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Retina (Philadelphia, Pa.) Nov 2020To describe persistent remnants of dexamethasone intravitreal implant (DEX implant) and evaluate the risk factors for remnant persistence in patients who received a DEX...
PURPOSE
To describe persistent remnants of dexamethasone intravitreal implant (DEX implant) and evaluate the risk factors for remnant persistence in patients who received a DEX implant.
METHODS
This retrospective observational study involved a retrospective chart review of 133 eyes from 129 patients who received DEX implant injection.
RESULTS
Seventeen eyes of 17 patients (12.78%) exhibited remnant persistence >1 year after DEX implant injection; eight eyes (13.33%) were diagnosed with branching retinal vein occlusion, three eyes (14.28%) were diagnosed with central retinal vein occlusion, and six eyes (35.3%) were diagnosed with diabetic macular edema. The number of intravitreal DEX implant injections and triamcinolone acetonide injections administered to eyes with remnant persistence was significantly higher than that administered to the eyes without remnant persistence (P < 0.001 and P = 0.024, respectively). Remnants caused symptomatic floaters in 11.7% (2/17 eyes) of the patients with remnants and in 1.5% (2/133) of the entire patient cohort.
CONCLUSION
DEX implant was not completely dissolved in the eyes that received multiple DEX implant or triamcinolone acetonide injections.
Topics: Aged; Dexamethasone; Diabetic Retinopathy; Drug Implants; Eye Diseases; Eye Foreign Bodies; Female; Glucocorticoids; Humans; Intraocular Pressure; Intravitreal Injections; Macular Edema; Male; Middle Aged; Retinal Vein Occlusion; Retrospective Studies; Visual Acuity; Vitreous Body
PubMed: 32058420
DOI: 10.1097/IAE.0000000000002778 -
ACS Applied Bio Materials Feb 2021To treat chronic posterior eye diseases, frequent intravitreal injections or sustained-release drug implants are the current standard of care. Sustained-release drug...
To treat chronic posterior eye diseases, frequent intravitreal injections or sustained-release drug implants are the current standard of care. Sustained-release drug implants often involve burst release of the drugs and the dosage from the implants cannot be controlled after implantation, which may lead to local side effects. The present study attempts to develop a dosage-controllable drug delivery implant that consists of a nanoporous biodegradable PLGA capsule and light-activated liposomes. Controllable drug release from the implant was achieved using a pulsed near-infrared (NIR) laser both in vitro and in vivo. The in vitro drug release kinetics from two different initial dose implants, 1000 and 500 μg, was analyzed by fitting zero-order and first-order kinetics, as well as the Korsmeyer-Peppas and Higuchi models. The 1000 and 500 μg implants fit the first-order and zero-order kinetics model, respectively, the best. The multiple drug releases in the vitreous were determined by an in vivo fluorimeter, which was consistent with the in vitro data. The dose released was also clinically relevant. Histology and optical and ultrasound imaging data showed no abnormality in the eyes received implant treatment, suggesting that the drug delivery system was safe to the retina. This on-demand dose-controllable drug delivery system could be potentially used for long-term posterior eye disease treatment to avoid frequent invasive injections.
Topics: Animals; Carbocyanines; Drug Implants; Drug Liberation; Fluorescent Dyes; Lasers; Methotrexate; Rabbits
PubMed: 35014495
DOI: 10.1021/acsabm.0c01334 -
Drug Delivery and Translational Research Feb 2021Implant-based local drug delivery is a unique surgical therapy with many clinical advantages. Atmospheric pressure plasma is a novel non-thermal surface biotechnology...
Implant-based local drug delivery is a unique surgical therapy with many clinical advantages. Atmospheric pressure plasma is a novel non-thermal surface biotechnology that has only recently been applied in enhancing a surgical implant. We are the first to use this technology to successfully create a dexamethasone-delivery metallic implant. Irrespective of the loaded medication, the surface of this novel implant possesses advantageous material features including homogeneity, hydrophilicity, and optimal roughness. UV-vis spectroscopy revealed much more sustainable drug release compared to the implants produced using simple drug attachment. In addition, our drug-releasing implant was found to have multiple biological benefits. As proven by the ELISA data, this multi-layer drug complex provides differential regulation on the cell apoptosis, as well as pro-osteogenic and anti-inflammatory effects on the peri-implant tissue. Furthermore, using the pathway-specific PCR array, our study discovered 28 and 26 upregulated and downregulated genes during osteogenesis and inflammation on our newly fabricated drug-delivery implant, respectively. The medication-induced change in molecular profile serves as a promising clue for designing future implant-based therapy. Collectively, we present atmospheric pressure plasma as a potent tool for creating a surgical implant-based drug-delivery system, which renders multiple therapeutic potentials. Graphical abstract Schematic of the APP-facilitated Dex-delivery implant. This layer-by-layer drug-releasing complex consisted of bottom plasma activation layer, middle medication layer, and top absorbable polymer layer.
Topics: Apoptosis; Dexamethasone; Drug Implants; Humans; Inflammation; Osteogenesis
PubMed: 31898081
DOI: 10.1007/s13346-019-00700-8 -
Biomedical Microdevices May 2022The standard of care for posterior segment disorders such as wet age-related macular degeneration, diabetic macular oedema and retinal vascular occlusions is...
The standard of care for posterior segment disorders such as wet age-related macular degeneration, diabetic macular oedema and retinal vascular occlusions is pharmacotherapy by intravitreal drug delivery. Since the therapeutic effect of these drugs lasts only around 4 to 8 weeks, repeated intravitreal injections are required. Pain is experienced by the patients during injection as the needle courses through the sclera and choroid. The current work describes the design and development of a novel anodized titanium alloy implant that allows for intravitreal injections through the implant so that the needle transverses only the conjunctiva, thus minimizing discomfort to the patient. Both ex-vivo testing of the implant in enucleated goat's eye as well as in-vivo validation in rabbit eyes was carried out. The implant was placed through pars plana via a minor surgical procedure and was sutured to the sclera and covered with conjunctiva. Subsequent intravitreal injections were administered under topical anaesthesia with a 30-gauge needle through the implant thus delivering the drug into the vitreous cavity. Repeated intravitreal injections were administered every 2 weeks via the implant for 3 months in 4 rabbits. Apart from cataract in 1 rabbit, no complications were observed. There was no evidence of intra-ocular inflammation or infection at final follow-up. Histopathological analysis did not reveal any inflammation or necrosis around the area of implant. The implants were subsequently removed at 5 months and scleral wound was closed with a single suture. The sclera and overlying conjunctiva healed well and no intraocular complications were observed after removal.
Topics: Animals; Drug Delivery Systems; Drug Implants; Humans; Inflammation; Intravitreal Injections; Pharmaceutical Preparations; Rabbits
PubMed: 35587289
DOI: 10.1007/s10544-022-00618-y -
AAPS PharmSciTech Nov 2020Drug delivery to vitreous in comparison with drug delivery to the other parts of the eye is complicated and challenging due to the existence of various anatomical and...
Drug delivery to vitreous in comparison with drug delivery to the other parts of the eye is complicated and challenging due to the existence of various anatomical and physiological barriers. Developing injectable intra-vitreal implant could be beneficial in this regard. Herein, poly(hydroxybutyrate-co-valerate) (PHBV) implants were fabricated and optimized using response surface method for budesonide (BZ) delivery. The acquired implants were characterized in regard to the stability of the ingredients during fabrication process, drug loading amount, and drug release pattern (in PBS-HA-A and in vitreous medium). According to this research and statistical analysis performed, first HV% (hydroxyvalerate) then molecular weight and ratio of PEG as pore former affect respectively release rate and burst strength of BZ with different coefficients. Drug release profile in rabbit eye correlated well with that of in vitro (R = 0.9861, p ˂ 0.0001). No significant changes were seen in ERG waves, intraocular pressure, and histological studies during the in vivo part of the project. Using 8% HV, 20% PEG/PHBV, and higher molecular weight PEG (i.e., 6000), the optimum formulation was achieved. Toxicity and biocompatibility of the optimized formulation, which were evaluated in vivo, indicated the suitability of design implant for intra-vitreal BZ delivery. Grapical abstract.
Topics: Animals; Anti-Inflammatory Agents; Budesonide; Drug Implants; Drug Liberation; Hydroxybutyrates; In Vitro Techniques; Molecular Weight; Nanoparticles; Polyesters; Polymers; Rabbits; Vitreous Body
PubMed: 33165678
DOI: 10.1208/s12249-020-01828-4 -
Turkish Journal of Ophthalmology Apr 2020We present patient characteristics and follow-up results of cases with anterior chamber dexamethasone implant migration. The common feature of all six presented cases...
We present patient characteristics and follow-up results of cases with anterior chamber dexamethasone implant migration. The common feature of all six presented cases was vitrectomized eyes. Four of the patients had sutured intraocular lens (IOL) implantation due to complicated cataract surgery, one had combined retinal detachment surgery with sutured IOL implantation, and one had vitrectomy for diabetic intravitreal hemorrhage cleaning and uncomplicated cataract surgery. Anterior chamber implant migration caused corneal edema in all cases and elevated intraocular pressure in three cases. In two cases, the dexamethasone implant was directed into the vitreous cavity after maximum pupillary dilation and corneal manipulation with cotton tip applicator with the patient in reverse Trendelenburg position. There was no other complication until dexamethasone implant degradation, with clear cornea at final examination. In two cases, the implant was removed from the anterior chamber by aspiration, but keratoplasty surgery was planned due to endothelial cell loss and persistent corneal edema during follow-up. In the last two cases, the dexamethasone implant was redirected into the vitreous chamber with a 23-gauge catheter and anterior chamber maintainer but they migrated into the anterior chamber again. In one of these patients, the implant was aspirated by catheter and corneal transplantation was performed due to corneal edema, while the other patient's implant was redirected into the vitreous chamber with no further anterior migration. The risk of dexamethasone implants migrating into the anterior chamber of vitrectomized eyes and those with sutured IOL implantation should be kept in mind and the patient should be informed and advised to see an ophthalmologist immediately before permanent corneal endothelial damage occurs.
Topics: Anterior Chamber; Dexamethasone; Drug Implants; Foreign-Body Migration; Humans; Macular Edema; Male; Middle Aged; Tomography, Optical Coherence
PubMed: 32367704
DOI: 10.4274/tjo.galenos.2019.43778 -
Scientific Reports Jul 2022The aim of the present study was to describe foveal eversion patterns in diabetic macular edema (DME) and to assess their relationship with the course of the disease and...
The aim of the present study was to describe foveal eversion patterns in diabetic macular edema (DME) and to assess their relationship with the course of the disease and the outcome. The study was designed as prospective, observational, with two years of follow-up. DME patients were divided in two groups, one treated by combined anti-VEGF injections and dexamethasone (DEX) implants, and the other treated by fluocinolone acetonide (FAc) implant with additional anti-VEGF retreatments if needed. Main outcome measures were foveal eversion prevalence, foveal eversion patterns, best-corrected visual acuity (BCVA), central macular thickness (CMT), structural OCT metrics, number of intravitreal injections. One hundred and forty-six eyes (146 patients; 80 males; mean age 67 ± 8 years) affected by already treated DME, with 84 eyes treated with anti-VEGF/DEX treatments (mean of 10 ± 3 injections) and 62 treated with FAc implant. Looking at the treatments administered before the inclusion into the study, 84 eyes (58%) were treated with anti-VEGF injections, whereas 62 eyes (42%) underwent a combination of anti-VEGF and corticosteroids implants. DME eyes showed statistically significant improvements of LogMAR BCVA and CMT over the 2-year follow-up. Foveal eversion was found in 83 eyes (57%), categorized as follows: Pattern 1a (16;19%); Pattern 1b (22;27%) and Pattern 2 (45;54%). BCVA improvement was detected in all the subgroups, excepting for Pattern 2, which showed also significantly worse structural OCT parameters. Pattern 1b and Pattern 2 were characterized by significantly higher prevalence of persistent DME (64% and 89% of cases, respectively). Foveal eversion patterns were correlated with progressively worse DME outcome. Foveal eversion may be associated to the loss of foveal homeostasis, with consequent poor response to intravitreal treatments and worse DME outcome.
Topics: Aged; Angiogenesis Inhibitors; Dexamethasone; Diabetes Mellitus; Diabetic Retinopathy; Drug Implants; Fovea Centralis; Glucocorticoids; Humans; Intravitreal Injections; Macular Edema; Male; Middle Aged; Prospective Studies; Retrospective Studies; Visual Acuity
PubMed: 35907954
DOI: 10.1038/s41598-022-17555-8 -
International Journal of Pharmaceutics Dec 2022By carefully controlling the dose administered and the drug release rate from drug-eluting implants, safety and efficacy of the therapeutic agent dispensed can be...
By carefully controlling the dose administered and the drug release rate from drug-eluting implants, safety and efficacy of the therapeutic agent dispensed can be improved. The present work focuses on the promising advantages of 3D Bioprinting process in developing two layers' implantable scaffolds. The two layers have different functions, in order to ensure a more effective and synergistic breast cancer therapy. First layer involves use of polymers such as Poly- ε-Caprolactone (PCL) and Chitosan (CS), and incorporation of 5-Fluorouracil (5-FU). The aim of the first layer is releasing the drug within 4 weeks, obtaining a prolonged and modified release. According to in vitro drug release tests performed, ∼32 % of 5-FU was released after one month, after an initial burst effect of 17.22 %. The sudden release of the drug into the body would quickly reach an effective therapeutic concentration, while the drug sustained release maintains an effective therapeutic concentration range during the administration time. The second layer is made exclusively from PCL as polymeric matrix, into which Gold Nanoparticles (AuNPs) were subsequently loaded, and its main purpose is to be radiation enhancement. The long biodegradation time of PCL would make the non-soluble scaffold an alternative to conventional chemotherapy, optimizing drug release to the specific needs of the patients.
Topics: Humans; Female; Polyesters; Breast Neoplasms; Gold; Metal Nanoparticles; Fluorouracil; Polymers; Drug Implants; Printing, Three-Dimensional
PubMed: 36336202
DOI: 10.1016/j.ijpharm.2022.122363 -
Drug Development and Industrial Pharmacy Dec 2020The present study was designed to formulate and develop fast disintegrating pellets of poorly soluble model drug (cilostazol) by reducing the proportion of...
The present study was designed to formulate and develop fast disintegrating pellets of poorly soluble model drug (cilostazol) by reducing the proportion of micro-crystalline cellulose with pre-gelatinized starch (PGS), lactose and chitosan. The bioavailability enhancement of a model drug was achieved by preparing inclusion complex with Captisol® (Sulfobutyl Ether β cyclodextrin - SBE-β-CD). Extrusion-spheronization technique was used to formulate pellets. Placket-Burman design was used for the initial screening of most significant factors such as screen size (mm), ratio of micro crystalline cellulose: PGS + lactose + chitosan and % of HPMC which affects pellet properties. The inclusion complex of drug and Captisol (SBE-β-CD) was prepared by Solvent Evaporation method and were incorporated into pellets in a predefined proportion. Formulation was optimized by using 3 full factorial design, the optimized batch was selected on the basis of dependent variables such as % yield, pellet size, disintegration time and % Cumulative drug release (%CDR), the obtained results were 87.15%, 0.75 mm, 13 min and 91.024% respectively. Differential scanning calorimetry (DSC) and Fourier transform infrared spectrometry (FTIR) study revealed no significant interaction between drug and polymer. Scanning electron microscopy (SEM) confirmed uniform and spherical shaped pellets having pores on the surface which facilitates wicking action and fast disintegrating property of pellets. A design space was constructed to meet the desirable target and optimized batch. The scope of study can further extended to hydrophobic molecules which may useful due to rapid disintegration and enhanced dissolution rate.
Topics: Cellulose; Cilostazol; Drug Implants; Excipients
PubMed: 33026265
DOI: 10.1080/03639045.2020.1826509 -
International Journal of Pharmaceutics Jan 2021In situ forming implants are attractive long-acting implant dosage forms due to their: i) ability to control drug release; ii) simple manufacturing process; and iii)...
In situ forming implants are attractive long-acting implant dosage forms due to their: i) ability to control drug release; ii) simple manufacturing process; and iii) minimally invasive administration. In situ forming implants are typically made of a drug, solvent, and a biocompatible polymer that controls drug release. Once injected in the subcutaneous tissue, they form solid depots through solvent/non-solvent exchange and phase separation of the biodegradable polymer (such as poly (lactic-co-glycolic acid), PLGA and poly (lactic acid), PLA). However, the mechanism of implant formation and the changes in their microstructure that determine drug release behavior are not fully understood. Furthermore, there is no standardized in vitro release testing method for in situ forming implants due to limitations in recreating bio-relevant and reproducible implant formation in vitro with controllable implant shape, dimensions and surface-to-volume ratio. In the present study, bio-relevant implant formation was recreated in vitro by testing five different methods to determine their effect on drug release kinetics, reproducibility, and internal microstructure formation. The leuprolide acetate formulation Eligard® was used as a model in situ-forming implant, consisting of lyophilized leuprolide acetate, and PLGA dissolved in N-methyl pyrrolidone. The results revealed that the in vitro implant formation method is a crucial step in the dissolution testing process that significantly impacts the release profile of in situ forming implants. An implant formation method that utilizes dissolvable polyvinyl alcohol (PVA) films allowed for initial drug burst release control by modulating implant dimensions (i.e. surface area) and resulted in reproducible in vitro release profiles. In addition, implant formation was shown to affect the internal microstructure of in situ forming implant and was the main factor controlling the release profile which consisted of an initial release phase followed by a release plateau (lag phase) and then a second erosion-controlled release phase.
Topics: Drug Implants; Drug Liberation; Kinetics; Lactic Acid; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Reproducibility of Results
PubMed: 33232755
DOI: 10.1016/j.ijpharm.2020.120105