SURGERY

FIELD OF THE INVENTION

[0001] The application claims benefit of U.S. Provisional Patent Application Serial Number 62/848,907, filed on May 16, 2019 and U.S. Contlnuation-in-Pari Patent Application Serial Number 16/426,712, fi led on .May 30, 2019, which are all incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] The invention relates to triamcinolone acetonide-loailed liposomes topical ophthalmic formulations for prevention of macular thickening and its associated visual outcomes after Sens surgery

[0003] The most commonly performed ophthalmologic procedure in the world is lens surgery, with approximately20 million surgeries done in 2010 and estimated to reach 32 million by 2020. Phacoemulsification is the current preferred method wherein the lens material is softened using ultrasonic energy f emulsify) followed by extraction from the eye through irrigation and suction. Specific steps in conventional lens surgery through phacoemulsification include creating corneal incisions using a blade or fceratome, manually opening the anterior capsule (eapsnlotomy) using a forceps or bent needle, fragmenting the lens with ultrasonic energy and chopper instruments, suction of lens material, implantation of an intraocular lens (lOL) and finally aspiration and cleanup of viscoelasti c and retained lens cortical fragments. In recent years, the femtosecond laser has been utilized to perform the vital steps of corneal incision anterior eapsnlotomy and lens fragmentation. A femtosecond laser is an infrared laser (1053 am) that works by photodisruption wherein laser energy absorbed by the tissue induces rapid expansion, creating microcavitation bubbles and acoustic shock waves that cause morphological changes (1). [0004| Femtosecond laser-assisted cataract and lens surgery (FLACS) appears to improve outcomes and safety over conventional phacoemulsification. In a recent study comparing FLACS and conventional phacoemulsification, both had comparable refractive and visual results. However, FLACS had less phacoemulsification energy, postoperative anterior chamber inflammation and corneal endothelial cell loss (1 ).

[0005] Therefore, current fens surgery techniques significantly reduce postoperative complications. However, pseudophakie cystoid macular edema { PCME) (macular thickening that develops after implantation of an lOL) continues to be the most common cause of decreased central visual acuity (CVA) after a successful cataract and lens surgery. The incidence of clinical PCME, defined by symptomatic vision loss, is reported between 1.17- 4.04% (2), however the incidence of PCME diagnosed by optical coherence tomography (OCT) can be as high as 10.9% (3). Though, previous FLACS vs. phacoemulsification cataract surgery studies have demonstrated less increase in central macular thickness and reduced anterior chamber flare (4, 5) with FLACS, (6) PCME can still happen in FLACS. The reported prevalence of postoperative cystoid macular edema (CME) associated with FLACS is about 0.8% (7), and it could be comparable to some published rates of CME in conventional cataract phacoemulsification surgery (0.1% to 2.35%) (8, 9).

[0006] Onset of clinically significant PCME is commonly 4 to 12 weeks after surgery with its peak at 4 to 6 weeks. The typical complaint is of impaired central vision following an initial postoperative period of improvement(l 0). Numerous risk factors have been associated with PCME occurrence, like systemic diseases including diabetes mellitus (2, 1 1), YAG capsuiotomy or preexisting conditions; as uveitis (2, 12), use of topical prostaglandin analogs(13, 14), trauma(l$), and intra-operative complications ( 16, 17).

[0007] The ideal treatment to prevent PCME has not been established. However, corticosteroids and topical nonsteroidal anti-inflammatory drugs (MSAIDs), either as monotherapy or in combination have proven to be useful (18-21 ), and are broadly used as first-line drugs (22). For instance, in a retrospective study for the prevention of PCME (defined as new or worsening of anatomic macular edema or thickening demonstrated by OCT), the postoperative rates of macular edema in patients receiving prednisolone acetate 1% and dexamethasone sodium phosphate 0.1% were 4 0% and 4 1% respectively (20). [0008] Recently, a topical triamcinolone acetonide-loaded liposomes formulation (TA-LF) was used to efficaciously deliver triamcinolone (TA) into vitreous and retina of rabbits (23) and its therapeutic efficiency was verified in patients with refractory PCME(24). Liposomes- based eye drops have been proposed as a drug delivery system into the posterior segment of the eye, and they have the potential to deliver drugs like TA in therapeutic concentrations to the vitreous cavity and retina (23) Liposomes (LPs) are particles composed of an aqueous core and delimited by a membrane-like lipid bilayer that works as carriers for water-soluble, lipid-soluble and amphiphilic drugs (25-28). LPs are non-toxic low antigenic, easily metabolized and biodegradable (29) and they have been employed to improve drug transport and bioavai lability in ocular tissues (30, 31).

SUMMARY OF THE INVENTION

[0009] The compositions of the present invention (a formulation) comprise a combi nation of triamcinolone aeetonide as die active pharmaceutical ingredient, polyethylene glycol (PEG- 12) glyceryl dimyristate as structural constituent of liposomes, ethyl alcohol as organic solvent for liposomes generation, koifiphor HS 15 as penetration enhancer, citric add anhydrous and sodium citrate dehydrate as buffers, henzalfconium chloride as preservative, and grade 2 purified water as inorganic solvent. Other suitable formulations are disclosed in U.S. Pat. Pub. 2015/0224055 which is hereby incorporated by reference in its entirety.

[0010] The formulations of the present invention ate useful for prevention of macular thickening and its associated visual outcomes after lens surgery, such as; visual acuity and contrast sensitivity.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. I shows a flow diagram representing the number of eyes randomized and analyzed, and shows TA-LF treatment provided significant results in preventing CSME (clinically significant macular edema). CSME was present in 6/27 cases of treatment with a. non-!iposomal commercial triamcinolone product versus 0/27 cases in the treatment arm with TA-LF (formulation 2) [0012] FIG. 2 shows Baseline a»d post-operative images of fluorescein eye surface staining and OCT images in the TA and TA-I.F groups. The tomographic images in the T A Group correspond to one of the six cases of CSME whereas the tomographic images in the TA-LF group showed only one case of CSME.

[0013] FIG 3 shows corneal endothelial ceil density analysis in healthy subjects treated with triamcinolone aeetoiiMe loaded liposomes formulation.

DETAILED DESCRIPTION OE THE INVENTION

[0014] The present in vention relates to topical ophthalmic formulations suitable for the treatment of conditions which occur in association with lens surgeries. In particular, the inventors have discovered a use of a topical ophthalmic liposomal formulation developed for the treatment of posterior segment diseases of the eye. The present invention relates to the further discovery that this formulation is particularly useful for the treatment of patients that Slave undergone cataract surgeries.

[0015] The compositions of the present invention contain a pharmaceutically effective amount of triamcinolone aeetonide (TA). The concentration of TA in liposomes formulations ranges front 0.01 to 2.00% (w/v).TA is a known synthetic corticosteroid with an empirical formula of C24H31FO _& and a molecular weight of 434.50 Da TA has a powerful antiinflammatory activity (7.5 times more potent than eortisone}(32). Polyethylene glycol (PEG- 12) glyceryl dim yri state is used as structural constituent of liposomes in a concentration of 5-15% (w/v) and ethyl alcohol is used as organic solvent for liposomes generation in a concentration of 0.7 to 2.1% (v/v),

[0016] Besides, the liposomes formulation contain polyethylene glycol (15)~hydroxystearate or KoiliphorHS 15 from 2 5 - 7.5% (w/v), as a potent non-ionic solubilizer and emulsifying agent, with low toxicity proposed to act as a permeability enhancer. KoiliphorHS 15 promotes drug transport across ceil membranes (increasing the endocytosis rate) andstimulates drug translocation through the paraceHukr route (affects actin organization on the cell eytoskeleton with the subsequent tight junction opening)(33). [0017] Additionally, the aqueous compositions of the present invention optionally comprise more excipients selected fro® the group consisting of buffering agents, pH-adjusting agents, and preservatives. Citric acid anhydrous (0.04 - 0.16%) and sodium citrate dehydrate (0.23 - 0.69%) are used as buffers, whereas benzalkomum chloride (0 00! - 0.015%) as preservative. All of these compounds in units of % w/v. The pH can range front about 5 to about 7.5.

[0018] Ingredient concentrations are presented in units of % weight/volume (% w/v) or % volume/volume (% v/v).

[0019] The compositions of the present invention may be prepared by conventional methods of preparing pharmaceutical suspension compositions. According to the preferred method, the drag (triamcinolone acetonide) is first added to a lipid mixture containing polyethylene glycol (PEG- 12) glyceryl dimyri state and ethyl alcohol. An aqueous mixture having grade 2 purified water, polyethylene glycol ( 15)~hydroxysiearate (KolIiphorHS 15), citric acid anhydrous, sodium citrate dehydrate and benzalkonium chloride was commingled in a flask and set aside for compounding. The water mixture is gently added to the lipid mixture to obtain the final formulation.

[0020] The following examples are intended to illustrate, but not limit, the present invention ECLMRί£ 1

[0021] The formulations shown below are representative of the compositions of the present invention.

[0022] The formulations shown in Table 1 were prepared and subjected to aphysicochemical characterization. pH of TA-FL was analyzed by a pH meter in triplicate at room temperature. OsmoSarlty was measured by a vapor pressure osmometer and performed in triplicate at 33°C (the ocular surface temperature)(34). Viscosity was measured also in triplicate at 33°C Viscosity was measured using a thermostatically controlled rheometer when the steady state was reached with shear rates increasing from 0 to 1000 s-I Particle size of the TA -LFs was analyzed by means of Dynamic Light Scattering and zeta potential (z) was calculated by measuring the velocity of the particles using Laser Doppler Veiocimetry at 25 ^e C (Zetasizer Nano ZS, Malvern Instruments, Malvern, UK). The Z-average (mean particle diameter) and polydispersity index (FDi) were calculated from the particle size distribution.

[0023] Posteriorly, TA-LF front example 1 was evaluated in an in vitro diffusion assay. Diffusion chambers and rabbit corneas were used to conduct diffusion experiments (CbeniQtaxis Chambers BW200S, NeuroProbe, Gaithersburg, MD, USA) Rabbit corneas from New Zealand white rabbits were used for this experiment The central corneal tissue was located between the top and botom compartments of the diffusion chambers to act as a TA diffusion barrier. The top compartment was rilled with 180 mΐ of balanced salt solution (ESS) while the bottom compartment was filled with 200 mΐ of TA-LFs (TA-LF1 to TA- LF4). To avoid evaporation, the diffusion chambers were located into a 37°C humidity camera. The TA concentration analysis of solutions obtained from the top compartment at 2, 4, 6 and 8 hours (h) after starting the diffusion assay, was performed by high performance liquid chromatography (HPLC) HPLC was performed using a Yarian 920 LC (A!igent Technologies, Santa Clara, CA, USA) with a Zorbax Eclipse Pins€18, 4 6 x 100 mm and 3.5-prn column (Agilent, Santa Clara, CA, USA) at 30°C. The samples (20 mI) were eluted from the column in a mobile phase comprised of water: methanol (30:70) at a flow rate of 1 ml/min. Detection was performed at 254 am. Retention time and detection limit were 6.8 min and 0.004 mg/ml respectively. The TA standard curve was linear from 0.004 to 0.100 mg/ml (correlative >0.99). In vitreous, concentrations of TA were determined for the recovery and intra- and inter-day reproducibility(35}

[0024] Result from the in vitro diffusion assay is exposed in table 3.

[0025| We observed that TA-LF presented a satisfactory diffusion performance, reaching the highest TA concentrations after 8 hours of follow up.

[0026] After in vitro assays and in vivo diffusion analysis of and tolerability assessment of TA-LF was performed in rabbits for diffusion analysis, concentrations of TA were determined by HPLC in ocular tissues from New Zealand white rabbits after multiple doses of TA-LF2. For tolerability assessment, eye examination of study animals was performed after topical administration of TA-LF The protocol for animals was the following. Rabbits were randomly distributed into four groups. One-drop TA-LF2 solution (50 mΐ) was applied to one eye every two hours (7 times during 14 days. Five rabbits were sacrificed after starting the instillation of TA-LF2 at 12 hours, 1, 7 and 14 days. Before tissue collecting, an eye examination was performed under anesthesia (intramuscular injection of ketamine hydrochloride 30 mg/kg and chioipromazine hydrochloride 15 mg/kg). This evaluation included slit-lamp btomicroscopy, fluorescein staining, funduscopy with direct ophthalmoscope, and intraocular pressure (IOP) measurement (iCare Tonometer 1350, Vaniaa, Finland). Additionally, ocular irritability test was evaluated according to pharmacopeia of Estados Unidos Mexicanos. A positive irritant reaction is considered when more than one rabbit presented: come! ulceration revealed by fluorescein staining, corneal opacity , iris or conjuncti val inflammation and dilatation of conjunctiva! vessels especially around the cornea. After enucleation, conjuncti va, cornea, retina, 150 mΐ of aqueous humor and 200 mΐ of vitreous were collected. The solid tissues were washed in PBS . Then, tissues were homogenized with 0.3 ml of acetonitrile (Sigma-Aldrich, Mexico). Posteriorly, each sample was centrifuged at 15,294* g for 5 min. The supernatants were evaporated to add 100 mί of methanol. Another centrifugation was performed and 20 m{ of the resultant supernatants were used for analysis of TA concentration by HPLC, performed as previously described.

[0027] The concentrations of ^' TA in retina and vitreous reached the highest peak at 12 hours (252.1 ± 90.00 ng/g and 32.6 ± 30.27 ng/g respectively) to subsequently decline to 24.0 ± 1 1 72 ng/g and 19 5 ± 13 14 ng/g respectively at 14 days of follow up TA concentration vs time in different ocular tissues are presented in Fig. 1 and Table 4.

[0028] Compaitmental and non-coinpartniental inode! were used to determine pharmacokinetics of TA-loaded liposomes in ocular tissues. Linear-trapezoidal method was employed to evaluate the area under the curve (AUC) The half-life (ti.rf was calculated by fineai· regression of the concentration at different times, Pharmacokinetic parameters are shown in table 5.

[0029] C _nm . was 215b 07 ± 1055.41 ng/g in cornea, 1886,33 ± 398.95 ng/g in conjunctiva, 9.9 ± 1.95 ng/g in aqueous humor, 83.3 ± 30.49 ng/g in lens, 32,6 ± 10.27 ng/g in vitreous and 252 10 ± 90.00 ng/g in retina.

[0030] Related to tolerability assessment; no Increase in intraocular pressure was observed in any of the study animals (normal intraocular pressure in litis rabbits is 12-28 ntmHg). Staining with fluorescein sodium and bengal rose showed superficial punctate keratitis in the first 6 hours after instillation of the formulation. This condition was resolved in all cases in the examination at 12 hours after the admini stration of the formulation. Therefore, according to pharmacopeia of Estados Unidos Mexicanos, ocular irritability test was satisfactory, and TA-LF2 is considered nonirritant. [0031] Finally, therapeutic activity of TA-LF was proved in humans. In three clinical trials (phase 0, phase I, and phase 11) the evaluation of tolerability, safety and efficacy of a topical TA-LF was performed.

Clinical {rial Phase 0

[0032] This study was performed to report tolerability, safety and efficacy of a topical triamcinolone acetonide-loaded liposomes formulation (TA-LF) to target the macular area in patients with refractory pseudophakic eystoid macular edema (PCME). For tolerability, safety and efficacy evaluation, 12 eyes of 12 patients with refractory PCME were exposed to one drop of TA-LF (TA at 0.2%) every two hours for 90 days or un til best-corrected visual acuity (BCVA) was achieved. Intraocular pressure (IOP), slit lamp examination and central fovea! thickness (CFT) were analyzed at every visit. Patients with refractory PCME under TA-LF therapy showed a significant improvement of BVCA and CFT without significant IOP modification (P~ 0.94). On average CFT decreases 184 ± 113.82 pm and BCVA improves 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 nor adverse events were recorded. 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 on patients with refractory PCME. The results of this clinical trial were recently published (24).

Clinical trial Phase /

[0033] This study was performed to report tolerability, safety and efficacy of a topical triamcinolone acetomde- loaded liposomes formulation (TA-LF) in healthy subjects, with no ocular nor systemic disease. They received the TA-LF and were instructed to apply one drop every two hours in the right eye, while awake (six times), for 2 weeks. Demographic and baseline clinical exams were collected on day 14 to I before starting the administration of TA-LF. Retinal optical coherence tomography (OCT) was performed at baseline (to confirm no CME by OCT) and every week until the end of the follow-up. BCVA using the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart at 4 m, slit lamp evaluation of the eye surface with fluorescein 2% staining and posterior segment findings were recorded on every visit. Subjects were withdrawn from the study if they presented any evidence of poor tolerability (any adverse event related to the use of the topical formulation). Tolerability was assessed through collection and summary of ocu lar and non -ocular adverse events (AEs), serious AEs (SAEs), ocular assessments and vital signs, whether volunteered by the patient, discovered by study site personnel during questioning, or other means. Subjects were withdrawn if they presented any evidence of poor tolerability or any adverse event such as cornea! ulcers, cornea! opacities, epithelial defects, anterior chamber inflammation (cell/flare) and conjunctival and/or epiescleral injection related to the use of this topical formulation. AEs were assigned standard codes terms for the event based upon the MedDRA Coding dictionary version 18.1.

[0034] Other ocular examinations included, contrast sensitivity (CS) evaluated by the Pe!li- 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 Stramenti Oftalmici, Firenze, Italy)

[0035] TA-LF was well tolerated in healthy subjects. Twenty right eyes of 20 healthy subjects (38.45 ± 9.06 years old, female; 45%, male; 55%) without evidence of systemic or eye disease were enrolled to evaluate tolerability of the TA-LF. These subjects were instructed to apply one drop of TA-LF every two hours in the right eye, while they were awake (six times), during 2 weeks. Demographic and baseline clinical characteristics of these subjects are summarized in Table 7. in data analysis, no AEs were reported. OCT showed no significant change in CFT as compared with baseline (CFT change of 0.85 ·±· 0.29 pm). BCVA did not have a significant change in all 20 patients (average change of -0.01 a- 0.16 ETDRS letters). Interestingly, CS presented a minimum 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 significant increase in IOP during the treatment period. None of the patients were excluded from the study due AEs. Clinical characteristics after TA-LF treatment in healthy subjects are summarized in Table 7.

[0036] Additionally, no subconjunctival hemorrhages were repotted in this study. Ocular surface staining _* which was graded as 0 (no changes) or 1 (mild Changes) in most cases was transient and considered clinically nonsignificant by the investigator. No pathological changes of the anterior eye chamber or lens were reported. No vitreous cells nor flares were observed. Retina structures appeared normal prior to and after dosing. Endothelial cell density and retina thickness were unaffected (2976.2 ± 414.21 cells/mm ² vs 3036.7 ± 377.25 cells/mm ² ) (Fig. 2). No clinically relevant changes in vital signs parameters were observed. TALF eye drops did not affect blood pressure or pulse rate. No local or systemic findings required TALF to be stopped.

[0037] FIG 3 A and B show corneal endothelial cell density analysis in healthy subjects treated with triamcinolone acetonide loaded liposomes formulation. A. Images of specular microscopy of a representative case at baseline and after 14 days of TALF instillation are presented. B. Column bar graph from cECD analysis is presented. Non-significant difference on cECD values was stabiished between baseline and after 14 days of TALF instillation cECD; comeal endothelial cell density, TALF; triamcinolone acetonide loaded liposomes formulation.

Clinical trial Phase P

[0038] The aim of this assay is to explore tolerability, safety and efficacy of a topical triamcinolone acetonide-loaded liposomes formulation (TA-LF) to prevent Clinical significant pseudophaldc cystoid macular edema (CSME) after femtosecond laser-assisted cataract surgery (FLAGS). Fifty-five eyes of 32 patients underwent FLAGS were enrolled. Twenty-seven eyes were assigned to TA group whereas twenty-eight eyes were assigned to TA-LF group. In TA group, eyes were exposed to a conventional topical formulation of triamcinolone acetonide 0 1% for 23 days postoperatively whereas patients in the TA-LF group received a liposomal formulation containing 2 mg/ml of TA (0.2%). A follow up consisting of slit lamp examination visual acuity, contrast sensitivity' central foveal thickness (CFT) and total macular volume (TMV) (both measured by retinal optical coherence tomography) was performed. Study visits were scheduled at I day, 6 and 32 weeks after surgery. Related to tolerability and safety outcomes, TA-LF was well tolerated during the study period. Neither ocular (increased intra-ocular pressure, ocular surface abnormalities) nor systemic adverse events were repotted. None of the patients required ΪOR lowering drugs. None of the patients showed signs of irritation or surface problems due to the study formulation application until the end of the study. On the other hand, only TA-LF group shown a significant improvement in contrast sensitivity (basal value; 1.087 ± 0.339 vs week 12; 1.266 ± 0.147) and visual acuity front the preoperative measures (basal value; 0.252 ± 0.248 vs week 12; 0.005 ± 0.136). Table 8 summarized the analysis of variables within groups.

[0039] Remarkably, CFT and TMV correlate significantly with contrast sensitivity only in TA-LF group. The r ² for CFT and contrast sensitivity was 0.1675 (P ^:::: §.0306) whereas the r* for TMV and contrast sensitivity was 0 1675 (P=O.0055) (Table 9). fable 9. Correlation between CFT and TMV with visual acuity and contrast sensitivity in TA and TALF groups.

10040] Lastly, TA-LF shown the best prevents ve action tor GSME. The incidences of cystoid macular edema (CME) and clinical significant CME (CSME) in TA group at 6 weeks were 3.7% and 22.2% respectively, whereas the incidences of these findings in the TA-LF group were in contrast 3 7% and 0% (Table 10)

[0041] The odds of developing CSME were significantly higher in the TA group than in TA- LF group (OR, 9.44; 93% Cl, 1.76 -50.66; F ^::: 0.027). All patients with CSME in the TA group required rescue treatment (a topical combination of prednisolone I % 4 times daily and nepafenac 0.1 % 3 times daily tor 4 weeks was considered when patients developed CSME during the course of the study).

[0042] In conclusion of this study, TA-!oaded Liposomal formulation is effective for the prevention of CSME associated with FLAGS and it seems that its therapeutic activity could be superior to the activity of conventional topical steroids formulation. The use of TA-LF was related to better visual outcomes like visual acuity and contrast sensitivity.

Table 10. Incidence of CME and CSME and Odds Ratio values.

Odds of developing CMF and CSME n the TA g oup am presented.

[0043] FIG. 1 represents the number of eyes randomized and analyzed. TA-LF showed excellent results preventing CSME (clinically significant macular edema), CSME (clinically significant macular edema) was present In 6/27 eases of triamcinolone (commercial product) vs. 0/27 eases with TA-LF. For CME (Cystoid macular edema) both groups have Ί patient each. Liposomal formulation containing 2 tng/ml of TA group.

[0044] FIG. 2 represents Baseline and post-operative images of fluorescein eye surface staining and OCT images in the TA and TA-LF groups are presented. The tomographic images in TA group correspond to one of the six cases of CSME, whereas the tomographic images in the TA-LF group correspond to the only case of CME. As shown in the photographs, non-ocular surface adverse events were revealed by fluorescein stain at 6 weeks of follow-up in any group.

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