CURCUMIN AND GLAUCOMA

Guest author

SABA ZARREEN

Ajmal Khan Tibbiya College

Aligarh, India

Introduction:

Glaucoma, principally involves the loss of retinal ganglion cells (RGCs).

RGC apoptosis has been identified as an early event in glaucomatous degeneration and the inhibition of this process has been advocated as a therapeutic strategy.

Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5dione) is a polyphenol extracted from turmeric (Curcuma longa) reported to modulate a range of biochemical processes implicated in neurodegenerative disorders.

Benefits of Curcumin:

Effective in most common ophthalmic disorders including:

(1) Mitochondrial oxidative stress.

(2) Inflammatory responses via PPAR-γ agonist activity.

(3) Down regulation of COX-2 and  iNOS.

(4) Down regulation of JAK2-STAS3 mediated astrogliosis.

(5) Beta-amyloid aggregation.

(6) Anti-angiogenic activity via modulation of VEGF/VEGFR/K-ras pathway.

Route of administration:

(1) Supplementing rodent diets with 0.01%-0.25% curcumin has previously been reported to protect RGCs and microvasculature against ischemia/reperfusion injury.

(2) More recently, iatrogenic administration of curcumin (10 mg/kg/day) for 6 weeks in a rodent model of ocular hypertension was reported to result in significant reduction in retinal microglial death.

(3) Topical administration is the preferred delivery route as it permits self-administration and localized dosing to ocular tissues minimizing the risk of side-effects associated with systemic absorption.

Adverse effects:

This equates to a typical human dose of 800 mg/day which has previously been associated with:

Nausea & diarrhea.

Increase in serum alkaline phosphate.

Increase in lactate dehydrogenase levels.

Limitations:

Poor water solubility (11 mg/ml).

Low bioavailability.

The extremely limited water solubility of curcumin has been a challenge for the development of a topically administered form of this drug.

Enhancing the solubility by:

Solubilization in an alkaline buffer (typically 0.5 M NaOH).

Dissolution in solvents such as DMSO (Dimethyl sulfoxide).

Incorporation into nano-carriers.

Note: Dissolution of Curcumin in DMSO or alkaline buffers is unsuitable for in vitro and in vivo application without further dilution into physiological buffers. After dilution they become frequently unstable and result in rapid precipitation.

Nanotechnology approaches:

(1) To provide hydrophobic environment for poorly soluble drug molecules which persist in stable aqueous suspensions.

(2) Nano particle mediated protection of encapsulated drug cargo from hydrolytic or enzymatic degradation to enhance transport across biological barriers.

(3) D-α-Tocopherol polyethene glycol 1000 succinate (TPGS) in a non-ionic surfactant forms stable micelles at a concentration of >0.2% w/w, this agent can inhibit P-glycoprotein activity.

(4) TPGS was combined with Pluronic F127, a difunctional block copolymer surfactant consisting of a central hydrophobic polyoxy propylene group flanked by hydrophilic poly-oxy-ethylene group.

Aim:

The aim of the present study was to develop a curcumin nano-carrier comprising of TPGS and Pluronic F127, suitable for use as a topical formulation in the treatment of ocular diseases.

To develop a novel nano-carrier formulation with an encapsulation efficiency exceeding 95%, average particle size <20 nm and good stability for over 2 months when stored at 25⁰C in liquid or lyophilized form.

The neuroprotective potential of this formulation was then assessed in the immortalized R20 retinal precursor cell line. (These models include the Cobalt chloride [hypoxia-mimetic] and glutamate induced toxicity).

This formulation was shown to be effective as an eyedrop in reducing RGC loss into well stabilized rodent models of optic nerve crush injury and ocular hypertension, as well as partial optic nerve transection.

The neuroprotective effect of curcumin loaded nano-carrier observed in this study found this therapy to be most effective for patients with risk of IOP spikes such as following phacoemulsification surgery or as a prophylactic in patients identified at high risk of developing Glaucoma such as those with ocular hypertension or other Glaucoma risk factors.

Conclusion:

This study described a novel carrier formulation of curcumin in TPGS/Pluronic F127 that increased the solubility of this drug by a factor of almost 400,000.

This formulation incorporates 4.3 mg/ml of curcumin with an encapsulation efficiency of >90 % consistently and excellent stability in liquid or lyophilized form.

It is neuroprotective against glutamate and Cobalt chloride induced optic nerve injury.