Abstract
Uveitis is a vision inflammatory disorder with a high prevalence in developing countries. Currently, marketed treatments remain limited and reformulation is usually performed to obtain a tacrolimus eye drop as a therapeutic alternative in corticosteroid-refractory eye disease. The aim of this work was to develop a mucoadhesive, non-toxic and stable topical ophthalmic formulation that can be safely prepared in hospital pharmacy departments. Four different ophthalmic formulations were prepared based on the tacrolimus/hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes’ formation. Phase solubility diagrams, Nuclear Magnetic Resonance (NMR) and molecular modeling studies showed the formation of 1:1 and 1:2 tacrolimus/HPβCD inclusion complexes, being possible to obtain a 0.02% (w/v) tacrolimus concentration by using 40% (w/v) HPβCD aqueous solutions. Formulations also showed good ophthalmic properties in terms of pH, osmolality and safety. Stability studies proved these formulations to be stable for at least 3 months in refrigeration. Ex vivo bioadhesion and in vivo ocular permanence showed good mucoadhesive properties with higher ocular permanence compared to the reference pharmacy compounding used in clinical settings (t1/2 of 86.2 min for the eyedrop elaborated with 40% (w/v) HPβCD and Liquifilm® versus 46.3 min for the reference formulation). Thus, these novel eye drops present high potential as a safe alternative for uveitis treatment, as well as a versatile composition to include new drugs intended for topical ophthalmic administration.
Highlights
Uveitis is a sight-threatening inflammatory disorder that affects a wide range of ages in the world population, being the main cause of 5–20% of blindness in Europe and UnitedStates and over 25% in developing countries [1,2]
Tacrolimus powder was acquired from Guinama® S.L.U. (La Pobla de Vallbona, Spain), 2-hydroxypropyl-β-cyclodextrin Kleptose® HPB (HPβCD; MW = 1399 Da, substitution degree = 0.65 molar ratio) was provided from Roquette Laisa S.A.® (Valencia, Spain), Liquifilm® was purchased from Allergan® Pharmaceuticals Ireland (Mayo, Ireland), Balanced Salt Solution (BSS® ) was acquired from Alcon® laboratories (Fort Worth, TX, USA)
The resulting profile indicates an AP -type diagram that shows a positive deviation from characteristic linearity, this being supported by previous studies [27,37]
Summary
States and over 25% in developing countries [1,2] This affection can lead to other types of complications, including cataract, increased intraocular pressure (IOP), macular edema (ME) or glaucoma, compromising visual loss [3,4,5]. It causes a great clinical and socioeconomic impact on the life quality of patients [6,7,8] and early diagnosis and treatment are important to prevent complications. Inflammatory cytokines promote the activation of T cells and trigger recruitment of large numbers of circulation inflammatory leukocytes into the eye This process may cause irreversible tissue damage and visual impairment. The use of immunosuppressants in uveitis is indicated in corticosteroid-refractory eye disease or after systemic side effects’ appearance
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