Influence of PLGA End Groups on the Release Profile of Dexamethasone from Ocular Implants.

The present study deals with the development of dexamethasone (DM)-loaded implants using ester end-capped Resomer RG 502 poly(lactic acid-co-glycolic acid) (PLGA) (502), acid end-capped Resomer RG 502H PLGA (502H), and a 502H:502 mixture (3:1) via hot melt extrusion (HME). The prepared intravitreal implants (20 and 40% DM loaded in each PLGA) were thoroughly investigated to determine the effect of different end-capped PLGA and drug loading on the long-term release profile of DM. The implants were characterized for solid-state active pharmaceutical ingredient (APIs) using DSC and SWAXS, water uptake during stability study, the crystal size of API in the implant matrix using hot-stage polarized light microscopy, and in vitro release profile. The kinetics of PLGA release was thoroughly investigated using quantitative 1H NMR spectroscopy. The polymorph of DM crystal was found to remain unchanged after the extrusion and stability study. However, around 3 times reduction in API particle size was observed after the HME process. The morphology and content uniformity of the RT-stored samples were found to be comparable to the initial implant samples. Interestingly, the samples (mainly 502H) stored at 40 °C and 75% RH for 30 d demonstrated marked deformation and a change in content uniformity. The rate of DM release was higher in the case of 502H samples with a higher drug loading (40% w/w). Furthermore, a simple digital in vitro DM release profile derived for the formulation containing a 3:1 ratio of 502H and 502 was comparable with the experimental release profile of the respective polymer mixture formulation. The temporal development of pores and/or voids in the course of drug dissolution, evaluated using µCT, was found to be a precursor for the PLGA release. Overall, the release profile of DM was found to be dependent on the PLGA type (independent of subtle changes in the formulation mass and diameter). However, the extent of release was found to be dependent on DM loading. Thus, the present investigation led to a thorough understanding of the physicochemical properties of different end-capped PLGAs and the underlying formulation microstructure on the release profile of a crystalline water-insoluble drug, DM, from the PLGA-based implant.

Early-switch versus late-switch in patients with diabetic macular edema: a cost-effectiveness study.

BACKGROUND: To evaluate the cost-effectiveness of early- versus late-switch to the intravitreal-dexamethasone implant (DEX-i) in patients with diabetic macular edema (DME) who did not adequately respond to vascular endothelial growth factor inhibitors (anti-VEGF). METHODS: Retrospective analysis of a multicenter Clinical Data Registry. The registry included DME eyes who received 3 intravitreal anti-VEGF injections (early-switch) or > 3 intravitreal anti-VEGF injections (late-switch) before switching to DEX-i injections. The primary outcome was to estimate the incremental cost needed to obtain a best-corrected visual acuity (BCVA) improvement ≥ 0.1 or a central-retinal thickness CRT ≤ 250 µm. RESULTS: The analysis included 108 eyes, 32 (29.6%) and 76 (70.4%) in the early- and late-switch groups, respectively. Early-switch strategy was associated with a cost saving of €3,057.8; 95% CI: €2,406.4-3,928.4, p < 0.0001). Regarding incremental-cost-effectiveness ratio, late-switch group was associated with an incremental cost of €25,735.2 and €13,533.2 for achieving a BCVA improvement ≥ 0.1 at month 12 and at any of the time-point measured, respectively. At month 12, 38 (35.2%) eyes achieved a BCVA improvement ≥ 0.1. At month 12, 52 (48.1) eyes had achieved a CRT ≤ 250 micron. As compared to baseline, the mean (95% CI) CRT reduction was - 163.1 (- 212.5 to - 113.7) µm and - 161.6 (- 183.8 to - 139.3) µm in the early-switch and late-switch groups, respectively, p = 0.9463. CONCLUSIONS: In DME eyes, who did not adequately respond to anti-VEGF, switching to DEX-i at early stages (after the first 3-monthly injections) was found to be more cost-effective than extending the treatment to 6-monthly injections of anti-VEGF.

Effectiveness and safety of fluocinolone acetonide intravitreal implant in diabetic macular edema patients considered insufficiently responsive to available therapies (REACT): a prospective, non-randomized, and multicenter study.

OBJECTIVE: To assess the effectiveness and safety of the intravitreal fluocinolone-acetonide implant (FAc-i) in patients with chronic diabetic macular edema who did not sufficiently respond to other available therapies. METHODS: This was a multicenter, prospective, non-randomized, and phase-IV observational study conducted on patients with recurrent-DME who were insufficient responders to currently available therapies (REACT-Study). The primary end-point was the mean change in best-corrected-visual-acuity from baseline to month-24 values. RESULTS: Thirty-one eyes from 31 patients were included in the study. Mean age was 68.0 ± 7.7 years, and 10 (32.3%) were women. Study patients had received 5.3 ± 7.3 previous DME treatments before starting the study. In the overall study sample, BCVA improved from 56.1 ± 12.3 letters at baseline to 62.4 ± 17.0 letters at month-24 (p = 0.0510). The eyes with a baseline BCVA < 70 ETDRS letters had a significant improvement in BCVA from 53.2 ± 10.2 letters at baseline to 61.5 ± 17.9 letters at month-24 (p = 0.0165). In the overall study population, central-subfoveal-thickness (CST) was significantly reduced from 474.0 ± 135.1 µm at baseline to 333.4 ± 135.6 at month-24 (p < 0.0001). Similarly, macular-volume (MV) was significantly reduced from 10.7 ± 2.7 mm3 at baseline to 9.6 ± 2.9 mm3 (p = 0.0027) at month-24. Among the 31 study eyes, 19 (61.3%) required an additional treatment for DME. Throughout the study, 9 (29.0%) eyes required ocular hypotensive medication for controlling their intraocular-pressure and 5 (16.1%) eyes underwent cataract surgery. CONCLUSIONS: In DME eyes who did not sufficiently respond to previous therapies, the FAc-i was associated with an improvement in visual and anatomic outcomes. There were no unexpected adverse-events. TRIAL REGISTRATION NUMBER: EudraCT identifier: 2016-001680-37.

Three-Year Safety and Efficacy of the 0.19-mg Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: The PALADIN Study.

PURPOSE: To assess the long-term safety and efficacy of the 0.19-mg fluocinolone acetonide (FAc) intravitreal implant (Iluvien; Alimera Sciences, Inc) in patients with diabetic macular edema (DME). DESIGN: Three-year, phase 4, nonrandomized, open-label observational study. PARTICIPANTS: Patients with DME who previously received corticosteroid treatment without a clinically significant rise in intraocular pressure (IOP; all eyes, n = 202 eyes of 159 patients; 36-month completion, n = 94 eyes). METHODS: A prospective, observational study in which patients received a 0.19-mg FAc intravitreal implant at baseline and then were observed for safety-, visual-, anatomic-, and treatment burden-related outcomes for up to 36 months. MAIN OUTCOME MEASURES: Primary safety outcomes included changes in IOP and interventions to manage IOP elevations. Secondary outcomes included changes in best-corrected visual acuity (BCVA), central subfield thickness (CST), and adjunctive DME treatment frequency RESULTS: At 36 months after FAc implantation, study eyes showed a mean CST change of -60.69 µm (P < 0.0001) and a mean BCVA change of +3.61 letters (P = 0.0222) compared with baseline. Overall median treatment frequency decreased from 3.4 treatments/year in the 36 months before FAc implantation to 1 treatment/year in the 36 months after FAc implant, a treatment burden reduction of 70.5%. Furthermore, among the group that completed 36 months of treatment (n = 94 eyes), 25.53% of eyes remained rescue free through 36 months. Mean IOP remained stable throughout the study, and IOP increases to more than 30 mmHg occurred in 10.89% of eyes. Intraocular pressure-related procedures were infrequent, with a surgical rate of 2.97%, with 1.49% attributable to steroid use (vs. surgeries attributable primarily to neovascular glaucoma). In addition, an IOP response of < 25 mmHg after the steroid challenge predicted that 96.92% of eyes would have a similar outcome to 0.19-mg FAc implant at the last visit. Intraocular pressure increases that did occur were manageable with standard treatments (n = 202 eyes). CONCLUSIONS: In patients with DME, the 0.19-mg FAc implant provided improved visual outcomes and reduced treatment burden compared with previous treatments while maintaining a favorable safety profile.

Use of selective laser trabeculoplasty as an alternative in patients who developed ocular hypertension after intravitreal dexamethasone implants: a series of 35 eyes.

PURPOSE: Steroid-induced ocular hypertension (OHT) occurs in about a third of cases after dexamethasone implant (DEXi) intravitreal injection (IVI), for which treatment discontinuation may be required. The aim of this study was to assess the benefit of selective laser trabeculoplasty (SLT) in patients who developed transient OHT after DEXi injection to prevent subsequent steroid-induced OHT peaks during reinjections. METHODS: A real-life, retrospective, and observational study was conducted to assess the intraocular pressure (IOP) after SLT in steroid responders after DEXi injection (IOP > 21 mmHg). Were analyzed: IOP 1 and 2 months after SLT, maximum IOP (IOPmax) after each new DEXi IVI, and the number of prophylactic hypotensive treatments needed at the time of DEXi reinjections. RESULTS: Thirty-five eyes of 29 patients were included. The mean macular edema follow-up duration was 38.4 ± 28.4 months. SLT was performed after a mean number of 6.3 ± 4.7 DEXi IVIs. After SLT, the IOPmax measured after the first reinjection was lowered by 36.6 ± 14.7% (p < 0.0001). The mean number of hypotensive treatments was 2.1 ± 0.9 before versus 1.5 ± 0.8 after SLT. The post-reinjection lowering in OHT peak was maintained during the subsequent 3 DEXi IVIs: - 29.1 ± 25.5% (p = 0.0009), - 35.8 ± 13.1% (p = 0.0078), and - 45.4 ± 8.6% (p = 0.0312) after the second, third, and fourth DEXi reinjections. SLT allowed continuing injections in 88.6% of patients. CONCLUSION: The use of 180° SLT in this indication could be an effective therapeutic alternative to control steroid-induced OHT and safely continue DEXi injections.

Effect of Extended Release Steroid Implants on the Contralateral Eye.

PURPOSE: To investigate the contralateral effect of extended release steroid implants on cystoid macular edema (CME). METHODS: Retrospective study of patients with bilateral CME receiving intravitreal injections of long-acting intravitreal corticosteroid implants in one eye. Changes in CME and central subfield thickness (CST) in the contralateral eye on optical coherence tomography (OCT) were compared to an untreated control group. The main outcome measures were the change in central subfield thickness (CST) and the change in the macular volume. RESULTS: Thirteen study patients and 14 controls were included in the study. There was no difference in the baseline LogMAR visual acuity (0.32 ± 0.35 vs 0.43 ± 0.26, p = 0.37) or the baseline central subfield thickness (341.4 ± 76.6 vs 296.5 ± 65.0 µm, p = 0.12) between groups. In the treatment group CST remained stable in 92.3% of the patients. Of the controls, CST worsened in 21.4% and remained stable in 78.6%. The mean change in CST (6.3 ± 30.3 vs. 27.5 ± 66.1 µm, p = 0.2) and the mean change in macular volume (0.08 ± 0.34 vs. -0.05 ± 0.21 mm3, P = 0.8) were not statistically different between the treatment group and control group. In the post-hoc analysis restricting the treatment group to patients who had not received intravitreal injections in the study eye within 6 months, CST decrement was not statistically significant (p = 0.11). CONCLUSION: In this study there was no statistically significant effect on CME of contralateral intravitreal corticosteroid implants.

Dexamethasone implant improves anatomic response to anti-VEGF therapy in treatment-resistant polypoidal choroidal vasculopathy.

BACKGROUND: A significant proportion of eyes with polypoidal choroidal vasculopathy (PCV) can be resistant to anti-vascular endothelial growth factor (VEGF) injections. We evaluated the efficacy of a combination of dexamethasone intravitreal implant (DXI) and anti-VEGF therapy in eyes resistant to anti-VEGF monotherapy. METHODS: In this retrospective study, patients with PCV resistant to anti-VEGF injections were additionally injected with a DXI along with an anti-VEGF agent. Best-corrected visual acuity (BCVA), slit-lamp examination, fundus evaluation, and optical coherence tomography (OCT) data were analyzed. Anatomical response on OCT was the primary outcome measure. Change in visual acuity and injection-free interval after DXI were evaluated as secondary outcome measures. RESULTS: Twelve eyes of 11 patients were included in the study. Mean age of patients at presentation was 64.7 ± 9.5 years (range, 49-78.8 years), and there were seven females (63.6%). Median number of anti-VEGF injections prior to DXI was 4 (interquartile range IQR, 3-7). Median follow-up duration after DXI was 32.2 months (IQR, 6.6-41.6 months). Median logMAR BCVA immediately prior to DXI was 0.41 (IQR, 0.30-0.88) and after injection was 0.40 (IQR, 0.30-1.05), which was not significantly different (p = 0.85). Median Central Retinal Thickness (CRT) after DXI was 305.5 µm (IQR, 249-409 µm), which was significantly (p = 0.003) lesser than pre-injection thickness of 547 µm (IQR, 431-771 µm). Median injection-free interval in these eyes after DXI was 5 months (IQR, 2.8-6.4 months). Kaplan-Meier estimates of first injection after DXI were 27.3% at 3 months, 67.3% at 6 months, and 89.1% at 12 months. CONCLUSIONS: Dexamethasone implant combined with anti-VEGF treatment can prolong the treatment-free interval in eyes with PCV resistant to anti-VEGF injection while maintaining visual acuity.

Risk factors for repeated dexamethasone intravitreal implant therapy for macular edema due to treatment-naïve branch retinal vein occlusion.

BACKGROUND: This study evaluated the effects of dexamethasone intravitreal implant on treatment-naïve branch retinal vein occlusion (BRVO)-induced macular edema (ME), and the risk factors for earlier repeated treatment. METHODS: Patients treated from 2013 to 2016 were enrolled. The patients' demographics, medical history, best-corrected visual acuity (BCVA), and central retinal thickness (CRT) were recorded. Risk factors for repeated treatment were identified using a Cox proportional hazard model and logistic regression. RESULTS: 29 patients (mean age: 58.64 ± 13.3 years) were included; 44.8% received only one injection, while 55.2% received two or more. The mean initial CRT was 457.8 ± 167.1 µm; the peak CRT and final CRT improved significantly to 248.9 ± 57.9 µm and 329.2 ± 115.1 µm, respectively. The peak BCVA improvement and final improvement were 29.5 ± 23.5 approximate ETDRS letters and 19.8 ± 24.4 letters, respectively, with 62.1% of patients improving by more than 15 letters. Older age, higher initial CRT, and diabetes were the risk factors for multiple injections. CONCLUSION: Dexamethasone intravitreal implant results in significant peak CRT and BCVA improvements, while older age, higher initial CRT, and diabetes are risk factors for repeated injections. The optimal retreatment schedule for these patients should be further explored.

Effect of Dexamethasone Intravitreal Implant on Visual Acuity and Foveal Photoreceptor Integrity in Macular Edema Secondary to Retinal Vascular Disease.

PURPOSE: The aim of this study was to evaluate the effect of the dexamethasone intravitreal (DEX) implant on the external limiting membrane (ELM) and ellipsoid zone (EZ) integrity in treatment-naïve patients with macular edema (ME) secondary to retinal vascular disease (RVD). METHODS: This is a retrospective study conducted on patients with ME secondary to RVD, who underwent a DEX implant. RESULTS: One-hundred eyes were included. Mean age was 70.3 ± 11.1 years. Mean ELM integrity significantly improved from 1,575.9 ± 285.9 µm at baseline to 1,711.7 ± 244.0 µm at month 3 (p < 0.0001). Similarly, there was a significant improvement in EZ integrity from baseline to month 3 (1,531.5 ± 317.1 vs. 1,694.3 ± 252.8 µm, respectively, p < 0.0001). At month 3, mean visual acuity (VA) gain was 9.9 ± 14.1 letters (p < 0.0001). Mean central retinal thickness (CRT) significantly decreased by -193.2 ± 185.7 µm from baseline to month 3 (p < 0.0001). Mean changes in VA and CRT were significantly correlated with baseline ELM integrity (p = 0.0065 and p = 0.0046, respectively) and EZ integrity (p = 0.0300 and p = 0.0035, respectively). At month 3, the proportion of eyes which had an intact ELM (mean difference 16.0%, 95% CI 5.4-26.4%, p = 0.0033) and EZ (mean difference 12.0%, 95% CI 1.8-22.1%, p = 0.0210) was significantly higher than at baseline. CONCLUSIONS: DEX implant was able to significantly improve ELM and EZ integrity in naïve patients with ME.

Sirolimus-Loaded Intravitreal Implant for Effective Treatment of Experimental Uveitis.

Non-infectious uveitis, an ocular inflammatory condition that affects the iris, ciliary body, choroid, and adjacent tissues (retina, optic nerve, and vitreous), is an important cause of blindness worldwide. Sirolimus (SRL), a potent immunomodulatory drug, has shown promising results in the treatment of inflammatory ocular diseases. Despite this therapeutic potential, its clinical use is a major challenge due to low bioavailability and poor solubility. Poly(lactic-co-glycolic acid) (PLGA) is a biodegradable polymer commonly used for ophthalmic drug delivery due to its suitable characteristics such as biocompatibility, good mechanical properties, and improvement of the pharmacokinetic profile of the drug. In the present study, we investigated the effects of SRL-PLGA implant on experimental autoimmune uveitis in rabbits. Clinical and histopathological examinations were performed, followed by assessment of protein levels and determination of myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) activity in the aqueous humor/vitreous. As a result, treated eyes had decreased average inflammatory scores, protein significant decreases in treated eyes, assessed after 35 days. Histopathological examination showed less severe intraocular inflammation and decreased tissue damage in treated eyes. According to these results, the SRL-PLGA implant evaluated in this study was apparently safe, reducing inflammation in treated eyes, with an extended effect possibly associated with prolonged release of SRL in the posterior segment of the eye. Therefore, intravitreal SRL-PLGA implant could be a promising alternative for treatment of non-infectious uveitis.