Dexamethasone-loaded Microspheres Research Articles

QS59. Pulsed-release Dexamethasone-loaded Microspheres Mitigate Scar Contracture and Adhesions in Composite Tissue Burn Reconstruction

Purpose: Soft-tissue loss after complex burns is devastating to quality of life, ability to work, and psychosocial well-being. These are disfiguring injuries requiring surgical management and are almost universally limited by contracture, adhesion, and soft-tissue deficit. We have previously described a fat-first, delayed-skin approach to complex burn reconstruction to treat the hypodermal deficit and improve soft tissue-mobility and deficits. Here we describe the use of timed- and pulse-release dexamethasone to augment this approach and mitigate contracture during skin-graft delay. Methods: Yorkshire swine received 16, 4x4 cm full-thickness burns. After 48 hours, eschar was removed to fascia. Wounds were stratified across untreated pigs to receive A) No Reconstruction, B) Skin-Only, C) Fat-Only, D) Immediate-Skin, Delayed-Fat, or E) Immediate-Fat, Delayed-Skin. Treatment pigs with Group E wounds then received either 1) Empty Microspheres or Dexamethasone as follows 2) Continuous/Sustained, 3) Immediate-Pulsed, 4) Delayed-Pulsed, or 5) Bimodal-Pulsed. At 8 weeks post-engraftment animals were sacrificed and all wounds were collected for photography, ultrasound, histology and serum studies. Results: Fat-first reconstruction minimizes adhesions soft-tissue deficits, however, is limited by rapid early contracture which was mitigated by the skin-first approach. Early dexamethasone blocks contracture, however, sustained dosing limited skin graft take. Pulsed-dosing was permissive of skin grafts in the drug elution nadir. Combination fat-first with pulsed-dexamethasone resulted in significant reduction in adhesion, soft-tissue deficit, and contracture vs. skin-first approaches. Conclusion: Here we demonstrate augmentation of a fat-first approach by timed-release dexamethasone to safely mitigate contracture, adhesion, and soft-tissue deficits vs. current reconstructive standards for complex burn wounds.

Lung Targeted Lipopolymeric Microspheres of Dexamethasone for the Treatment of ARDS.

Acute respiratory distress syndrome (ARDS), a catastrophic illness of multifactorial etiology, involves a rapid upsurge in inflammatory cytokines that leads to hypoxemic respiratory failure. Dexamethasone, a synthetic corticosteroid, mitigates the glucocorticoid-receptor-mediated inflammation and accelerates tissue homeostasis towards disease resolution. To minimize non-target organ side effects arising from frequent and chronic use of dexamethasone, we designed biodegradable, lung-targeted microspheres with sustained release profiles. Dexamethasone-loaded lipopolymeric microspheres of PLGA (Poly Lactic-co-Glycolic Acid) and DPPC (Dipalmitoylphosphatidylcholine) stabilized with vitamin E TPGS (D-α-tocopheryl polyethylene glycol succinate) were prepared by a single emulsion technique that had a mean diameter of 8.83 ± 0.32 μm and were spherical in shape as revealed from electron microscopy imaging. Pharmacokinetic and biodistribution patterns studied in the lungs, liver, and spleen of Wistar rats showed high selectivity and targeting efficiency for the lung tissue (re 13.98). As a proof-of-concept, in vivo efficacy of the microspheres was tested in the lipopolysaccharide-induced ARDS model in rats. Inflammation markers such as IL-1β, IL-6, and TNF-α, quantified in the bronchoalveolar lavage fluid indicated major improvement in rats treated with dexamethasone microspheres by intravenous route. Additionally, the microspheres substantially inhibited the protein infiltration, neutrophil accumulation and lipid peroxidation in the lungs of ARDS bearing rats, suggesting a reduction in oxidative stress. Histopathology showed decreased damage to the pulmonary tissue upon treatment with the dexamethasone-loaded microspheres. The multipronged formulation technology approach can thus serve as a potential treatment modality for reducing lung inflammation in ARDS. An improved therapeutic profile would help to reduce the dose, dosing frequency and, eventually, the toxicity.

Design and Evaluation of Long Acting Biodegradable PLGA Microspheres for Ocular Drug Delivery

Background:: The research work involves the development of PLGA biodegradable microspheres loaded with dexamethasone for intraocular delivery. Objective:: The study aimed to design and evaluate long acting PLGA microspheres for ocular delivery of dexamethasone. Methods:: The present formulation involves the development of long-acting dexamethasone loaded microspheres composed of a biodegradable controlled release polymer, Poly(D,L-lactide-coglycolide) (PLGA), for the treatment of posterior segment eye disorders intravitreally. PLGA with a monomer ratio of 50:50 of lactic acid to glycolic acid was used to achieve a drug release for up to 45 days. Quality by Design approach was utilized for designing the experiments. Single emulsion solvent evaporation technique along with high-pressure homogenization was used to facilitate the formation of microspheres. Results:: Particle size evaluation, drug content and drug entrapment efficiency were determined for the microspheres. Particle size and morphology were observed using Field Emission Gun- Scanning Electron Microscopy (FEG-SEM) and microspheres were in the size range of 1-5 μm. Assessment of drug release was done using in vitro studies and trans retinal permeation was observed by ex vivo studies using goat retinal tissues. Conclusion:: Considering the dire need for prolonged therapeutic effect on diseases of the posterior eye, an intravitreal long-acting formulation was designed. The use of biodegradable polymer with biocompatible degradation products was a rational approach to achieve this aim. The outcome of the present research shows that developed microspheres would provide a long-acting drug profile and reduce the frequency of administration thereby improving patient compliance.

An Injectable Click-Crosslinked Hydrogel that Prolongs Dexamethasone Release from Dexamethasone-Loaded Microspheres.

Our purpose was to test whether a preparation of injectable formulations of dexamethasone (Dex)-loaded microspheres (Dex-Ms) mixed with click-crosslinked hyaluronic acid (Cx-HA) (or Pluronic (PH) for comparison) prolongs therapeutic levels of released Dex. Dex-Ms were prepared using a monoaxial-nozzle ultrasonic atomizer with an 85% yield of the Dex-Ms preparation, encapsulation efficiency of 80%, and average particle size of 57 μm. Cx-HA was prepared via a click reaction between transcyclooctene (TCO)-modified HA (TCO-HA) and tetrazine (TET)-modified HA (TET-HA). The injectable formulations (Dex-Ms/PH and Dex-Ms/Cx-HA) were fabricated as suspensions and became a Dex-Ms-loaded hydrogel drug depot after injection into the subcutaneous tissue of Sprague Dawley rats. Dex-Ms alone also formed a drug depot after injection. The Cx-HA hydrogel persisted in vivo for 28 days, but the PH hydrogel disappeared within six days, as evidenced by in vivo near-infrared fluorescence imaging. The in vitro and in vivo cumulative release of Dex by Dex-Ms/Cx-HA was much slower in the early days, followed by sustained release for 28 days, compared with Dex-Ms alone and Dex-Ms/PH. The reason was that the Cx-HA hydrogel acted as an external gel matrix for Dex-Ms, resulting in the retarded release of Dex from Dex-Ms. Therefore, we achieved significantly extended duration of a Dex release from an in vivo Dex-Ms-loaded hydrogel drug depot formed by Dex-Ms wrapped in an injectable click-crosslinked HA hydrogel in a minimally invasive manner. In conclusion, the Dex-Ms/Cx-HA drug depot described in this work showed excellent performance on extended in vivo delivery of Dex.

Effect of Drug Carrier Melting Points on Drug Release of Dexamethasone-Loaded Microspheres.

Here, we examined the effect of melting point of drug carriers on drug release of dexamethasone (Dex)-loaded microspheres. We prepared poly(L-lactide-ran-ε-caprolactone) (PLC) copolymers with varying compositions of poly(ε-caprolactone) (PCL) and poly(L-lactide) (PLLA). As the PLLA content increased, the melting points of PLC copolymers decreased from 61 to 43°C. PLC copolymers in vials solubilized at 40-50°C according to the incorporation of PLLA into the PCL segment. Dexamethasone (Dex)-loaded PLC (MCxLy) microspheres were prepared by the oil-in-water (O/W) solvent evaporation/extraction method. The preparation yields were above 70%, and the mean particle size ranged from 30 to 90μm. The MCxLy microspheres also showed controllable melting points in the range of 40-60°C. Dex-loaded MCxLy microspheres showed similar in vitro and in vivo sustained release patterns after the initial burst of Dex. The in vitro and in vivo order of the Dex release was MC80L20>MC90L10>MC95L5, which agreed well with the melting point order of the drug carrier. Using in vivo fluorescence imaging of fluorescein (FI)-loaded microspheres implanted in animals, we confirmed the sustained release of FI over an extended period. In vivo inflammation associated with the PLC microsphere implants was less pronounced than that associated with Poly(lactide-co-glycolide) (PLGA). In conclusion, we successfully demonstrated that it is possible to control Dex release using Dex-loaded MCxLy microspheres with different melting points.

Downregulation of endotoxin-induced uveitis by intravitreal injection of polylactic-glycolic acid (PLGA) microspheres loaded with dexamethasone

We tested the short- and long-term ability of polylactic-glycolic acid (PLGA) microspheres loaded with dexamethasone to reduce ocular inflammation in rabbits elicited by intravitreal lipopolysaccharide (LPS) injection. PLGA microspheres loaded with dexamethasone were prepared by the solvent evaporation technique from an oil/water emulsion and sterilized by gamma irradiation (25 kGy). The microsphere fraction selected was 2:10 (dexamethasone:PLGA) and contained 141 ± 0.38 μg dexamethasone/mg PLGA. Microsphere diameters were 20–53 μm, and the mean encapsulation efficiency was 92.97 ± 0.75%. Seven days prior to the induction of panuveitis, 10 mg of dexamethasone-free or dexamethasone-loaded microspheres were injected into the vitreous. Control animals received no injection. Panuveitis was induced in male New Zealand rabbits (2.5–3.0 kg) by intravitreal injection of Escherichia coli LPS. Clinical evaluation, electroretinography and histopathologic studies were performed in short-term studies of 15 days and in long-term studies of 33 days. Efficacy in reducing inflammation was also studied in vitrectomized eyes. In short-term studies eyes injected with dexamethasone-loaded microspheres had less inflammation than control eyes and eyes injected with blank microspheres. Inflammation reverted in all groups by 15 days after LPS injection. A second LPS dose given on Day 30 provoked a high peak of inflammation in control eyes and in those injected with blank microspheres. In contrast, only slight inflammation occurred in eyes injected with dexamethasone-loaded microspheres. Histopathology and electroretinography supported these results. Dexamethasone-loaded microspheres effectively reduced intraocular inflammation caused by LPS in both short- and long-term studies.

Sustained local drug delivery to the arterial wall via biodegradable microspheres.

This study was designed to evaluate the feasibility of applying locally delivered polylactic acid microspheres for drug delivery to the arterial wall. To study drug persistence, rhodamine-loaded microspheres were infused into one carotid artery of 14 rabbits and plain rhodamine solution into the other by using a porous balloon. To study tissue response, plain microspheres and dexamethasone-loaded microspheres were infused into the carotid arteries of another group of rabbits. To study the antiproliferative effects of locally delivered drug, 20 rabbits were subjected to overstretch balloon injury to both carotid arteries and divided into 4 groups: injury alone, plain microspheres, dexamethasone-loaded microspheres, and microspheres containing colchicine and dexamethasone. Fluorescent microspheres persisted in the vessel wall for 4 wk, whereas rhodamine without microspheres disappeared at 72 h. Histopathologic studies in arteries infused with unloaded microspheres showed inflammatory cell infiltrate with polymorphonuclear cells at 1 wk and macrophages and giant cells at 4 wk. Arteries infused with dexamethasone-loaded microspheres did not show any inflammatory cell infiltrate. Local delivery of dexamethasone or dexamethasone plus colchicine did not result in significant change in the intima-to-media ratio or in residual lumen following balloon injury. Polylactic acid microspheres may be used for prolonged delivery of drugs or other bioactive agents locally to the arterial wall. They induce an inflammatory reaction that is suppressable by dexamethasone in the microspheres. Dexamethasone or dexamethasone and colchicine delivered via this system, however, failed to reduce the degree of intimal hyperplasia after overstretch balloon injury to the rabbit carotid arteries.