TOPICAL OPHTHALMIC FORMULATIONS OF TRIAMCINOLONE ACETONIDE-LOADED LIPOSOMES FOR THE PREVENTION OF MACULAR THICKENING AND ITS ASSOCIATED VISUAL OUTCOMES AFTER LENS SURGERY

Abstract

The invention relates to topical ophthalmic formulations of triamcinolone acetonide-loaded liposomes for the prevention of macular thickening and its associated visual outcomes following lens surgery. The liposome formulation comprises thermodynamically self-forming liposomes that are useful topically for treating diseases of the posterior segment of the eye.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to topical ophthalmic formulations suitable for the treatment of conditions occurring in association with lens surgery. In particular, the inventors have discovered a use for a topical ophthalmic liposomal formulation developed for the treatment of diseases of the posterior segment of the eye. The present invention relates to the further discovery that this formulation is particularly useful for the treatment of patients who have undergone cataract surgery. The compositions of the present invention contain a pharmaceutically effective amount of triamcinolone acetonide (TA). The concentration of TA in the liposomal formulations ranges from 0.01 to 2.00% (w / v). TA is a known synthetic corticosteroid with an empirical formula of C24H31FO6 and a molecular weight of 434.50 Da. TA has potent anti-inflammatory activity (7.5 times more potent than cortisone)(32).Polyethylene glycol (PEG-12) glyceryl dimyristate is used as a structural constituent of liposomes at a concentration of 5-15% (w / v) and ethyl alcohol is used as an organic solvent for liposome generation at a concentration of 0.7 to 2.1% (v / v). In addition, the liposome formulation contains polyethylene glycol (15)-hydroxystearate or KolliphorHS 15 at 2.5–7.5% (w / v), a potent nonionic solubilizer and emulsifying agent with low toxicity proposed to act as a permeability enhancer. KolliphorHS 15 promotes drug transport across cell membranes (increasing the rate of endocytosis) and stimulates drug translocation via the paracellular pathway (affecting the organization of actin in the cell cytoskeleton with subsequent opening of the tight junction)(33). Additionally, the aqueous compositions of the present invention optionally comprise further excipients selected from the group consisting of buffering agents, pH adjusting agents, and preservatives. Anhydrous citric acid (0.04–0.16%) and dehydrated sodium citrate (0.23–0.69%) are used as buffers, while benzalkonium chloride (0.001–0.015%) is used as a preservative. All these compounds are expressed in % w / v units. The pH can range from approximately 5 to approximately 7.5. The concentrations of the ingredients are presented in units of % weight / volume (% w / v) or % volume / volume (% v / v). The compositions of the present invention can be prepared using conventional methods for preparing pharmaceutical suspension compositions. According to the preferred method, the drug (triamcinolone acetonide) is first added to a lipid mixture containing polyethylene glycol (PEG-12) glyceryl dimyristate and ethyl alcohol. An aqueous mixture 5, comprising grade 2 purified water, polyethylene glycol (15)-hydroxystearate (KolliphorHS 15), anhydrous citric acid, dehydrated sodium citrate, and benzalkonium chloride, is mixed in a flask and set aside for compounding. The aqueous mixture is then gently added to the lipid mixture to obtain the final formulation. The following examples are intended to illustrate, but not limit, the present invention. EXAMPLE 1 The formulations shown below are representative of the compositions of the present invention. Table 1. Topical ophthalmic formulation of liposomes loaded with acetone and triamcinolone (TA-LF) (pov) (%) Triamcinolone acetónido 2.0 mg 0.2 p / v Kolliphor HS 15 50 mg 5 p / v PEG-12 dimiristato de glicerilo 100 mg 10 p / v Alcohol etílico 14 mL 1.40% v / v Citrato de sodio deshidratado 4.675 mg 0.4675 p / v Benzalkonium chloride 0.1 mg 0.01 p / v Hydrogen purifier: 2 QS1.0 mi NA NA NA; no applicable, v; volume, p, weight The formulations shown in Table 1 were prepared and subjected to physicochemical characterization. The pH of the TA-FL was analyzed using a pH meter in triplicate at room temperature. Osmolarity was measured using a vapor pressure osmometer in triplicate at 33 °C (ocular surface temperature)(34). Viscosity was also measured in triplicate at 33 °C. Viscosity was measured using a thermostatically controlled rheometer when steady state was reached with shear rates increasing from 0 to 1000 s⁻¹. The particle size of the TA-LF was analyzed by dynamic light scattering, and the zeta potential (ζ) was calculated by measuring the particle velocity using laser Doppler velocimetry at 25 °C (Zetasizer Nano ZS, Malvern Instruments, Malvern, UK).The average Z (mean particle diameter) and the polydispersity index (PDI) were calculated from the particle size distribution. Table 2. Physicochemical properties of TA-LF. Formulation Physicochemical parameters TA-LF Average pH Viscosity Osmolarity Z PDI (cP) (mOsm / l) (nm) (nm) 5.8 70 334 187.8 0.369 pH = potential of hydrogen ions, cP = centipoise, PDI = polydispersity index The values ​​represent the average of three measurements Subsequently, the TA-LF from Example 1 was evaluated in an in vitro diffusion assay. Diffusion chambers and rabbit corneas were used to perform diffusion experiments (Chemotaxis Chambers BW200S, NeuroProbe, Gaithersburg, MD, USA). For this experiment, New Zealand rabbit corneas were used. The central corneal tissue was positioned between the upper and lower compartments of the diffusion chambers to act as a TA diffusion barrier. The upper compartment was filled with 180 ml of balanced saline (BSS), while the lower compartment was filled with 200 ml of TA-LF (TA-LF1 to TA-LF4). To prevent evaporation, the diffusion chambers were placed in a 37°C humidity chamber.The TA concentration of solutions obtained from the upper compartment at 2, 4, 6, and 8 hours (h) after the start of the diffusion assay was analyzed using high-performance liquid chromatography (HPLC). HPLC was performed using a Varian 920 LC (Agilent Technologies, Santa Clara, CA, USA) with a Zorbax Eclipse Plus C18 column, 4.6 x 100 mm, 3.5-pm (Agilent, Santa Clara, CA, USA) at 30 °C. Samples (20 µL) were eluted from the column in a water:methanol (30:70) mobile phase at a flow rate of 1 mL / min. Detection was performed at 254 nm. The retention time and limit of detection were 6.8 min and 0.004 mg / mL, respectively. The standard TA curve was linear from 0.004 to 0.100 mg / ml (correlative >0.99). In the vitreous humor, TA concentrations were determined for recovery and intraday and interday reproducibility (35). The result of the in vitro diffusion assay is shown in Table 3. Table 3. TA concentration in the upper solution of the diffusion chamber over time Time (hours) Blood Pressure Concentration (pg / mL) 0.22 ινΐΛ / a / zuz i / ui 4uuu 0.35 40.5 50.65 60.8 70.95 81.1 The values ​​represent the average of three measurements. We observed that TA-LF exhibited satisfactory diffusion performance, reaching the highest TA concentrations after 8 hours of monitoring. Subsequently, in vitro assays, in vivo diffusion analysis, and tolerability assessment of TA-LF were performed in rabbits. For diffusion analysis, TA concentrations were determined by HPLC in ocular tissues from New Zealand rabbits after multiple doses of TA-LF2. For tolerability assessment, an ocular examination was performed on the study animals after topical administration of TA-LF2. The animal protocol was as follows: Rabbits were randomly assigned to four groups. One drop of TA-LF2 solution (50 µL) was applied to one eye every two hours, six times over 14 days. Five rabbits were euthanized after the start of TA-LF2 instillation at 12 hours, 1.7 days, and 14 days. Before tissue collection, an ocular examination was performed under anesthesia (intramuscular injection of 30 mg / kg ketamine hydrochloride and 15 mg / kg chlorpromazine hydrochloride).This evaluation included slit-lamp biomicroscopy, fluorescein staining, direct ophthalmoscope funduscopy, and intraocular pressure (IOP) measurement (Care Tonometer i350, Vantaa, Finland). In addition, ocular irritation testing was performed according to the Mexican Pharmacopoeia. A positive irritant reaction was defined as the presence of corneal ulceration revealed by fluorescein staining, corneal opacity, iris or conjunctival swelling, and conjunctival vessel dilation, particularly around the cornea. After enucleation, the conjunctiva, cornea, retina, 150 µL of aqueous humor, and 200 µL of vitreous humor were collected. Solid tissues were washed in PBS. The tissues were then homogenized with 0.3 ml of acetonitrile (Sigma-Aldrich, Mexico). Subsequently, each sample was centrifuged at 15,294 x g for 5 min.The supernatants were evaporated to add 100 μL of methanol. Another centrifugation was performed and 20 μL of the resulting supernatants were used for TA concentration analysis by HPLC, performed as described above. TA concentrations in the retina and vitreous humor reached their highest peak at 12 hours (252.1 ± 90.00 ng / g and 32.6 ± 10.27 ng / g, respectively) and subsequently decreased to 24.0 ± 11.72 ng / g and 19.5 ± 13.14 ng / g, respectively, at 14 days of follow-up. TA concentration versus time in different ocular tissues is presented in Figure 1 and Table 4. ινΐΛ / a / zuz i / ui 4uuu Table 4. TA concentration in ocular tissues after topical administration of TA-LF in rabbit eyes. Triamcinolone acetonide concentration (ng / g) Time Humor (days) Conjunctiva Cornea Lens Retina Aqueous Humor Vitreous Humor 0.5 1886.3 + 398.95 2156.1 ± 1055.41 83.3 ± 30.49 252.1 ± 90.00 9.9 ± 1.95 32.6 ± 10.27 1 1524.8 + 356.04 657.5 ± 260.37 62.2 ± 18.54 196.9 ± 133.10 9.8 ± 2.12 18.6 ± 7.07 7 359.3 + 166.54 132.5 ± 78.37 52.3 + 37.42 57.7 + 20.92 8.1 ± 2.71 20.7 ± 11.35 14 52.3 + 27.82 92.3 + 42.13 5.2 ± 3.38 24 ± 11.72 2.8 ± 0.13 19.5 + 13.14 The values ​​represent the average ± standard deviation of the mean of four samples A compartmental and a non-compartmental model were used to determine the pharmacokinetics of TA-laden liposomes in ocular tissues. The linear trapezoidal method was used to evaluate the area under the curve (AUC). The half-life (tv2) was calculated by linear regression of the concentration at different time points. The pharmacokinetic parameters are shown in Table 5. Cmax was 2156.07 ± 1055.41 ng / g in the cornea, 1886.33 ± 398.95 ng / g in the conjunctiva, 9.9 ± 1.95 5 ng / g in the aqueous humor, 83.3 ± 30.49 ng / g in the lens, 32.6 ± 10.27 ng / g in the vitreous humor and 252.10 ± 90.00 ng / g in the retina. Table 5. Pharmacokinetic parameters in ocular tissues after topical administration of TA-FL. IVIA / a / ¿U¿ I / U14UUU Parameter Conjunctiva Humor Cornea aqueous Vitreous lens Retina ke (d1) 0.263 0.26 - - 0.79 0.26 T1 / 2 (d) 2.64 2.66 0.23 0.09 0.87 3.62 Cmax (ng / g) 1886.33 2156.075 9.94 83.328 32.6 252.1 Cmin (ng / g) 52.26 92.348 2.795 5.183 18.613 24 ki2 (d·1) - 2.365 - - 13.48 0.383 k21 (d1) - 0.045 - - 0.018 0.478 ABC0 ' (ng*g / d) 7,945.35 3,860.50 96.75 610.052 271.378 1,159.40 ABC0 ” (ng*g / d) 8,144.32 3,933.12 - - 296.054 1,251.69 ke = elimination rate constant; d = day; T^2 = elimination half-life; Cmax = maximum observed concentration; Cmin = minimum observed concentration; k12 = transfer rate from the central compartment to the peripheral compartment; k21 = transfer rate from the peripheral compartment to the central compartment; AUCO^ = area under the curve up to the last measurement; AUCCT = area under the curve from point 0 to infinity. Regarding the tolerability assessment, no increase in intraocular pressure was observed in any of the study animals (normal intraocular pressure in these rabbits is 12–28 mmHg). Sodium fluorescein and rose bengal staining showed superficial punctate keratitis within the first 6 hours after instillation of the formulation. This condition resolved in all cases by the 12-hour post-administration examination. Therefore, according to the Mexican Pharmacopoeia, the ocular irritation test was satisfactory, and TA-LF2 is considered non-irritating. Finally, the therapeutic activity of TA-LF was demonstrated in humans. The tolerability, safety, and efficacy of a topical TA-LF were evaluated in three clinical trials (phase 0, phase I, and phase II). Phase O of the clinical trial This study was conducted to report the tolerability, safety, and efficacy of a topical triamcinolone acetonide-loaded liposome (TA-LF) formulation for targeting the macular area in patients with treatment-resistant pseudophakic cystoid macular edema (PCME). To assess tolerability, safety, and efficacy, 12 eyes of 12 patients with treatment-resistant PCME were exposed to one drop of TA-LF (0.2% TA) every two hours for 90 days or until best-corrected visual acuity (BCVA) was achieved. Intraocular pressure (IOP), slit-lamp examination, and central foveal thickness (CFT) were assessed at each visit. Patients with treatment-resistant PCME on TA-LF therapy showed a significant improvement in BCVA and CFT without a significant change in IOP (P = 0.94). On average, the CFT decreases by 184 ± 113.82 pm and the BCVA improves by 22.33 ± 4.32 letters (P < 0.0005). BCVA was achieved at 10.58 ± 7.20 weeks (range, 2–18). TA-LF was well tolerated in all cases. No ocular surface abnormalities or adverse events were recorded. The results of the intervention are summarized in Table 6. In conclusion of the phase 0 study: TA-LF was well tolerated and improved BCVA and CFT in patients with treatment-resistant PCME. The results of this clinical trial were recently published (24). Table 6. Demographic and clinical characteristics of PCME patients treated with TA-LF. ινΐΛ / a / zuz i / ui 4uuu Age Eye Initial Value Results of TA-LF Therapy CFT BCVA (letters IOP Vitrectomy CFT at time of BCVA Change in CFT (pm) BCVA (letters Change in BCVA (letters Weeks to BCVA ΊΟΡ Change in IOP (mmHg) AE Patient Sex (years) study (pm) ETDRS) (mmHg) (pm) ETDRS) ETDRS) (mmHg) 1 F 63 OD 545 52 17 Yes 330 -215 70 18 2 12 5 No 2 F 76 OD 580 46 15 Yes 333 -247 73 27 7 11 4 No 3 M 59 OS 461 43 12 Yes 329 -132 67 24 17 11 1 No 4 F 58 OS 369 49 15 Yes 328 -41 80 31 2 17 -2 No 5 F 62 OS 605 53 13 No 352 -253 73 20 13 14 -1 No 6 F 74 OD 487 50 12 Yes 288 -199 80 30 2 11 1 No 7 F 78 OS 600 54 14 No 352 -248 58 4 17 16 -2 No 8 M 59 OS 415 47 14 No 391 -24 73 26 22 13 1 No 9 M 64 OS 354 53 17 No 262 -92 70 17 18 13 4 No 10 F 66 OD 666 52 11 No 260 -406 80 28 13 18 -7 No 11 M 60 OD 596 50 14 No 316 -280 58 8 11 18 -4 No 12 M 64 OS 360 45 12 No 289 -71 80 35 3 13 -1 No 68.08 M: 5 + OD: 5 503.17 49.5 ± 13.83 ± Yes: 5 319.17± -184 ± 71.83 ± 22.33 ± 10.58 ± 13.92 ± -0.08 ± Yes: 0 (41.66%) 12.16 (41.66%) ±110 3.55 1.95 (41.66%) 38.68 t 113.82 7.881 4.32 7.20 2.68 $ 3.50 (0.00%) F: 7 OS: 7 No: 7 No: 12 (58.33%) (58.33%) (58.33%) (100%). F; female, M; male, OD; right eye, OS; left eye, CFT; central foveal thickness, BCVA; Best-corrected visual acuity, ETDRS; Early treatment study of diabetic retinopathy ________________________________________________14__________________________________________ IOP; intraocular pressure, TA-LF; triamcinolone acetonide-loaded liposome formulation, AE; adverse events JORP; IOP at 20 weeks of follow-up; t; statistically significant differences from baseline (P< 0.0005), φ; no statistically significant differences from baseline (P> 0.05). Phase I of the clinical trial This study was conducted to report the tolerability, safety, and efficacy of a topical triamcinolone acetonide-loaded liposome formulation (TA-LF) in healthy subjects without ocular or systemic disease. Participants received TA-LF and were instructed to apply one drop every two hours to the right eye while awake (six times) for 2 weeks. Demographic and baseline clinical examinations were collected on days 14 to 1 before the start of TA-LF administration. Retinal optical coherence tomography (OCT) was performed at baseline (to confirm the absence of ocular mucosal lesions by OCT) and weekly until the end of follow-up. BCVA using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart was recorded at 4 months, along with slit-lamp assessment of the ocular surface using 2% fluorescein staining and posterior segment findings at each visit.Subjects were withdrawn from the study if they exhibited any evidence of poor tolerability (any adverse event related to the use of the topical formulation). Tolerability was assessed through the collection and summarization of ocular and non-ocular adverse events (AEs), serious AEs (SAEs), ocular assessments, and vital signs, whether voluntarily reported by the patient, discovered by study center staff during questioning, or by other means. Subjects were withdrawn if they exhibited any evidence of poor tolerability or any adverse event, such as corneal ulcers, corneal opacities, epithelial defects, anterior chamber inflammation (cells / inflammation), and conjunctival and / or episcleral injection related to the use of this topical formulation.Standard code terms were assigned to the AE for the event based on the MedDRA coding dictionary, version 18.1. Other eye examinations included contrast sensitivity (CS) assessed by the Pelli-Robson contrast sensitivity test, intraocular pressure (IOP) measurement using a Goldmann applanation tonometer, and corneal endothelial cell density (cECD) determined by specular microscopy (Perseus endothelial microscope, Costruzione Strumenti Oftalmici, Florence, Italy). TA-LF was well tolerated by healthy subjects. Twenty right eyes from 20 healthy subjects (38.45 ± 9.06 years, 45% female, 55% male) with no evidence of systemic or ocular disease were enrolled to evaluate TA-LF tolerability. These subjects were instructed to apply one drop of TA-LF every two hours to the right eye while awake (six times) for two weeks. The baseline demographic and clinical characteristics of these subjects are summarized in Table 7. No adverse events were reported in the data analysis. OCT showed no significant change in the TFC compared to baseline (TFC change of 0.85 ± 0.29 μm). BCVA showed no significant change in the 20 patients (mean change of -0.01 ± 0.16 ETDRS letters). Interestingly, CS showed a minimal but significant change from 1.48 ± 0.13 at baseline to 1.56 ± 0.10 after 14 days of TA-LF therapy.No ocular surface abnormalities were recorded during the follow-up period. None of the patients showed a significant increase in IOP during the treatment period. None of the patients were excluded from the study due to adverse events. The clinical characteristics after TA-LF treatment in healthy subjects are summarized in Table 7. Furthermore, no subconjunctival hemorrhages were reported in this study. Ocular surface staining, which was graded as 0 (no change) or 1 (mild change) in most cases, was transient and considered clinically insignificant by the investigator. No pathological changes were reported in the anterior chamber of the eye or the lens. No vitreous cells or inflammation were observed. Retinal structures appeared normal before and after dose administration. Endothelial cell density and retinal thickness were unaffected (2976.2 ± 414.21 cells / mm² vs. 3036.7 ± 377.25 cells / mm²) (Figure 2). No clinically relevant changes in vital sign parameters were observed. TA-LF eye drops did not affect blood pressure or pulse rate. There were no local or systemic findings that required discontinuation of TA-LF. Table 7. Demographic and clinical characteristics of healthy subjects treated with TA-LF. Patient Sex Age (years) Study eye Initial characteristics Week 12 (TA-LF) CFT (µm) BCVA (ETDRS letters) IOP (mmHg) CFT (µm) Change in CFT (mm) BCVA (ETDRS letters) Change in Change in IOP (mmHg) AE BCVA (ETDRS letters) IOP (mmHg) 1 F 46 OD 260 81 13 262 2 81 0 16 3 No 2 M 45 OD 241 80 14 245 4 79 -1 13 -1 No 3 F 58 OD 247 82 15 247 0 81 -1 16 1 No 4 M 47 OD 262 80 15 262 0 80 0 12 -3 No 5 M 37 OD 254 84 12 254 0 84 0 14 2 No 6 M 32 OD 250 85 15 255 5 85 0 16 1 No 7 F 50 OD 243 82 16 241 -2 82 0 16 0 No 8 F 35 OD 265 85 17 270 5 85 0 17 0 No 9 M 28 OD 259 85 13 256 -3 85 0 15 2 No 10 M 31 OD 240 85 13 243 3 84 -1 12 -1 No 11 F 33 OD 259 85 10 260 1 85 0 11 1 No 12 F 36 OD 248 83 14 248 0 84 1 15 1 No 13 M 39 OD 249 82 16 249 0 82 0 14 -2 No 14 F 50 OD 257 80 17 257 0 80 0 15 -2 No 15 M 48 OD 247 84 14 248 1 84 0 14 0 No 16 F 24 OD 249 85 14 250 1 85 0 11 -3 No 17 M 27 OD 245 85 13 245 0 85 0 12 -1 No 18 F 33 OD 242 84 13 242 0 85 1 15 2 No Μ 35 OD 257 83 12 257 0 82 -1 12 0 No Μ 35 OD 248 82 15 248 0 82 0 18 3 No M: 11 38.45 ± OD:20 251.1 ± 83.1 ± 14.05 ± 251.9 ± 0.85 ± 83 ± -0.01 ± 14.2 ± 0.15 ± Yes: 0 (55%) 9.06 (100%) 7.49 1.86 1.76 7.79 φ 0.29 2.02 φ 0.16 2.04 φ 0.28 (0.00%) F: 9 SO: 0 No: 12 (45%) (0.00%) (100%) F; female, M; male, OD; right eye, BCVA; best corrected visual acuity, ETDRS; Early treatment study of diabetic retinopathy, IOP; intraocular pressure, CFT; central foveal thickness, AE; adverse events, TA-LF; triamcinolone acetonide-loaded liposome formulation, t; statistically significant differences from baseline (P< 0.05), φ; no statistically significant differences from baseline (P> 0.05). Figure 3 A and B show the corneal endothelial cell density analysis in healthy subjects treated with the triamcinolone acetonide-loaded liposome formulation. A. Specular microscopy images of a representative case are presented at baseline and after 14 days of TALF instillation. B. The column bar chart of the cECD analysis is presented. A non-significant difference in cECD values ​​was established between baseline and after 14 days of TA-LF instillation. cECD; corneal endothelial cell density, TA-LF; triamcinolone acetonide-loaded liposome formulation. Phase II of the clinical trial The aim of this trial was to explore the tolerability, safety, and efficacy of a topical triamcinolone acetonide-loaded liposome formulation (TA-LF) for preventing clinically significant pseudophakic cystoid macular edema (CSME) following femtosecond laser-assisted cataract surgery (FLACS). Fifty-five eyes from 32 patients undergoing FLACS were enrolled. Twenty-seven eyes were assigned to the TA group, while twenty-eight eyes were assigned to the TA-LF group. In the TA group, eyes were exposed to a conventional 0.1% topical formulation of triamcinolone acetonide for 21 days postoperatively, while patients in the TA-LF group received a liposomal formulation containing 2 mg / mL of TA (0.2%).Follow-up included slit-lamp examination, visual acuity, contrast sensitivity, central foveal thickness (CFT), and total macular volume (TMV) (both measured by retinal optical coherence tomography). Study visits were scheduled at 1 day, 6, and 12 weeks post-surgery. Regarding tolerability and safety, TA-LF was well tolerated throughout the study period. No ocular (increased intraocular pressure, ocular surface abnormalities) or systemic adverse events were reported. None of the patients required medication to lower IOP. None of the patients showed signs of irritation or surface problems due to the application of the study formulation until the end of the study. On the other hand, only the TA-LF group showed a significant improvement in contrast sensitivity (baseline: 1.087 ± 0.339 vs. week 12: 1.266 ± 0.147) and visual acuity from preoperative measurements (baseline: 0.252 ± 0.248 vs. week 12: 0.005 ± 0.136). Table 8 summarizes the within-group analysis. Table 8. Differences within groups in visual acuity, contrast sensitivity, macular thickness, and total macular volume. Baseline 6w 12w p-value Visual acuity TA 0.054 ±0.148 0.072 ±0.189 0.077 ±0.195 0.9779 (logMar) TA-LF 0.252 ± 0.248 0.03 ±0.142 0.005 ±0.136 <0.0001 TA 1.214 ± 0.219 1.194 ± 0.173 1.229 ±0.178 0.513 Sensitivity to contrast 1.217 ± 0.191 1.266 ± 0.147 0.0346 1.087 ± 0.339 (1 / contrast) TA-LF TA 258.33 ± 32.50 275.37 ± 43.22 275.38 ± 47.26 0.0143 CFT (μm) TA-LF 256.21 ± 15.16 266.42 ± 16.06 265.92 ± 18.55 < 0.0001 TA 10.14 ± 0.70 10.41 ± 0.58 10.52 ± 0.69 0.031 TMV (mm3) TA-LF 10.08 ±0.71 10.55 ±0.52 10.50 ±0.52 <0.0001 TA 15.11 ±3.25 12.88 ±3.02 13.52 ±2.50 0.0193 IOP (mmHg) TA-LF 15.71 ±2.20 12.89 ±2.69 13.50 ±1.93 0.0193 IVIA / a / ZUZ I 4UUU CFT; central foveal grosor, IOP; intraocular pressure, logMar: logarithm of the minimum angle of resolution; TA; triamcinolone acetonide group, TA-LF; liposome formulation containing 2 mg / ml of the TA, TMV group; total macular volume, w; week. It is worth noting that the CFT and TMV correlate significantly with contrast sensitivity only in the TA-LF group. The correlation between CFT and contrast sensitivity was 0.1675 (P = 0.0306), while the correlation between TMV and contrast sensitivity was 0.1675 (P = 0.0055) (Table 9). Table 9. Correlation between CFT and TMV with visual acuity and contrast sensitivity in the TA and TALF groups. Visual acuity (logMar) p-value Contrast sensitivity (1 / contrast) r2 p-value TA-LF CFT TMV CFT TMV 0.04249 0.00008 0.1036 0.06301 0.3023 0.9629 0.0948 0.1976 0.01382 0.01236 0.1675 0.2605 0.854 0.5809 0.0306 0.0055 ινΐΛ / a / zuz i / ui 4uuu CFT; central foveal thickness, logMar: logarithm of the minimum angle of resolution; TA; triamcinolone acetonide group, TA-LF; liposome formulation containing 2 mg / ml of the TA group, TMV; total macular volume, w; week. Finally, TA-LF showed the best preventive action against CSME. The incidences of cystoid macular edema (CME) and clinically significant CME (CSME) in the TA group at 6 weeks were 3.7% and 22.2% respectively, while the incidences of these findings in the TA-LF group were, in contrast, 3.7% and 0% (Table 10). The odds of developing CSME were significantly higher in the TA group than in the TA-LF group (OR, 9.44; 95% CI, 1.76–50.66; P = 0.027). All patients with CSME in the TA group required rescue treatment (a topical combination of prednisolone 1% four times daily and nepafenac 0.1% three times daily for four weeks was considered when patients developed CSME during the course of the study). In conclusion, this study found that TA-loaded liposomes are effective for preventing FLACS-associated chronic glaucoma (CGM) and appear to have superior therapeutic activity compared to conventional topical steroid formulations. TA-LF use was associated with improved visual outcomes, such as visual acuity and contrast sensitivity. Table 10. Incidence of CGM and CSGM and odds ratios. 21 Value Parameter TA TA-LF OR (95 % Cl)* P Incidence Incidence n / N (%) n / N (%) CME within 6 w 1 / 27 (3.7) 1 / 28 (3.5) 1.038 (0.0617-17.48) 0.97 CME within 12 w 1 / 21 (4.7) 1 / 28 (3.5) 1.33 (0.078 - 22.57) 0.84 CSME within 6 w 6 / 27 (22.2) 0 / 28 (0) 9.44 (1.76 -50.66) 0.027 CSME within 12 w 0 / 21 (0) 0 / 28 (0) 1.325 (0.025 - 69.52) 0.88 Cl; confidence interval, CME; cystoid macular edema, CSME; ινΐΛ / a / zuz i / ui 4uuu clinically significant macular edema, OR; odds ratio, TA; triamcinolone acetonide group, TA-LF; Liposome formulation containing 2 mg / ml of the TA group. The probabilities of developing CME and CSME in the TA group are presented. Figure 1 represents the number of eyes randomized and analyzed. TA-LF demonstrated excellent results in the prevention of clinically significant macular edema (CSME). CSME was present in 6 / 27 cases in the triamcinolone (commercial product) group versus 0 / 27 cases in the TA-LF group. For cystoid macular edema (CME), both groups had 1 patient each. Liposome formulation containing 2 mg / ml of the TA group. Figure 2 shows initial and postoperative images of the ocular surface stained with fluorescein, and OCT images are presented in the TA and TA-LF groups. The 10 tomographic images in the TA group correspond to one of the six cases of CSME, while the tomographic images in the TA-LF group correspond to the single case of CME. As shown in the photographs, non-ocular surface adverse events were revealed by fluorescein staining at 6 weeks of follow-up in both groups.

Claims

1. An ophthalmic liposome formulation for topically administering comprising triamcinolone acetonide; a thermodynamically stable liposome in a weight percent of approximately 2-20% (w / v) and a non-ionic surfactant selected from a polyethylene glycol hydroxystearate in a weight percent of approximately 2-20%.

2. A thermodynamically stable liposome formulation comprising triamcinolone acetonide and a liposome comprising PEG-12 glyceryl dimyristate and a non-ionic surfactant wherein the formulation has a pH of between 5-6; a viscosity (cP) of between 60-80 and an osmolarity (mOsm / l) of between 300-350 and a PDI (polydispersity index) of between 0.350 and 0.380 nm.

3. An ophthalmic liposome formulation for topical administration according to claim 1 or 2 comprising: a) triamcinolone acetonide (TA) from 0.01% to 2.00% (w / v); b) polyethylene glycol (PEG-12) glyceryl dimyristate from 5-15% (w / v); c) ethyl alcohol from 0.7% to 2.1% (v / v); d) polyethylene glycol (15)-hydroxystearate (KolliphorHS 15) from 2.5-7.5% (w / v); e) anhydrous citric acid from 0.04-0.16% (w / v); f) dehydrated sodium citrate from 0.23-0.69% (w / v); g) benzalkonium chloride from 0.001-0.015% (w / v). h) Grade 2 purified water 4. A method for treating or preventing macular thickening or macular cysts in a patient in need, comprising administering a topical ophthalmic formulation comprising triamcinolone acetonide; a thermodynamically stable liposome in a weight percent of approximately 2-20% (w / v) and a non-ionic surfactant 28 selected from a polyethylene glycol hydroxystearate in a weight percent of approximately 2-20%.

5. The method according to claim 4, wherein the treatment is provided after manual cataract surgery or small manual incision procedures on the cataract and lens of said patient.

6. The method according to claim 4, wherein the treatment is provided after phacoemulsification of cataracts or the lens or after laser-assisted cataract or lens surgery.

7. The method according to claim 4 wherein such treatment results in the improvement of selected visual outcomes from the group consisting of visual acuity and contrast sensitivity after phacoemulsification of cataracts or lens or after laser-assisted cataract or lens surgery in said patient.

8. The method according to claim 4 wherein the treatment results in the improvement of the visual outcomes of said selected patients from the group consisting of visual acuity and contrast sensitivity after phacoemulsification of cataracts or lens, and after laser-assisted cataract or lens surgery.

9. A method for treating a patient undergoing cataract surgery with a topical ophthalmic formulation comprising triamcinolone acetonide; a thermodynamically stable liposome in a weight percent of approximately 2-20% (w / v) and a non-ionic surfactant selected from a polyethylene glycol hydroxystearate in a weight percent of approximately 2-20%.

10. The method according to claim 9 wherein said formulation has a pH of between 5-6; a viscosity (cP) of between 60-80 and an osmolarity (mOsm / l) of between 300-350 and a PDI (polydispersity index) of between 0.350 and 0.380 nm.