Dry eye is a multifactorial disease, with two major recognized forms: one is characterized by a reduction of tear production, and the other is characterized by tear hyperosmolarity, mainly due to excessive evaporative water loss.
1,2 These two components of dry eye engender inflammation and ocular surface irritation. Thus, the goals for the treatment of this disease are to improve the patient's ocular comfort and to return the ocular surface and tear composition to their basal and healthy states. Two main therapeutic approaches are used in the clinic: instillation of artificial tears for tear supplementation and stimulation and instillation of anti-inflammatory drugs to reduce ocular surface inflammation.
3 Inflammation can be reduced by the use of corticosteroids, tetracyclines or cyclosporin A. For CyA, the mechanism of action of how tear production is increased is not totally clear, but it seems to be related to its immuno-modulatory activity, which decreases the local inflammation.
3 CyA is a neutral, cyclic undecapeptide with many pharmacological activities: suppression of T-cell–mediated responses, inhibition of chronic inflammatory reactions, fungicidal activity, and anti-hepatitis C virus activity.
4 This drug has been extensively used to suppress the alloimmune response after solid organ transplantation since the 1970s. Other applications of CyA are the treatment of ophthalmic diseases such as dry eye syndrome and autoimmune uveitis, and the prevention of corneal graft rejection.
5 CyA has also been investigated for treating several eye infections, such as posterior blepharitis,
6 atopic keratoconjunctivitis,
7 and herpetic stromal keratitis.
8 For many of these diseases, high systemic concentrations of CyA have to be administered to reach therapeutic ocular drug levels (50–300 ng
CyA/g
tissue),
9 resulting in serious side effects, such as nephrotoxicity and hypertension.
4 Hence, a topical and local CyA administration would be favorable to directly target the disease site, especially for the ocular surface treatment in dry eye. However, due to its high hydrophobicity (log P octanol/water = 8.2) and its low water solubility at 25°C (0.012 mg/mL),
10 CyA is difficult to formulate into a topical aqueous solution at an effective concentration. Despite many research efforts, only one emulsion for dry eye treatment has reached the US market: Restasis (Allergan, Irvine, CA). This formulation reduces the disease symptoms by decreasing activated lymphocytes.
11 However, it has drawbacks, such as burning and stinging sensations.
12 To decrease local side effects and to enhance the patient's comfort, CyA colloidal drug delivery systems are an interesting option for formulations to enable them to overcome ocular barriers.
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