A polymeric aqueous tacrolimus formulation for topical ocular delivery with no plasma exposure

Tacrolimus is a 23-member cyclic macrolide lactone and was isolated from Streptomyces tsukubaensis in 1984. It was initially developed as an immunosuppressant agent for use following organ transplantation, but now Tacrolimus in an ointment formulation is also marketed for the treatment of atopic dermatitis. In the past, antiallergic drug and steroid therapy has been used to treat severe allergic conjunctivitis. Unfortunately, antiallergic drug therapy is often insufficient without concomitant steroid use. However, topical steroids put patients at high risk of developing cataracts and/or glaucoma. Although tacrolimus suspension is used to treat moderate to severe atopic keratoconjunctivitis and vernal keratoconjunctivitis, its use is associated with ocular irritation, pain and transient blurring of vision.

To overcome these limitations, Dr. Moutaz Badr, Dr. Nurul  Abdulrahman, Dr. Andreas  Schatzlein and Professor Ijeoma Uchegbua from the School of Pharmacy at University College London in the United Kingdom developed the hydrophobic compound tacrolimus in a new innovative formulation of an aqueous eye drop and examined its ocular biodistribution with the sole purpose of using it to treat atopic keratoconjunctivitis and vernal keratoconjunctivitis. Their results showed that they developed a topical ocular aqueous tacrolimus eye drop formulation with the ability to deliver adequate drug to the relevant ocular surface tissues. The original research work is now published in the International Journal of Pharmaceutics.

The research team made use of a thin-film hydration method to encapsulate tacrolimus within a chitosan-based amphiphile (Molecular Envelope Technology – MET) in an aqueous formulation. They characterized the formulation and examined its stability under three storage conditions for one month. The viscosity, osmolarity and pH of the formulation was within the ocular comfort range and the formulation was found to be stable on refrigeration for one month.

The authors found detectable and quantifiable levels of tacrolimus in the cornea and conjunctiva following the topical single instillation of 0.1% w/v MET-tacrolimus. Tacrolimus concentrations were also quantified in the aqueous humor and detected in choroid – retina. However, tacrolimus was not detected in the vitreous humor and the whole blood at all time points.

The ocular administration of MET-tacrolimus did not result in any visible signs of tearing, swelling or erythema. The permeation of the insoluble TAC into ocular tissues was aided by MET as well as the delivery of the drug to the target tissues-the cornea and conjunctiva at a concentration that was higher than its therapeutic levels.

In summary, through this new study the authors have tried to overcome the difficulties associated with the application of suspension forms and topical ointments of tacrolimus in ocular allergic conditions. They achieved this by developing a 0.1% w/v aqueous-based MET-tacrolimus formulation. This formulation possessed all the characteristics ideal for an eye drop formulation and when applied in healthy New Zealand White rabbits, a single topical dose delivered a drug concentration higher than the therapeutically effective levels to the target tissues. They have therefore proposed that this formulation may be useful in treating atopic keratoconjunctivitis and vernal keratoconjunctivitis.

Based on their findings, the authors have proposed the use of MET as a new carrier for tacrolimus as it helps to overcome both the dynamic and static barriers to reach the ocular tissues. Future studies will investigate the specific mechanism through which MET delivers tacrolimus to the back of the eye tissues.

“We are really pleased that this formulation further validates our MET platform as an effective topical ocular delivery system for hydrophobic drugs,” says Chief Scientific Officer of Nanomerics – Professor Ijeoma F. Uchegbu