Purpose: The aim of this study was to develop and characterize a liposomal product containing sirolimus to be administered subconjunctivally for the treatment of nonresponsive keratoconjunctivitis sicca (KCS) or dry eye. Methods: Formulations were prepared using an ethanol injection method and an adaptation of the heating method in pursuance of the most suitable methodology for future industrial production. Liposomes were loaded with either a high dose of 1 mg/mL of sirolimus or a less toxic dose of 0.4 mg/mL. The effects of critical process and formulation parameters were investigated. Liposomes were characterized in terms of size, zeta potential, polydispersity, differential scanning calorimetry, morphology, entrapment efficiency, phospholipid content, thermal stability, and sterility. The formulation was evaluated clinically in dogs with spontaneous KCS. Results: Sterile liposomal dispersions with sizes ranging from 140 to 211 nm, were successfully obtained. High entrapment efficiency of 93%-98% was achieved. The heating method allowed an easier production of liposomes with high entrapment efficiency, to significantly shorten production time and the elimination of the use of alcohol. The poor stability of the obtained liposomes in aqueous dispersion made the inclusion of a lyophilization step necessary to the manufacturing process. In vivo testing of the liposomal sirolimus formulations in the spontaneous KCS dog model have produced promising results, particularly with a sirolimus dose of 1 mg/mL, indicating the need for further development and study of proposed formulations in the treatment of canine KCS. Clinical improvement in tear production in dogs with spontaneous KCS treated with the 1 mg/mL dose product was observed. Conclusions: The heating method allowed easier production of high entrapment efficiency liposomes to significantly shorten production time and the elimination of the use of alcohol. Tear production was increased in dogs administered with the formulation.
Objective: The aim of this study was to evaluate the therapeutic utility of sirolimus liposomes (prepared by two different techniques at two different doses) by subconjunctival injection, and tacrolimus ophthalmic solution at 0.03% in canine patients diagnosed with keratoconjunctivitis sicca (KCS) non-responsive to conventional treatment. Procedures: 20 privately owned pet dogs with clinically confirmed non-responsive KCS were randomized into 5 groups. Patients were administered with 0.15 ml of placebo or product respectively every 2 weeks for 60 days. Also, all patients received topically tacrolimus 0.03% solution 3 times a day for 90 days. Each animal was given a full ophthalmic examination prior and during the evaluation. Results: During the evaluation, no adverse effects were observed. For a 0.16 mg/ml dose of sirolimus, the heating method provided liposomes with enhanced immunomodulating activity in contrast to the ethanol injection method. On the other hand, the improvement in lacrimal production achieved by a 0.4 mg/ml sirolimus dose was independent of the preparation technique. HM4 and EI16 formulations showed important decrease in secondary pigmentary keratitis. Also, the use of sirolimus liposomes exhibited reduction in corneal vascularization and conjunctival discharge. Conclusions: The 0.4 mg/ml dose provided greater improvement of lacrimal production and minimization of ocular irritation indicators with no influence of the preparation technique used. The heating method generated liposomal dispersions with enhanced immunomodulating activity at a lower dose of 0.16 mg/ml. Besides lacrimal production improvement, the treatment significantly improved patient vision clarity.
Purpose To determine the effectiveness of subconjunctival application of a novel sirolimus liposomal formulation for the treatment of dry eye. Methods A randomized, triple-blind, Phase II clinical trial. Thirty-eight eyes of 19 patients were included. Nine patients (18 eyes) assigned to the sham group (Sham) and 10 patients (20 eyes) to sirolimus-loaded liposomes group (Sirolimus). The treatment group received three doses of subconjunctival liposome-encapsulated sirolimus and the sham group received three doses of liposomal suspension without sirolimus. Subjective (Ocular Surface Disease Index, OSDI) and measured (corrected distance visual acuity, conjunctival hyperemia, tear osmolarity, Schirmer’s test, corneal/conjunctival staining and matrix metalloproteinase-9) variables were measured. Results Sirolimus-entrapped liposomes-treated group OSDI scores changed from 62.19 (± 6.07) to 37.8 (± 17.81) (p=0.0024), and conjunctival hyperemia from 2.0 (± 0.68) to 0.83 (± 0.61) (p<0.0001); Sham group with OSDI scores from 60.02 (± 14.2) to 36.02 (± 20.70) (p=0.01), and conjunctival hyperemia from 1.33 (± 0.68) to 0.94 (± 0.87) (p=0.048). All the other evaluated outcomes only showed significant differences in the sirolimus group: corneal/conjunctival staining score (p=0.0015), lipid layer interferometry (p=0.006), and inferior meibomian gland dropout (p=0.038). No local or systemic adverse effects regarding the medication itself were reported, and the administration route was well accepted. Conclusion Our findings suggest that sub-conjunctival sirolimus-loaded liposomes are effective in reducing both signs and symptoms of dry eye in patients with poorly controlled moderate-to-severe DED, while avoiding other topical administration adverse effects. Further investigation with a larger sample size is required to determine long-term effects.
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