Short-term effect of intravitreal dexamethasone implant in refractory diabetic macular edema.

PURPOSE: To evaluate the short-term effects (hours-days) of intravitreal dexamethasone implant (IDI) in eyes with diabetic macular edema (DME) refractory to anti-vascular endothelial growth factor (VEGF) injections. METHODS: This was a prospective, single-arm, interventional clinical series. Eyes with DME and 3-9 injections of ranibizumab without a good response were included. Patients underwent a single IDI. Best-corrected visual acuity (BCVA) measurement, complete ophthalmic evaluation, and spectral-domain optical coherence tomography (SD-OCT) were performed at baseline, 2 h, 3 h, 24 h, 7 days, and 1 month. The main outcomes were change in central retinal thickness (CRT) on SD-OCT and BCVA. RESULTS: Fifteen eyes of 15 patients were included. Mean CRT decreased after treatment from 515.87 µm ± 220.00 µm at baseline to 489.60 µm ± 176.53 µm after 2 h (p = 0.126), and 450.13 µm ± 163.43 at 24 h (p = 0.006). Change in BCVA was from 0.85 ± 0.44 logMAR baseline to 0.58 ± 0.37 log MAR at 1 month (p = 0.003). CONCLUSIONS: Eyes treated with IDI showed significant decrease in CRT detectable 1 day after injection. In some patients, the effect could be observed 3 h post-implantation. TRIAL REGISTRATION: Clinicaltrials.gov NCT05736081 . Registered 20 February 2023, Retrospectively registered.

Bioavailability of three novel oral, sustained-release pellets, relative to an immediate-release tablet containing 500 mg flucytosine: A randomized, open-label, crossover study in healthy volunteers.

The opportunistic fungal infection cryptococcal meningoencephalitis is a major cause of death among people living with HIV in sub-Saharan Africa. We report pharmacokinetic (PK) and safety data from a randomized, four-period crossover phase I trial of three sustained-release (SR) oral pellet formulations of 5-flucytosine conducted in South Africa. These formulations were developed to require less frequent administration, to provide a convenient alternative to the current immediate release (IR) formulation, A. Formulations B, C, and D were designed to release 5-flucytosine as a percentage of the nominal dose in vitro. We assessed their safety and PK profiles in a single dose (1 × 3000 mg at 0 h), relative to commercial IR tablets (Ancotil 500 mg tablets; 3 × 500 mg at 0 h and 3 × 500 mg at 6 h) in healthy, fasted participants. Forty-two healthy participants were included. All treatments were well-tolerated. The primary PK parameters, maximum observed plasma concentration (Cmax ) and area under the concentration-time profiles, were significantly lower for the SR formulations than for the IR tablets, and the geometric mean ratios fell outside the conventional bioequivalence limits. The median maximum time to Cmax was delayed for the SR pellets. Physiologically-based PK modeling indicated a twice-daily 6400 mg dose of SR formulation D in fasted condition would be optimal for further clinical development. This regimen is predicted to result in a rapid steady-state plasma exposure with effective and safe trough plasma concentration and Cmax values, within the therapeutic boundaries relative to plasma exposure after four times per day administration of IR tablets (PACTR202201760181404).

In-situ forming biodegradable implants for sustained Fluocinolone acetonide release to the posterior eye: In-vitro and in-vivo investigations in rabbits.

Delivering medication to the posterior segment of the eye presents a significant challenge. Intravitreal injection has emerged as the preferred method for drug delivery to this area. However, current injectable non-biodegradable implants for fluocinolone acetonide (FA) require surgical removal after prolonged drug release, potentially affecting patient compliance. This study aimed to develop an in-situ forming biodegradable implant (ISFBI) optimal formulation containing PLGA504H and PLGA756S (50:50 w/w%) with the additive NMP solvent. The goal was to achieve slow and controlled release of FA over a two-month period with lower burst release, following a single intravitreal injection. Through morphology, rheology, stability and in-vitro release evaluations, the optimal formulation demonstrated low viscosity (0.12-1.25 Pa. s) and sustained release of FA at a rate of 0.36 µg/day from the third day up to two months. Furthermore, histopathology and in-vivo studies were conducted after intravitreal injection of the optimal formulation in rabbits' eye. Pharmacokinetic analysis demonstrated mean residence time (MRT) of 20.02 ± 0.6 days, half-life (t1/2) of 18.80 ± 0.4 days, and clearance (Cl) of 0.29 ± 0.03 ml/h for FA in the vitreous humor, indicating sustained and slow absorption of FA by the targeted retinal tissue from vitrea over the two-month period and eliminating through the anterior section of the eye, as revealed by its presence in the aqueous humor. Additionally, FA exhibited no detection in the blood and no evidence of systemic side effects or damage on the retinal layer and other organs. Based on these findings, it can be concluded that in-situ forming injectable biodegradable PLGA implants can show promise as a long-acting and controlled-release system for intraocular drug delivery.

Amenorrhea in adolescents using the etonogestrel contraceptive implant.

OBJECTIVE: Clinical factors related to development of amenorrhea in adolescents with the etonogestrel contraceptive implant are not well-understood. The purpose of this study is to describe what baseline clinical characteristics are associated with amenorrhea in adolescents with a contraceptive implant 12 months after placement. STUDY DESIGN: This retrospective cohort study included 252 post-menarchal individuals aged 12-22 years with a contraceptive implant placed between 2016-2020. Data abstracted at insertion, three months post-insertion, and 12 months post-insertion included demographics, baseline bleeding pattern, prior contraception use, post-insertion bleeding pattern, and method discontinuation. We assessed possible predictive characteristics of our outcomes using bivariate and multivariable logistic regression analyses. RESULTS: Twenty nine percent of patients were amenorrheic 12 months after placement. Patients who were amenorrheic at 12 months were more likely to be obese (41.1% vs 24.6%, p = 0.01), to have been amenorrheic prior to implant insertion (16.9% vs 5.4%, p < 0.01, to have used hormonal contraception immediately prior to insertion (42.5% vs 26.3%, p = 0.01), to have had the most recent contraceptive method being another implant (12.3% vs 3.6%, p = 0.02), and to have developed amenorrhea within three months after placement (22.2% vs 12.6%, p < 0.01). After multivariable regression analysis, only obesity (adjusted odds ratio [aOR] 2.2 95% CI 1.1-4.2) and amenorrhea at three months (aOR 3.6, CI 1.1-11.5) were associated with amenorrhea at 12 months. CONCLUSION: Obesity and early amenorrhea were associated with 12-month amenorrhea in adolescents using the etonogestrel subdermal implant. Understanding this can help with contraceptive method selection and counseling for patients and providers. IMPLICATIONS: Obesity and early amenorrhea with the etonogestrel contraceptive implant are associated with longer-term amenorrhea in adolescents using this method. These findings can aid providers with method selection and pre-insertion decision-making for adolescents considering contraceptive implant use, as well as continued counseling after placement.

Wurster Technology-Assisted Step-by-Step Engineering of Multi-layered Pellets (Sprinkles): Microscopy, Micro-CT, and e-Tongue-Based Analysis.

The advancement in the formulation and characterization techniques have paved the path for development of new as well as modification of existing dosage forms. The present work explores the role of micro-computed tomography (micro-CT) as advanced characterization technique for multi-layered-coated pellets to ascertain the quality of coated pellets. The work further explored in-house e-tongue technique for understanding palatability of formulation in early stages of development thus by reducing clinical taste evaluation time. The developed multi-layered-coated pellets were characterized using microscopy (optical and electron microscopy). The obtained results demonstrated formation of spherical-shaped pellets with uniform coating. The uniform coating was further confirmed by results obtained from scanning electron microscopy (SEM) and cross-sectional SEM analysis, which showed visible difference in pellet surface before and after multi-layered coating. The micro-CT results confirmed the visible demarcation of layers (drug and polymer, i.e., hydroxypropyl methylcellulose (HPMC) and eudragit (EPO)) along with uniform thickness of various layering. The dissolution study of developed pellets suggested the role of layering EPO on drug release from pellets. The e-tongue analysis proved to be an excellent tool for early prediction of taste masking of drug via multi-layered pellets and can serve as potential platform for taste masking with high specificity. The overall results suggest the suitability of developed multi-layered platform as efficient dosage form (sprinkle) in pediatric/geriatric product development.

The effect of glycosylated hemoglobin levels on the response to intravitreal dexamethasone implant for treating diabetic macular edema.

This study investigates the impact of glycosylated hemoglobin (HbA1c) on the efficacy of intravitreal dexamethasone (DEX) implants in patients with diabetic macular edema (DME) over a 12-month period. We retrospectively reviewed 90 DME patients treated with DEX implants, categorizing them based on baseline HbA1c levels (≤ 7% and > 7%) and 12-month changes in HbA1c ("improved", "stable", "worsened"). At the 2-month mark, the mean central subfield thickness (CST) reduction in the HbA1c ≤ 7% group was - 147.22 ± 113.79 µm compared to -130.41 ± 124.50 µm in the > 7% group (p = 0.506). Notably, 12-month outcomes between these groups showed no significant difference. The "improved" HbA1c subgroup experienced a more pronounced CST reduction at 2 months (p = 0.042), with outcomes leveling off with other groups by 12 months. Conclusively, DEX implant outcomes in DME were not influenced by either baseline HbA1c levels or their changes over time. This suggests that local alterations in the inflammation milieu may have a potentially stronger impact on DME treatment outcomes, highlighting the importance of considering local factors in DME treatment.

Rapid characterization of physical properties for the pharmaceutical pellet cores based on NIR spectroscopy and ensemble learning.

During the development of sustained-release pellets, the physical characteristics of the pellet cores can affect drug release in the preparation. The method based on near-infrared (NIR) spectroscopy and ensemble learning was proposed to swiftly assess the physical properties of the pellet cores. In the research, the potential of three algorithms, direct standardization (DS), partial least squares regression (PLSR) and generalized regression neural network (GRNN), was investigated and compared. The performance of the DS, PLSR and GRNN models were improved after applying bootstrap aggregating (Bagging) ensemble learning. And the Bagging-GRNN model showed the best predictive capacity. Except for inter-particle porosity, the mean absolute deviations of other 11 physical parameters were less than 1.0. Furthermore, the cosine coefficient values between the actual and predicted physical fingerprints was higher than 0.98 for 15 out of the 16 validation samples when using the Bagging-GRNN model. To reduce the model complexity, the 60 variables significantly correlated with angle of repose, particle size (D50) and roundness were utilized to develop the simplified Bagging-GRNN model. And the simplified model showed satisfactory predictive capacity. In summary, the developed ensemble modelling strategy based NIR spectra is a promising approach to rapidly characterize the physical properties of the pellet cores.

Formulation and optimization of a single-layer coat for targeting budesonide pellets to the descending Colon.

The current budesonide formulations are inadequate for addressing left-sided colitis, and patients might hesitate to use an enema for a prolonged time. This study focuses on developing a single-layer coating for budesonide pellets targeting the descending colon. Pellets containing budesonide (1.5%w/w), PVP K30 (5%w/w), lactose monohydrate (25%w/w) and Avicel pH 102 (68.5%w/w) were prepared using extrusion spheronization technique. Coating formulations were designed using response surface methodology with pH and time-dependent Eudragits. Dissolution tests were conducted at different pH levels (1.2, 6.5, 6.8, and 7.2). Optimal coating formulation, considering coating level and the Eudragit (S + L) ratio to the total coating weight, was determined. Budesonide pellets were coated with the optimized composition and subjected to continuous dissolution testing simulating the gastrointestinal tract. The coating, with 48% S, 12% L, and 40% RS at a 10% coating level, demonstrated superior budesonide delivery to the descending colon. Coated pellets had a spherical shape with a uniform 30 µm thickness coating, exhibiting pH and time-dependent release. Notably, zero-order release kinetics was observed for the last 9 h in colonic conditions. The study suggests that an optimized single-layer coating, incorporating pH and time-dependent polymers, holds promise for consistently delivering budesonide to the descending colon.

Cushion-coated pellets for tableting without external excipients.

Multiple-unit dosage forms prepared by compacting pellets offer important manufacturing and compliance advantages over pellet-filled capsules. However, compaction may negatively affect the release control mechanism of pellets, and subunits may not be readily available after intake. Application of a cushioning layer to the starting units is here proposed as a strategy to obtain tablets with satisfactory mechanical strength, rapid disintegration and maintenance of the expected release profile of individual subunits while avoiding the use of mixtures of pellets and excipients to promote compaction and limit the impact of the forces involved. Cushion-coating with PEG1500, a soft and soluble material, was proved feasible provided that the processing temperature was adequately controlled. Cushioned gastro-resistant pellets were shown to consolidate under relatively low compaction pressures, which preserved their inherent release performance after tablet disintegration. Adhesion problems associated with the use of PEG1500 were overcome by applying an outer Kollicoat® IR film. Through design of experiment (DoE), robustness of the proposed approach was demonstrated, and the formulation as well as tableting conditions were optimized. The tableted cushion-coated pellet systems manufactured would allow a relatively high load of modified-release units to be conveyed, thus setting out a versatile and scalable approach to oral administration of multiple-unit dosage forms.

Tableting of coated multiparticulates: Influences of punch face configurations.

The influences of the punch face design on multi-unit pellet system (MUPS) tablets were investigated. Drug-loaded pellets coated with sustained release polymer based on ethylcellulose or acrylic were compacted into MUPS tablets. Punch face designs used include standard concave, deep concave, flat-faced bevel edge and flat-faced radius edge. MUPS tablets compacted at 2 or 8 kN were characterized for their tensile strength. The extent of pellet coat damage after tableting was evaluated from drug release profiles. Biconvex tablets were weaker by 0.01-0.15 MPa, depending on the pellet type used, and had 1-17 % higher elastic recovery (p < 0.000) than flat-faced tablets. At higher compaction force, the use of the deep concave punch showed a 13-26 % lower extent of pellet coat damage, indicated by a relatively higher mean dissolution time, compared to other punch face configurations (p < 0.000). This was attributed to increased rearrangement energy of the compacted material due to the high punch concavity, which sequestered compaction stress exerted on pellet coats. Although the deep concave punch reduced the stress, the resultant tablets containing pellets coated with acrylic were weaker (p = 0.01). Overall, the punch face configuration significantly affected the quality of MUPS tablets.

Influence of prior treatment protocol on intravitreal dexamethasone implant behavior in patients with diabetic macular edema in real-world practice.

BACKGROUND AND OBJECTIVE: Intravitreal dexamethasone implant (DEXI) has been placed as an effective option to treat diabetic macular edema (DME). However, there is no consensus on the best time to introduce it. We conducted a study to evaluate anatomical and functional behavior after the first DEXI according to previous treatment. RESEARCH DESIGN AND METHODS: This retrospective, real-world study between 2013 and 2020 investigated changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT at months 2 and 6 after the first DEXI in DME. Patients were divided into naive, early switch (≤3 anti-VEGF injections), or late switch (>3 anti-VEGF injections) groups. RESULTS: Among 112 consecutive eyes, mean BCVA and CMT improved significantly in all groups at month 2, with no difference between them. However, this improvement was not maintained at 6 months. The Naíve group presented better BCVA all over the study period. The previously treated groups, which started with worse initial visual acuity, showed more visual gain without reaching the BCVA of the naive group. CMT performance was similar between groups. CONCLUSIONS: There was similar anatomical and functional behavior in all groups. Poorer visual acuity at baseline was associated with worse functional outcome despite good anatomic response.

Development of in situ forming implants for controlled delivery of punicalagin.

Due to efficient drainage of the joint, the development of intra-articular depots for long-lasting drug release is a difficult challenge. Moreover, a disease-modifying osteoarthritis drug (DMOAD) that can effectively manage osteoarthritis has yet to be identified. The current study was undertaken to explore the potential of injectable, in situ forming implants to create depots that support the sustained release of punicalagin, a promising DMOAD. In vitro experiments demonstrated punicalagin's ability to suppress production of interleukin-1ß and prostaglandin E2, confirming its chondroprotective properties. Regarding the entrapment of punicalagin, it was demonstrated by LC-MS/MS to be stable within PLGA in situ forming implants for several weeks and capable of inhibiting collagenase upon release. In vitro punicalagin release kinetics were tunable through variation of solvent, PLGA lactide:glycolide ratio, and polymer concentration, and an optimized formulation supported release for approximately 90 days. The injection force of this formulation steadily increased with plunger advancement and higher rates of advancement were associated with greater forces. Although the optimal formulation was highly cytotoxic to primary chondrocytes if cells were exposed immediately or shortly after implant formation, upwards of 70 % survival was achieved when the implants were first allowed to undergo a 24-72 h period of phase inversion prior to cell exposure. This study demonstrates a PLGA-based in situ forming implant for the controlled release of punicalagin. With modification to address cytotoxicity, such an implant may be suitable as an intra-articular therapy for OA.

Anatomical and Functional Results of Early or Late Switching from Anti-VEGF to Dexamethasone Implant in Case of Poor Anatomical Response in Naïve Patients with Macular Edema Secondary to Branch Retinal Vein Occlusion.

PURPOSE: To compare the outcomes of early or late switching from intravitreal (IV) anti-vascular endothelial growth factor (anti-VEGF) injection to IV Dexamethasone (DEX) implant injection in treatment-naïve patients with macular edema secondary to branch retinal vein occlusion. METHODS: This study included 68 eyes of 68 treatment-naïve BRVO patients who started anti-VEGF treatment. After the loading dose, the patients were divided into two groups: Early DEX group (n:34) (DEX implant treatment started after 3 loading doses) and Late DEX group (n:34) (DEX implant treatment started after 6 months). Visual acuity and examination findings were recorded at baseline, 3rd, 6th, and 12th month follow-ups. Optical coherence tomography data were recorded for central macular subfield thickness assessment. RESULTS: A total of 30 (44.1%) women and 38 (55.9%) men participated, and the average age was 67.6 ± 6.4 years. The mean letter gains at week 52 was 15.1 and 20.9 in the Early DEX and Late DEX groups, respectively. The group with the highest gain of ≥15 letters was the Late DEX group (26/34 patients) and the gain of ≥15 letters was 14/34 in the Early DEX group (p: 0.006). At week 52, the anatomical gain was 115.3 µm and 136.9 µm in the Early DEX and Late DEX groups, respectively. CONCLUSIONS: A gain of 15 or more letters was demonstrated to be higher in patients who switched to DEX implant late after anti-VEGF treatment. If it is necessary to switch, the late switch may be more effective for more visual gain at the end of the first year.

One-Minute Preparation of Iron Foam-Drug Implant for Ultralow-Power Magnetic Hyperthermia-Based Combination Therapy of Tumors in Vivo.

The magnetic hyperthermia-based combination therapy (MHCT) is a powerful tumor treatment approach due to its unlimited tissue penetration depth and synergistic therapeutic effect. However, strong magnetic hyperthermia and facile drug loading are incompatible with current MHCT platforms. Herein, an iron foam (IF)-drug implant is established in an ultra-facile and universal way for ultralow-power MHCT of tumors in vivo for the first time. The IF-drug implant is fabricated by simply immersing IF in a drug solution at an adjustable concentration for 1 min. Continuous metal structure of IF enables ultra-high efficient magnetic hyperthermia based on eddy current thermal effect, and its porous feature provides great space for loading various hydrophilic and hydrophobic drugs via "capillary action". In addition, the IF has the merits of low cost, customizable size and shape, and good biocompatibility and biodegradability, benefiting reproducible and large-scale preparation of IF-drug implants for biological application. As a proof of concept, IF-doxorubicin (IF-DOX) is used for combined tumor treatment in vivo and achieves excellent therapeutic efficacy at a magnetic field intensity an order of magnitude lower than the threshold for biosafety application. The proposed IF-drug implant provides a handy and universal method for the fabrication of MHCT platforms for ultralow-power combination therapy.

Effect of intralenticular dexamethasone implant: A case report.

INTRODUCTION: Intravitreal dexamethasone (DEX) implant is indicated for the treatment of macular oedema due to diabetic retinopathy, retinal vein occlusion and uveitis. The most common complications are cataract and elevated intraocular pressure (IOP). Accidental injection of DEX implant into the lens is a rare complication and only few papers presented it. CASE PRESENTATION: A 40-year-old man was treated with DEX implant for diabetic macular oedema in both eyes. At 1 week follow-up visit, slit lamp examination showed the DEX implant was located in the crystalline lens of the right eye (RE) without any sign of inflammation, cataract or elevated IOP, so we decided to plan a normal follow-up schedule. Macular oedema relapsed 5 months after the injection in the left eye (LE), whereas the RE did not show any sing of intraretinal or subretinal fluid. Six months after DEX implantation an uneventful phacoemulsification and intraocular lens placement were performed in the RE because of IOP elevation. CONCLUSIONS: The therapeutic effect of DEX implant can be maintained for a longer period of time than intravitreal implant, determining complete reabsorption of macular oedema. Intralenticular implant can be maintained inside the lens until either IOP increases, cataract progresses, or other complications occur.

Anterior chamber bleeding due to intravitreal dexamethasone implant sclerotomy without vitreous hemorrhage.

BACKGROUND: Anterior Chamber bleeding without vitreous hemorrhage had been described after the removal of 23G vitrectomy cannulas. We report the case of an anterior chamber bleeding after an intravitreal Dexamethasone implant. CASE REPORT: One patient with macular edema due to central retinal vein occlusion in a vitrectomized eye underwent an intravitreal Dexamethasone implant. After the injection the patient suffered from anterior chamber bleeding without signs of vitreous hemorrhage. The complication resolved with a conservative treatment. CONCLUSION: Anterior Chamber bleeding is a possible complication of dexamethasone implant, that can be treated in a conservative way.

Resolution of Macular Edema secondary to rituximab after intravitreal dexamethasone: A case report and a review of the literature.

PURPOSE: to report a case of bilateral macular edema (ME) secondary to Rituximab infusions in a woman affected by IgG4-Related Disease and to review of prior cases of ME related to Rituximab. OBSERVATIONS: ME completely resolved after Intravitreal Dexamethasone Implant (IDI). CONCLUSIONS AND IMPORTANCE: ME is a rare complication after Rituximab infusions and very few cases are reported in the literature. Usually, ME occurs a few weeks after systemic administration and is probably related to a local release of cytokines. It resolves with oral, subtenon or intravitreal steroids. Our case is the first showing that IDI is a safe and effective treatment in ME secondary to Rituximab. Rituximab is not required to be discontinued if treatment for ME is started.

The 0.19-mg Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: Intraocular Pressure-Related Effects over 36 Months.

PURPOSE: To evaluate effects of the 0.19-mg fluocinolone acetonide (FAc) intravitreal implant (ILUVIEN) on intraocular pressure (IOP) in patients with diabetic macular edema (DME). DESIGN: Secondary analysis of a 36-month, phase IV, nonrandomized, open-label, observational study. PARTICIPANTS: The study included 202 eyes from 159 patients who received the 0.19-mg FAc implant after a successful prior steroid challenge per the United States label indication. METHODS: Study eyes were assessed for IOP values, incidence of IOP elevations, and best-corrected visual acuity (BCVA) for up to 36 months post-FAc implant. RESULTS: Mean IOP was stable over 36 months post-FAc; IOP change from baseline peaked at 2.12 mmHg at 9 months, then declined to baseline levels. At 36 months, eyes had a 32.5% cumulative probability of an IOP event > 25 mmHg and a 15.6% probability of an IOP event > 30 mmHg (Kaplan-Meier). The probability of requiring IOP-lowering medication at any time by month 36 was 38.3%. A total of 78% of eyes did not have IOP elevations > 25 mmHg if similar values were seen with the previous steroid challenge. Although 7.4% of eyes had an IOP > 30 mmHg during a scheduled study visit, most exceeded this threshold only once (60%). Regardless of IOP status, mean BCVA remained stable. CONCLUSIONS: Over 36 months, the 0.19-mg FAc implant was associated with relatively stable IOPs in patients with DME, and there was no significant impact of IOP elevations identified regarding their effects on long-term visual outcomes. The probability that a prior corticosteroid challenge will not predict an IOP elevation > 25 mmHg over 36 months post-FAc is 22%; therefore, routine IOP monitoring should be scheduled. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.