Sustained Release Of Dexamethasone Research Articles

A Study of the Pharmacokinetic Properties and the In Vivo Kinetics of Erythrocytes Loaded With Dexamethasone Sodium Phosphate in Healthy Volunteers.

The objectives of this 2-phase study were to elucidate pharmacokinetics (PK), in vivo 24-hour recovery, and red blood cell (RBC) survival properties of RBC-encapsulated dexamethasone sodium phosphate (DSP) prepared using the EryDex System (EDS). The 24-hour RBC recovery and T50 survival phase studied subjects were randomized to receive autologous RBCs loaded with either 15-20 mg DSP (Group 1A) or sham saline (Group 2A). Loaded RBCs were radiolabeled with 51-Cr, and the labeled RBCs were followed over time in vivo. The PK phase evaluated dose levels of 2.5-5 mg (Group 1B) and 15-20 mg (Group 2B) DSP encapsulated in RBCs infused into healthy randomized subjects. The mean ± SD 24-hour RBC recovery was 77.9% ± 3.3% and 72.7% ± 10.5% for Groups 1A and 2A, respectively. The mean ± SD RBC life span was 84.3 ± 8.3 days in Group 1A and 88.9 ± 6.2 days in Group 2A. The PK phase actual DSP loading doses (mean ± SEM) were 4.2 ± 0.27 mg and 16.9 ± 0.90 mg in Groups 1B and 2B, respectively. Release of dexamethasone from RBCs in vivo peaked at 1 hour, and a sustained release of dexamethasone could be detected until 35 days after the single intravenous infusion in Group 2B. The mean RBC in vivo recovery for DSP-loaded processed cells compares similarly to the 24-hour recovery of regulated RBC products intended for transfusion. There was a minimal but acceptable adverse impact on the survival of EDS-processed RBCs. DSP-loaded autologous RBCs, prepared using the EDS, delivered a sustained dose of dexamethasone in vivo.

The In Vivo Recovery/Survivaland Pharmacokinetic Properties of Dexamethasone Sodium Phosphate Encapsulated in Autologous Erythrocytes

IntroductionCrohn's disease and Ataxia Telangiectasia have been managed by extended release of dexamethasone from autologous red blood cells (RBC) with encapsulated dexamethasone sodium phosphate DSP. The EryDexSystem (EDS) is an automated system that loads RBC ex vivo using hypotonic opening of RBC followed by hypertonic resealing of the RBC and washing to prepare the DSP-RBC for infusion. In vivo, DSP is dephosphorylated within the RBC to dexamethasone which passively diffuses into the plasma. The objective of this two-phase study was to elucidate pharmacokinetics (PK) and in vivo 24-hour recovery of RBCs as well as RBC survival (T50) properties of RBC encapsulated DSP.Materials and MethodsThe study was conduct in two separate Phases, A and B. Phase A, the 24-hour RBC recovery and T50 survival phase, was designed as a randomized, concurrently controlled, single-blind, single-center study to determine the in vivo kinetics of EDS-processed autologous RBC. Healthy volunteer consenting subjects were randomized to receive autologous RBCs prepared using EDS and loaded with either 15-20mg DSP (Group 1A) or sham hypotonic saline (Group 2A). EDS prepared RBC were radiolabeled with 51-Cr following standard methods, and the in vivo labeled RBC followed over 49 days post infusion.The Phase B PK study was designed as an open-label, single-center Phase I study that evaluated two dose levels of DSP encapsulated in RBCs using the EDS. Healthy volunteer consenting subjects were randomized to receive autologous RBCs loaded with either 2.5-5 mg DSP (Group 1B) or 15-20 mg (Group 2B). Post-infusion plasma levels of dexamethasone were followed (over 42 days).Both studies conformed to the Declaration of Helsinki.ResultsPhase A: Ten subjects (3male; 7 female) were randomized to Groups 1A or 2A. The mean 24-hour RBC recovery ± SD [95% CL] was 77.9 ± 3.3% [73.8-81.9%] and 72.7 ± 10.5% [57.8-85.7%] for Groups 1A and 2A, respectively. The mean ± SD RBC life span in Group 1A was 84.3 ± 8.3 days with a mean T50 of 42.1 ± 4.1 [95% CL: 37.0, 47.3] days, whereas these values were 88.9 ± 6.2 days and 44.4 ± 3.1 [95% CL: 40.6, 48.3] days, respectively, in Group 2A. Sixteen (16) treatment-emergent adverse events (TEAEs) were recorded in Group 1A and 23 in Group 2A. All TEAEs were judged to be unlikely related to the treatment.Phase B: Eighteen subjects (12 male; 6 female) were randomized to Groups 2A and 2B. The actual DSP loading doses (mean ± SEM) were 4.2±0.27 mg and 16.9±0.90 mg. Release of dexamethasone from RBCs in vivo peaked at 1 hour after the end of IV infusion independent of the dose. A detailed summary of the PK parameters for dexamethasone for each treatment group is shown in Table 1. A sustained release of dexamethasone could be detected until 14 and 35 days after the single IV infusion ofEryDex in Group 1B and 2B, respectively. Six (6) TEAEs were reported in each group and were judged to be unlikely related to the study drug or procedure.ConclusionThe results for the mean RBC in vivo recovery for DSP-loaded EDS-processed cells meet the FDA criteria for 24-hour RBC recovery of ≥ 75%, without adverse impact on the survival of EDS-processed RBCs. Most of the dexamethasone was rapidly released from the RBCs in vivo with a maximum peak occurring 1 hour after the end of the intravenous infusion, independent of the dose administered, but sustained release of dexamethasone could be detected until 14 and 35 days post infusion for the low and high doses, respectively. DSP-loaded autologous RBCs prepared using the EDS delivered a sustained dose of dexamethasone in vivo. Additional efficacy studies in targeted patient populations are indicated. [Display omitted] DisclosuresSzczepiorkowski:EryDel S.P.A.: Research Funding. Ferrari:EryDel S.P.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Benatti:EryDel S.P.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Mambrini:EryDel S.P.A.: Employment, Equity Ownership. Hartman:EryDel S.P.A.: Consultancy. Dumont:EryDel S.P.A.: Research Funding.

The synergistic effect of nano-hydroxyapatite and dexamethasone in the fibrous delivery system of gelatin and poly(l-lactide) on the osteogenesis of mesenchymal stem cells

Recently, electrospun nanofibrous scaffolds are vastly taken into consideration in the bone tissue engineering due to mimicking the natural structure of native tissue. In our study, surface features of nanofibers were modified through simultaneous electrospining of the synthetic and natural polymers using poly l-lactide (PLLA) and gelatin to fabricate the hybrid scaffold (PLLA/gelatin). Then, hydroxyapatite nanoparticles (nHA) were loaded in electrospun PLLA nanofibers (PLLA,nHA/gelatin) and also dexamethasone (DEX) was incorporated in these fibers (PLLA,nHA,DEX/gelatin) in the second experiment. Fabricated nanofibrous composite scaffolds were characterized via SEM, FTIR spectroscopy, contact angle, tensile strength measurements, DEX release profile and MTT assay. After seeding adipose derived mesenchymal stem cells, osteoinductivity and osteoconductivity of fabricated scaffolds were analyzed using common osteogenic markers such as alkaline phosphatase activity, calcium depositions and gene expression. These results confirmed that all properties of nanofibers were improved by modifications. Moreover, osteogenic differentiation of stem cells increased in PLLA,nHA/gelatin group in comparison with PLLA/gelatin. The sustained release of DEX was obtained from PLLA,nHA,DEX/gelatin which subsequently led to more osteogenic differentiation. Taken together, PLLA,nHA,DEX/gelatin showed significant potential to support the stem cell proliferation and ostogenic differentiation, and can be a good candidates for tissue engineering and regenerative medicine applications.

Dexamethasone-loaded biopolymeric nanoparticles promote gingival fibroblasts differentiation.

Polymer-based nanoparticles (NPs) can be efficiently used for the delivery of bioactive molecules for both in vitro and in vivo applications affording high drug loading and controlled release profiles. Within this framework polylactic-co-glycolic acid (PLGA) NPs with a diameter of 290 ± 41 nm have been fabricated and loaded with dexamethasone (DXM) using a patented procedure. The aim of the project was to setup a controlled delivery system to promote the in vitro differentiation of Human Gingival Fibroblasts (HGFs). First the uptake of fluorescent PLGA NPs by HGFs cells was investigated; then experiments were also addressed to analyze the specific cell response to DXM, in order to evaluate its functional efficiency in comparison with its conventional addition to the culture medium. The results showed that cells treated with DXM-loaded NPs acquired the osteoblast phenotype faster in comparison to those treated with the free drug. The slow and sustained release of DXM from PLGA NPs produced a constant and uniform concentration of drug inside cells with long-term and enhanced biochemical effects.

Effects of a dexamethasone-releasing implant on cochleae: A functional, morphological and pharmacokinetic study

AimThis study evaluated the impact of a dexamethasone-releasing silicone implant on hearing function preservation, cochlear morphology and perilymph pharmacokinetics after cochlear implantation. MethodsGuinea pigs were implanted unilaterally with silicone rods containing either 2% dexamethasone (DEXA group, n = 18) or no dexamethasone (control group, n = 17). Auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs) were measured preoperatively and over 6 months postoperatively. Cochlear histology using standard hematoxylin and eosin (H&E) staining and tumor necrosis factor (TNF)-alpha staining was performed 1 month postoperatively. Twenty-two guinea pigs were involved in the pharmacokinetic study, and real-time drug concentrations in perilymph were investigated using high-performance liquid chromatography (HPLC). The Mann–Whitney U test (1-tailed) was used for statistical analyses. ResultsABR and DPOAE testing demonstrated decreased hearing function immediately postoperatively followed by a progressive hearing loss within the first day postoperatively. There was almost no observable hearing improvement in the control group from 1 week to 6 months postoperatively, but hearing levels in the DEXA group improved gradually from 1 week to 12 weeks. Hearing loss in the DEXA and control group was 5.0 ± 3.4 dB and 21.7 ± 5.3 dB, respectively at a 16-kHz stimulus frequency 6 months postoperatively. The difference in threshold shifts was present throughout all measured frequencies, and it was significant at 4–24 kHz. The morphological study revealed new fibrosis formation in the scala tympani, which encapsulated the implanted electrode. TNF-alpha positive staining in the cochleae of the DEXA group was less evident than the control group. The pharmacokinetic study revealed a peak perilymph concentration 30 min postoperatively and sustained dexamethasone release at least 1 week postoperatively. ConclusionCochlear implants that incorporate dexamethasone can release drug chronically in the inner ear and induce significant long-term recovery and preservation of auditory function after implantation.

PCL-forsterite nanocomposite fibrous membranes for controlled release of dexamethasone.

The well-known treatment of the alveolar bone defects is guided tissue regeneration (GTR). Engineered membranes combined with osteo-differentiation factors have been offered a promising strategy for GTR application. Recently, poly(ε-caprolactone) (PCL)-forsterite (PCL-F) nanocomposite fibrous membranes have been developed. However, PCL-F membranes could not promote bone tissue regeneration. The aim of this research is to encapsulate an osteogenic factor [dexamethasone (DEX)] in PCL-F membranes and evaluate the effects of forsterite nanopowder (particle size = 25-45 nm) and fiber organization on DEX delivery for GTR application. The hypothesis is that the release kinetic and profile of DEX could be controlled through variation of forsterite content (0, 5 and 10 wt%) and fiber arrangement (aligned and random). Results demonstrated while DEX release was sustained over a period of 4 weeks, its kinetic was governed by the membrane architecture and composition. For example, aligned PCL-F nanocomposite fibrous membrane consisting of 10 %(w/v) forsterite nanopowder exhibited the least initial burst release (13 % release in the first 12 h) and allowed sustained release of DEX. Additionally, forsterite nanopowder inclusion changed the kinetic of DEX release from Fickian diffusion to an anomalous transport. The bioactivity of released DEX was estimated using culturing the stem cells from human exfoliated deciduous teeth (SHED) on the membranes. Results demonstrated that proliferation and osteogenic differentiation of SHED could be governed by DEX release process. While DEX release from the membranes decreased SHED proliferation, stimulated the matrix mineralization. Our finding indicated that aligned PCL-F/DEX membrane could be used as a carrier for the sustained release of drugs relevant for GTR trophy.

Controlled Release of Dexamethasone in PCL/Silk Fibroin/Ascorbic Acid Nanoparticles for the Initiation of Adipose Derived Stem Cells into Osteogenesis

Mimicking hybrid extracellular matrix is one of the major challenges in bone tissue engineering. Biocomposite micro/nanoparticle of polycaprolactone (PCL), silk fibroin (SF), ascorbic acid (AA) and dexamethasone (DM) were fabricated by the electrospraying methods in order to generate an improved osteogenic environment for the proliferation and differentiation of adipose derived stem cells (ADSCs) into osteogenesis. Fabricated electrosprayed micro/nanoparticle was characterized for particle morphology, hydrophilicity, porosity and FTIR analysis for bone tissue regeneration. FESEM micrographs of the nanoparticles revealed porous, fibreless, uniform particles with particle diameter in the range of 720 ± 1.8 nm - 3.5 ± 4.2 μm. The drug release profile indicates that the sustained release of dexamethasone up to 10 days and degradation of nanoparticles around 13-20% after 60 days. ADSCs were cultured on these nanoparticles and were induced to undergo osteogenic differentiation in the presence of AA/DM. The cells morphology, proliferation and interaction were analysed by CMFDA dye extraction method, MTS assay and FESEM analysis respectively.ADSCs differentiation into osteogenesis was confirmed using alkaline phosphatase activity and mineralisation by Alizarin Red staining. The significance of AA and DM biomolecules initiates particular biological functions for the proliferation of ADSCs and differentiation into osteogenic lineages. The obtained results proved that the biocomposite PCL/SF/AA/DM micro/nanoparticle stimulated osteogenic differentiation and mineralisation of ADSCs for bone tissue regeneration.

Overcoming glucocorticoid resistances and improving antitumor therapies: lipid and polymers carriers.

To improve chemotherapy protocols of lymphoid malignancies, by using polymeric and lipid microparticles as controlled delivery systems of dexamethasone, part of all combined chemotherapy protocols for its strong-inducing effect on malignant lymphoblasts. Polymeric microparticles were prepared by the oil-in-water-emulsion cosolvent evaporation method, andlipid microparticles by spray drying. Their cytotoxic effects on GC-sensitive PC12 cells and GC-resistant PC3 cells were characterized by cell proliferation and apoptosis assays. Both elaboration methods rendered optimal-sized microparticles for parenteral administration with high drug loading. In vitro assays showed sustained dexamethasone release from polymeric microparticles over a month, whereas 100% dexamethasone release from lipid microparticles was achieved within 24 h. Similar PC12 cell death to that obtained with dexamethasone solution administered every 48 h was achieved with dexamethasone polymeric microparticles in 26-days assays. Dexamethasone solution and loaded polymeric microparticles induced apoptosis around 15.8 and 19.9%, respectively, after 2 days of incubation. Lipid microparticles increased further apoptosis induction in PC12 cells and, unlike dexamethasone solution and polymeric microparticles, showed antiproliferative effects on PC3 cells. Dexamethasone polymeric microparticles constitute an alternative to current dexamethasone administration systems in combined chemotherapy, whereas dexamethasone lipid microparticles represent a potential tool to revert glucocorticoid resistance.

Synthesis and photopolymerisation of maleic polyvinyl alcohol based hydrogels for bone tissue engineering

The novel synthesis of photopolymerisable polyvinyl alcohol (PVA) was achieved by reacting maleic anhydride with the hydroxyl groups of PVA. The incorporation of photopolymerisable double bonds onto the PVA polymeric chain was confirmed by both 1H NMR and 13C NMR spectroscopy. Hydrogel blends were prepared by mixing maleic PVA and polyethylene glycol dimethacrylate (PEGDMA) precursors at different concentrations and molecular weights. It was observed that the increase in crosslinking with the introduction of maleic PVA crosslinks resulted in higher compressive properties and storage modulus values. These values fall below those reported for bone; however, if these scaffolds were used in conjunction with fixation devices and with the sustained release of dexamethasone it would allow for faster regeneration of bone defects. Drug release results showed that the release profile of the hydrogels was between 11 and 16 days. This was as a result of altering the swelling and pore sizes of the hydrogels by varying the precursor concentrations. Preliminary in vitro cytotoxicity evaluations were performed using the MTT assay as an end point, showing that these novel hydrogels are non-toxic to mouse embryonic fibroblast cell line.

Anti-inflammatory drug releasing absorbable surgical sutures using poly(lactic-co-glycolic acid) particle carriers

The goal of the current study was to develop an absorbable surgical suture incorporating poly(lactic-co-glycolic acid) (PLGA) particles loaded with dexamethasone (DEX) as an anti-inflammatory drug. DEX-loaded PLGA (DEX/PLGA) particles, prepared using a water-in-oil emulsion method, were electrostatically immobilized onto the surface of absorbable sutures. The surfaces of these DEX/PLGA particles were coated with positively charged polyethyleneimine (PEI) molecules, which imparted a net positive surface charge. These modified PEI-coated DEX/PLGA (PEI/DEX/PLGA) particles were then immobilized on negatively charged absorbable suture surfaces by electrostatic attraction. The results showed that DEX was efficiently loaded into PLGA particles and that the surfaces of DEX/PLGA particles were successfully coated with PEI. PEI/DEX/PLGA particles were well dispersed and immobilized onto suture surfaces. In addition, PEI/DEX/PLGA particles remained adherent to suture surfaces in vitro and demonstrated sustained DEX release in phosphate-buffered saline (pH 7.4) at 37 °C for up to 28 days under static conditions. The tensile strength and elongation at break of PEI/DEX/PLGA particle-treated sutures were almost the same as that of non-treated control sutures. Findings of this study show that various therapeutic drugs could be efficiently incorporated into absorbable sutures using biodegradable polymeric particles, and suggest that the devised absorbable, drug-eluting, sutures offer a promising basis for a novel absorbable surgical suture system.

The releasing behavior and in vitro osteoinductive evaluations of dexamethasone-loaded porous calcium phosphate cements

In the present study, the effect of adding different concentrations of dexamethasone (DEX) on setting time, apatite formation and mechanical properties of micro/macroporous calcium phosphate cements (CPCs) was studied. The liberation of loaded DEX was evaluated over 0–840 h in simulated body fluid (SBF). Differentiation of mesnchymal stem cells on DEX-free and loaded CPCs were also compared by expression of bone marker proteins. The results showed that setting time decreased by adding DEX to CPCs whereas mechanical strength and conversion rate of cement reactants into apatite phase. A sustained release of DEX was observed from the loaded CPCs in which the rate of DEX release increased by introducing macroporosity and higher portion of loaded DEX. Osteogenic differentiation of MSCs on DEX-loaded CPCs was confirmed by elevated gene expressions of bone markers such as alkaline phosphatase, osteopontin and osteocalcin. Overall, the results reveal that DEX-loaded CPCs may be potentially osteoinductive material with enhanced biological functions but more in vivo evaluations are required to prove this suggestion.

Intravitreal Dexamethasone Implant for the Treatment of Macular Edema after Retinal Vein Occlusion in a Clinical Setting

To study the efficacy and safety of a new intravitreal implant (sustained release of dexamethasone, Ozurdex®) recently approved in Switzerland for the treatment of macular edema secondary to retinal vein occlusion in a clinical setting. Prospective non-consecutive study of patients with macular edema secondary to central retinal vein occlusion or branch retinal vein occlusion treated with implant of dexamethasone 0.7 mg. Follow-up visits were performed at day 1, week 1 and monthly thereafter. ETDRS best corrected visual acuity, Goldmann tonometry and macular thickness on SD-OCT were registered. Retreatment was carried out on a pro re nata basis starting from month 3. Fifteen eyes of 15 patients were included (8 branch retinal vein occlusions, 7 central retinal vein occlusions). 33% of the patients achieved 3 lines or more of vision gain. The central retinal vein occlusion subgroup showed a mean decline in visual acuity at month 3. A reduction of 36% of macular edema was already observed at day 1. All maculae were dry at month 1. The mean time of recurrence of macular edema for both groups was 4.6 months. A similar reduction of macular edema was obtained after a second implantation. An intraocular pressure increase of ≥ 20% was observed after the first implantation in 53% of patients. Our study showed efficacy and safety of intravitreal dexamethasone implant in the treatment of macular edema due to retinal vein occlusion. Anatomical efficacy was observed at day 1 but seems to have shorter effect than previously published data. No serious side effects were observed.

Intravitreal Administration of Dexamethasone-Loaded PLGA-TPGS Nanoparticles for the Treatment of Posterior Segment Diseases

The purpose of this research was to investigate the possibility of dexamethasone (DEX)-loaded PLGA-TPGS nanoparticles (NPs) in rabbits after intravitreal administration for the treatment of posterior segment diseases. The DEX-loaded PLGA-TPGS NPs were fabricated and characterized in terms of surface morphology, particle size and size distribution, entrapment efficiency, and in vitro drug release. The animals were classified randomly into two groups: experimental group with thirty rabbits, and control group with eighteen rabbits. Rabbits in the experimental group received intravitreal injections of 0.1 mL of DEX-loaded PLGA-TPGS NPs suspension and the control rabbits received intravitreal injection of 0.1 mL DEX (20 g/L in saline). The DEX concentrations in plasma and the ocular tissues such as the cornea, aqueous humor, lens, iris, vitreous humor, and chorioretina were determined by HPLC. The DEX-loaded PLGA-TPGS nanoparticle suspension were transparent and maintained a sustained release of DEX for about 45 days in vitreous and provided relatively constant DEX levels for more than 30 days with a mean concentration of 3.93 mg/L. Based on the area-under-the-curve (AUC), the bioavailability of DEX in the experimental group was significantly higher than that in the control group administrated with regular DEX. These results suggest that intravitreal administration of DEX-loaded PL.3A-TPGS NPs leads to a sustained release of DEX with a high bioavailability, providing a basis for a novel approach to treat posterior segment diseases.

Porous calcium phosphate granules containing drug-loaded polymeric nanoparticles for bone regeneration

A simple and highly efficient method for fabrication of drug-loaded porous calcium phosphate (CP) granules using biodegradable nanoparticles was developed in this study. Porous CP granules were used as a bone graft substitute with a localized drug delivery structure. Spherical CP granules with open micro-channels and PLGA nanoparticles loaded with dexamethasone (DEX) as a model drug were fabricated by a liquid nitrogen method and a single emulsion method, respectively. The produced nanoparticles were pre-coated with positively charged poly(ethyleneimmine) (PEI) molecules and then immobilized via electrical interaction in the micro-channels on the surfaces of CP granules, which have a negative charge. The results indicated that the PEI-coated PLGA nanoparticles loaded with DEX were successfully incorporated and well-dispersed in the micro-channels of the CP granules. The nanoparticles were not released from the CP granules and allowed a sustained release of DEX from the nanoparticle-based CP granules over the course of 1month.

Proliferation, differentiation and gene expression of osteoblasts in boron-containing associated with dexamethasone deliver from mesoporous bioactive glass scaffolds

Boron is one of the trace elements in the human body which plays an important role in bone growth. Porous mesopore bioactive glass (MBG) scaffolds are proposed as potential bone regeneration materials due to their excellent bioactivity and drug-delivery ability. The aims of the present study were to develop boron-containing MBG (B-MBG) scaffolds by sol–gel method and to evaluate the effect of boron on the physiochemistry of B-MBG scaffolds and the response of osteoblasts to these scaffolds. Furthermore, the effect of dexamethasone (DEX) delivery in B-MBG scaffold system was investigated on the proliferation, differentiation and bone-related gene expression of osteoblasts. The composition, microstructure and mesopore properties (specific surface area, nano-pore volume and nano-pore distribution) of B-MBG scaffolds have been characterized. The effect of boron contents and large-pore porosity on the loading and release of DEX in B-MBG scaffolds were also investigated. The results have shown that the incorporation of boron into MBG scaffolds slightly decreases the specific surface area and pore volume, but maintains well-ordered mesopore structure and high surface area and nano-pore volume compared to non-mesopore bioactive glass. Boron contents in MBG scaffolds did not influence the nano-pore size distribution or the loading and release of DEX. B-MBG scaffolds have the ability to maintain a sustained release of DEX in a long-term span. Incorporating boron into MBG glass scaffolds led to a controllable release of boron ions and significantly improved the proliferation and bone-related gene expression (Col I and Runx2) of osteoblasts. Furthermore, the sustained release of DEX from B-MBG scaffolds significantly enhanced alkaline phosphatase (ALP) activity and gene expressions (Col I, Runx2, ALP and BSP) of osteoblasts. These results suggest that boron plays an important role in enhancing osteoblast proliferation in B-MBG scaffold system and DEX-loaded B-MBG scaffolds show great potential as a release system to enhance osteogenic property for bone tissue engineering application.

OTO-104

To investigate whether OTO-104, a poloxamer-based hydrogel containing micronized dexamethasone for intratympanic delivery, can provide long-lasting inner ear exposure and be well tolerated. OTO-104 was administered intratympanically to guinea pigs and sheep, and its pharmacokinetic and toxicity profiles were examined. After a single intratympanic injection of OTO-104 (from 0.6% to 20%, w/w), significant and prolonged exposure to dexamethasone in the inner ear was observed. Increasing the concentration of OTO-104 resulted in higher perilymph drug levels as well as a more prolonged duration of exposure. At the highest dose, therapeutic perilymph levels of dexamethasone could be sustained over 3 months in guinea pigs and more than 1 month in sheep. A toxicologic evaluation was conducted, including assessments of middle and inner ear function and physiology, as well as appraisal of local and systemic toxicity. A small and transient shift in hearing threshold was observed, most probably conductive in nature. No significant histologic changes in middle or inner ear tissues were noted. Although macroscopically mild erythema/inflammation was documented in a subset of guinea pigs treated with 20% OTO-104, the nature and the severity of these changes were not different between the poloxamer vehicle, saline, and 20% OTO-104 groups. No evidence of acute dermal toxicity, delayed hypersensitivity, or systemic adverse effects was found. OTO-104 is a novel proprietary therapeutic delivery system that can achieve prolonged, sustained release of dexamethasone within the inner ear fluids. The administration of this clinical candidate formulation via intratympanic injection is expected to be well tolerated both locally and systemically.

Biomaterial adjuvant effect is attenuated by anti-inflammatory drug delivery or material selection

Biomaterials have been shown to differentially support dendritic cell (DC) maturation, a prerequisite for an adjuvant effect. Treatment of DCs with poly(D,L-lactic- co-glycolic acid) (PLGA) films resulted in DC maturation but agarose films did not. In these studies, the biomaterial adjuvant effect was attenuated by material selection (PLGA or agarose scaffolds) or local delivery of an anti-inflammatory/immunosuppressive glucocorticoid, dexamethasone (DX), from PLGA scaffolds. Porous scaffolds (SCs) of PLGA or agarose were produced to deliver equivalent amounts of model antigen, ovalbumin (OVA). Alternatively, PLGA SCs with incorporated OVA were produced with or without DX. These SCs were implanted individually, subcutaneously, and dorsally in C57BL/6 mice. Blood was collected from mice at specific times over a 12-week duration for measurement of antibody production against OVA. Scaffolds were explanted at 12 weeks for histological examination of foreign body response. Scaffolds of PLGA, but not of agarose, were found to elicit higher antibody production against co-delivered OVA, than negative controls. Short-term delivery of DX from PLGA SCs delivering OVA temporarily delayed onset of anti-OVA antibody production. More sustained release of DX at an effective dose and with an appropriate time course is expected to extend the effect of DX on the biomaterial adjuvant effect. The immunomodulatory ability of biomaterials to affect the immune response to co-delivered antigen is demonstrated wherein this immunomodulatory ability correlates with the observed in vitro differential effects of biomaterials on DC maturation.

Novel Nanoparticulate Gel Formulations of Steroids for the Treatment of Macular Edema

This article describes the development and characterization of PLGA nanoparticles of dexamethasone (DEX), hydrocortisone acetate (HA), and prednisolone acetate (PA) suspended in thermosensitive gels indicated for the treatment of macular edema (ME). Nanoparticles were prepared by oil-in-water (O/W) emulsion and dialysis methods using PLGA 50:50 and PLGA 65:35. These particles were characterized for entrapment efficiency, size distribution, surface morphology, crystallinity, and in vitro release. Further, ex vivo permeation studies of DEX in suspension and nanoparticulate formulations were carried out across the rabbit sclera. Entrapment efficiencies of DEX, HA, and PA were found to be lower with the dialysis method. O/W emulsion/solvent evaporation technique resulted in higher entrapment efficiencies, that is, 77.3%, 91.3%, 92.3% for DEX, HA, and PA, respectively. Release from nanoparticles suspended in thermosensitive gels followed zero-order kinetics with no apparent burst effect. Ex vivo permeability studies further confirmed sustained release of DEX from nanoparticles suspended in thermosensitive gels. These novel nanoparticulate systems containing particles suspended in thermosensitive gels may provide sustained retina/choroid delivery of steroids following episcleral administration.

Pharmacokinetics and tolerance study of intravitreal injection of dexamethasone-loaded nanoparticles in rabbits.

The aim of the study was to investigate the tolerance and pharmacokinetics of dexamethasone (DEX)-loaded poly(lactic acid-co-glycolic acid) nanoparticles (DEX-NPs) in rabbits after intravitreal injection. The DEX-NPs were prepared and characterized in terms of morphology, particle size and size distribution, encapsulation efficiency, and in vitro release. Ophthalmic investigations were performed, including fundus observation and photography, intraocular pressure measurement, and B-scan ocular ultrasonography. There were no abnormalities up to 50 days after administration of DEX-NPs in rabbits. The DEX concentrations in plasma and the ocular tissues such as the cornea, aqueous humor, lens, iris, vitreous humor, and chorioretina were determined by high-pressure liquid chromatography. The DEX-NPs maintained a sustained release of DEX for about 50 days in vitreous and provided relatively constant DEX levels for more than 30 days with a mean concentration of 3.85 mg/L(-1). Based on the areas under the curve, the bioavailability of DEX in the experimental group was significantly higher than that in the control group injected with regular DEX. These results suggest that intravitreal injection of DEX-NPs lead to a sustained release of DEX with a high bioavailability, providing a basis for a novel approach to the treatment of posterior segment diseases.

Dexamethasone-loaded scaffolds prepared by supercritical-assisted phase inversion

The aim of this study was to evaluate the possibility of preparing dexamethasone-loaded starch-based porous matrices in a one-step process. Supercritical phase inversion technique was used to prepare composite scaffolds of dexamethasone and a polymeric blend of starch and poly( l-lactic acid) (SPLA) for tissue engineering purposes. Dexamethasone is used in osteogenic media to direct the differentiation of stem cells towards the osteogenic lineage. Samples with different drug concentrations (5–15 wt.% polymer) were prepared at 200 bar and 55 °C. The presence of dexamethasone did not affect the porosity or interconnectivity of the polymeric matrices. Water uptake and degradation studies were also performed on SPLA scaffolds. We conclude that SPLA matrices prepared by supercritical phase inversion have a swelling degree of nearly 90% and the material presents a weight loss of ∼25% after 21 days in solution. Furthermore, in vitro drug release studies were carried out and the results show that a sustained release of dexamethasone was achieved over 21 days. The fitting of the power law to the experimental data demonstrated that drug release is governed by an anomalous transport, i.e., both the drug diffusion and the swelling of the matrix influence the release of dexamethasone out of the scaffold. The kinetic constant was also determined. This study reports the feasibility of using supercritical fluid technology to process in one step a porous matrix loaded with a pharmaceutical agent for tissue engineering purposes.