1 Hz using a rotational rheometer (MCR-501 of Anton Paar) equipped with a cone-and-plate geometry. Each composition was tested three times, and the standard deviation was estimated to be < 0.03 Pa or < 1.5%. There is no variation in the ordinate variable since the temperature sweeps are electronically controlled
Fig. 2
Fig. 2
Pareto plot for the evaluation of the effect of HA wt.%, MC wt.%, and NP size and their interactions on the sol-gel transition temperature of NP-laden HA-MC composites (statistical significance codes: ***P = 0; **P = 0.001; *P = 0.01)
Fig. 3
Fig. 3
HPLC and 1H–NMR analysis of CBGA synthesized in vitro. a CBGA was detected at 270 nm. An isocratic mobile phase comprising 15–85% water-acetonitrile solution containing 0.01% TFA was used to elute the metabolites from a C18 stationary phase. b Preparative HPLC and 1H-NMR were employed to confirm the synthesis of CBGA in the in vitro reactions
Fig. 4
Fig. 4
Enhancing GPP flux to the synthesis of CBGA enhances productivity of the strains. CBGA synthase is expressed on a high-copy plasmid under the control of a T5 promoter, whereas the rate-limiting enzymes of the non-mevalonate pathway, whose overexpression is critical for enhancing GPP production, are expressed on a medium-copy plasmid under the control of an IPTG-inducible Trc promoter. The replication and expression of both plasmids is compatible with one another. Error bars represent the standard deviation in the titer of CBGA
Fig. 5
Fig. 5
Dropwise addition of a 10-mL solution of CBGA and the co-polymer in ethyl acetate to water produces NPs of the desired size (186 nm) and polydispersity index (0.118). This condition has been highlighted in red in the figure. While sonication is also observed to facilitate dense packing in the core of the NPs, avoiding its use is preferable owing to higher energy demand, particularly at larger scales
Fig. 6
Fig. 6
SEM and AFM analysis of the NPs and composite. a SEM analysis confirms the formation of spherical NPs with an average diameter of 190 nm. The median and mean particle diameters were determined to be 184 and 196 nm, respectively, and the standard deviation is 6.03 nm. b, c The formulation exhibits a smooth texture and is uniformly embedded with the NPs
Fig. 7
Fig. 7
Temperature sweep for the optimized formulation provides a sol-gel transition temperature that is very close to that of ocular surface. The experiment was repeated three times, and the transition temperature was determined to be 31.5 ± 0.2 °C
Fig. 8
Fig. 8
The formulations successfully release CBGA into the bulk aqueous phase and the release kinetics mirrors unsteady state Fickian diffusion, which suggests that the NPs and the formulation behave as intended. Error bars represent the standard deviation in CBGA concentration in the cassette
Fig. 9
Fig. 9
Drug uptake by the cornea and lens after exposing the corneal surface to either the HA-MC hydrogel that is embedded with CBGA-loaded PEO-b-PLA NPs or the control formulation comprising 230 μg/mL CBGA in mineral oil. Error bars represent the standard deviation in CBGA concentration in the tissue
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