PLGA Rods Research Articles

Design of PLGA-Based Drug Delivery Systems Using a Physically-Based Sustained Release Model

An extensive data set has been developed and used to further the progress of a model-informed design of controlled drug release. An improved drug-release model with mechanistic modeling of hydrolytic polymer degradation is used and validated by comparing model predictions to in vitro experiments. Combining parameter estimates from the literature with model fits to the data set, this study can aid in achieving a priori design of controlled drug release from a model PLGA release system. A systematic series of model release systems were formulated with FITC-labeled dextran, as a surrogate for biopharmaceuticals, in PLGA rods over a broad range of compositions. While general comparisons between the model and experiments were favorable, important discrepancies were identified for several formulations with significant first-phase drug release. Supported by cross-sectional fluorescence microscopy images of the FITC-dextran distribution within the rods, this first-phase release was attributed to a combination of two main factors: (1) percolation of the drug particles and (2) swelling of and pore formation in the rods due to water uptake. These observations indicate the importance of careful selection of the PLGA polymer grade when designing drug release systems but also reflect a need for better understanding of phenomena such as pore formation. Adapting model parameters, without modifying the physical processes included in the model, enabled accurate fitting of the experimental data for all formulations, highlighting the applicability of the model.

The Effect of Diclofenac Sodium-Loaded PLGA Rods on Bone Healing and Inflammation: A Histological and Histomorphometric Study in the Femur of Rats.

Implants made of poly(lactide-co-glycolide) (PLGA) are biodegradable and frequently provoke foreign body reactions (FBR) in the host tissue. In order to modulate the inflammatory response of the host tissue, PLGA implants can be loaded with anti-inflammatory drugs. The aim of this study was to analyze the impact of PLGA 80/20 rods loaded with the diclofenac sodium (DS) on local tissue reactions in the femur of rats. Special emphasis was put on bone regeneration and the presence of multinucleated giant cells (MGCs) associated with FBR. PLGA 80/20 alone and PLGA 80/20 combined with DS was extruded into rods. PLGA rods loaded with DS (PLGA+DS) were implanted into the femora of 18 rats. Eighteen control rats received unloaded PLGA rods. The follow-up period was of 3, 6 and 12 weeks. Each group comprised of six rats. Peri-implant tissue reactions were histologically and histomorphometrically evaluated. The implantation of PLGA and PLGA+DS8 rods induced the formation of a layer of newly formed bone islands parallel to the contour of the implants. PLGA+DS rods tended to reduce the presence of multi-nucleated giant cells (MGCs) at the implant surface. Although it is known that the systemic administration of DS is associated with compromised bone healing, the local release of DS via PLGA rods did not have negative effects on bone regeneration in the femora of rats throughout 12 weeks.

Foreign Body Reaction, Retinal Degeneration, and Epiretinal Membranes Associated With Intravitreal Administration of PLGA Rods

Long-acting delivery platforms for intravitreal therapies are an active area of research in ophthalmic drug development. The aim of these platforms is to decrease the burden of intravitreal therapies for patients, by increasing the period between intravitreal injections. This brief communication describes the in-life, histologic and immunohistochemical findings associated with repeat-dose intravitreal administration of poly D, L sustained lactide-co-glycolide polymeric rods, an intravitreal depot, in the cynomolgus monkey (Macaca fascicularis). These nonclinical investigations illustrate a pattern of foreign body reaction around intravitreal depots at the temporal pars plana and demonstrated the histopathologic and immunohistologic features of retinal degeneration and epiretinal membrane formation in the inferior retina.

Trehalose Limits Fragment Antibody Aggregation and Influences Charge Variant Formation in Spray-Dried Formulations at Elevated Temperatures.

The preparation of PLGA rods for sustained release applications via a hot-melt extrusion process employs heat and mechanical shear. Understanding protein stability and degradation mechanisms at high temperature in the solid state is therefore important for the preparation of protein-loaded PLGA rods. The stability of a model protein, labeled Fab2, has been investigated in solid-state formulations containing trehalose at elevated temperatures. Spray-dried formulations containing varying levels of trehalose were exposed to temperatures ranging from 90 to 120 °C. Measurement of aggregation and chemical degradation rates suggests that trehalose limits Fab2 degradation in a concentration-dependent manner, but the effect tends to saturate when the mass ratio of trehalose to protein is around 1 in the solid formulation. The Fab2 secondary structure and spray-dried particle morphology were studied using circular dichroism and scanning electron microscopy techniques, respectively. On the basis of temperature and trehalose-dependent aggregation kinetics as well as changes in spray-dried particle morphology, a mechanism is proposed for the trehalose stabilization of proteins in solid state at elevated temperatures. The results reported here suggest that when fragment antibodies in the solid state are formulated with trehalose as excipient, a high temperature process such as hot-melt extrusion can be successfully accomplished with minimal degradation.

Modified two-step emulsion solvent evaporation technique for fabricating biodegradable rod-shaped particles in the submicron size range

HypothesisThough the emulsion solvent evaporation (ESE) technique has been previously modified to produce rod-shaped particles, it cannot generate small-sized rods for drug delivery applications due to the inherent coupling and contradicting requirements for the formation versus stretching of droplets. The separation of the droplet formation from the stretching step should enable the creation of submicron droplets that are then stretched in the second stage by manipulation of the system viscosity along with the surface-active molecule and oil-phase solvent. ExperimentsA two-step ESE protocol is evaluated where oil droplets are formed at low viscosity followed by a step increase in the aqueous phase viscosity to stretch droplets. Different surface-active molecules and oil phase solvents were evaluated to optimize the yield of biodegradable PLGA rods. Rods were assessed for drug loading via an imaging agent and vascular-targeted delivery application via blood flow adhesion assays. FindingsThe two-step ESE method generated PLGA rods with major and minor axis down to 3.2 µm and 700 nm, respectively. Chloroform and sodium metaphosphate was the optimal solvent and surface-active molecule, respectively, for submicron rod fabrication. Rods demonstrated faster release of Nile Red compared to spheres and successfully targeted an inflamed endothelium under shear flow in vitro and in vivo.

High‐Yield Fabrication of PLGA Non‐Spherical Microarchitectures by Emulsion‐Solvent Evaporation Method

Recently, it has been recognized the shape of particles plays an essential role in the design of materials with unique properties. In this study, PLGA non-spherical microarchitectures, rods and fibers, were fabricated successfully in high yield by single emulsion-solvent evaporation method in the presence of sodium tripolyphosphate. The assay of PVA residue was carried out and the hydrogen bonds formation was verified as well. The presented data show that viscosity and coagulation agent have a synergistic effect on forming the rod- and fiber-like microarchitectures in the shear response and the formation mechanisms were proposed accordingly.

Release of nestorone from biodegradable rods system in vitro

To study the controlled effect of poly (lactic acid) (PLA), poly lactic-co-glycolic (PLGA) and ethylenediamine (EDA)-maleic anhydride (MAH) modified PLA (EMPLA) for in vitro release of nestorone, rods were prepared using the solvent evaporation method. Amount of drug release in vitro was determined by UV spectrophotometry. Effects of rods diameter, the molecular weight of PLA, the drug percentage and the hydrophilicity of polymers on the release of biodegradable nestorone rods in vitro were investigated. It is indicated that the controlled effect of the biodegradable rods for the release of nestorone in vitro is good. The amount of drug released every week from rods in different diameter is similar to one another. The amount of drug released every week and the accumulative drug released during 12 week were almost in direct proportion with the drug percentage of the rods. The amount of drug released every week is increased as the decreasing of PLA molecular weight. As the hydrophlicity of polymer is improved, the rate of drug release every week is accelerated. The studies show that the plausibility of controlled release of nestorone from PLA, PLGA and EMPLA rods imply the possibility of their application as a controlled delivery system for nestorone. The results show that the greater the molecular weight of PLA is, the slower its degradation is and the slower the drug released; the greater the percentage of nestorone is, the more quickly the drug release. An increase of the hydrophilicity of the polymers will increase their degradation rate and leads to a fast drug release. Anyhow, these rods systems should be further evaluated in vivo.

Antihyperalgesic effect of simultaneously released hydromorphone and bupivacaine from polymer fibers in the rat chronic constriction injury model

We aimed to evaluate the antihyperalgesic efficacy of a combination of hydromorphone (HM) and bupivacaine (BP) delivered via controlled release from a biodegradable cylindrical rod. In vivo studies were performed using a rat model of thermal hyperalgesia induced by chronic constriction injury (CCI) of the sciatic nerve with loose ligatures. Poly(lactic-co-glycolic acid) (PLGA) rods (10 mm length, 1 mm diameter) loaded with HM (5 mg per rod), BP (5 mg per rod) or no drug (placebo) were implanted subcutaneously, in single or dual pairs, adjacent to the constriction injury, immediately after nerve ligation. We evaluated the efficacy of two dose levels for each drug, alone or in combination, in attenuating thermal hyperesthesia over a period of 12 days according to a prevention protocol. Plasma levels of drugs released from the rods and also released in an in vitro simulation were evaluated. In vitro studies demonstrated that drug release is maintained for at least 10 days. HM (5 mg) alone and BP (5 mg) alone did not attenuate hyperalgesia. Their combination provided a significant increase in the paw withdrawal latency as compared to single agents or placebo. When the dose in each group was doubled, implanting four rods, significant attenuation of hyperalgesia was observed. Analyses of rods retrieved after termination of experiments (after 12 days) revealed 30% residual HM and 70% residual BP content. Prolonged delivery of HM and BP alone or in combination via locally applied PLGA rods may offer a feasible alternative to provide long-lasting analgesia.

Antinociceptive effects of hydromorphone, bupivacaine and biphalin released from PLGA polymer after intrathecal implantation in rats

Intraspinal drug delivery, based on the concept of controlling pain by delivering drug to a nociceptive target rich in opioid and other relevant receptors is increasingly used clinically. The therapeutic ratio for opioids or other centrally acting agents is potentially greater if they are administered intrathecally (i.t.) than outside the central nervous system (CNS). The present study was designed with the ultimate goal of formulating a controlled release system for intrathecal analgesia characterized by effectiveness, rapid onset and few side effects for chronic pain control. A biodegradable copolymer poly( l-lactide-co-glycolide) (PLGA) was used to prepare a rod-shaped drug delivery system containing hydromorphone (HM), bupivacaine (BP), both HM and BP, or biphalin (BI). In vitro drug release kinetics of these systems showed a zero-order release rate for HM and BP from PLGA (85:15) rods. Drug-loaded rods were implanted i.t. Control groups received only placebo implants. Measurement of analgesic efficacy was carried out with tail flick and paw-withdrawal tests. In vivo studies showed potent, prolonged analgesia in comparison to controls for all active treatments. Analgesic synergy was observed with HM and BP. With further refinements of drug release rate, these rods may offer a clinically relevant alternative for intrathecal analgesia.

In vivo pain relief effectiveness of an analgesic-anesthetic carrying biodegradable controlled release rod systems

Pain is the most common and feared symptom for patients, especially those with cancer. Treatment of chronic pain with conventional ways of medication usually fails with increasing severity of the pain. New approaches enabling the prolonged provision of pain relievers are required. We designed a controlled release system of pain relievers, mainly for opioids (morphine, M, codeine, C, and hydromorphone, HM), and a local anesthetic (bupivacaine, BP) in the form of poly(L-lactide-coglycolide) (PLGA) rods. The efficacy of these rods implanted alone or in combination in relieving chronic pain in rats caused by the ligation of the sciatic nerve of their right hind limbs was studied. The two most common tests for measuring analgesia, i.e. tail-flick tests, that show analgesia at sites other than the site of injury, were used to study the degree of systemic distribution of the drugs and paw-withdrawal tests were used to study the analgesia at the site of injury. Alleviation of this chronic and severe neuropathic pain could be obtained for about 3-4 days when rods for two drugs, 'dual drug' (analgesic-anesthetic), were used. This duration is decreased by half (2 days) with the single-drug rods. Also the dual-drug rods, though at half the dose of each single drug application, enhanced the degree of analgesia of the first day. These in vivo results are also consistent with the previous in vitro results as in the case with codeine which had a higher first-day analgesia than morphine, despite a lower potency due to the faster in vitro release rate. Similarly, slower release of hydromorphone from PLGA (85 :15) rods resulted in less systemic analgesia than the more rapidly eroding PLGA (50 : 50) rods of the same drug.

Assessment of biodegradable controlled release rod systems for pain relief applications

Control of chronic, severe pain is a difficult and important clinical problem for most patients, especially those with cancer. Although current applications are insufficient for a satisfactory solution to this problem, the rate of disease incidence is increasing worldwide, thus making the problem more apparent. Based on this fact, this study was designed with the ultimate goal of formulating a controlled release system of pain relievers, mainly opioids, for the local treatment of pain to achieve satisfactory, fast, and less side effect-related relief and to provide a better life status for chronic pain patients. Two copolymers of a biodegradable polymer poly(L-lactide-coglycolide) (PLGA) were used to prepare an implantable rod type drug release system containing either an analgesic or anesthetic type of pain reliever. In vitro drug release kinetics of these systems were studied. It was observed that release from PLGA 85 : 15 was more zero-order than it was from PLGA 50 :50. A zero-order release rate was obtained for codeine, hydromorphone, and bupivacaine from PLGA (85 :15) rods. They, however, were released from PLGA (50 :50) rods with Higuchi kinetics. The drug solubility was also influential on release rate, as shown by the zero-order morphine release from PLGA (50 :50) rods. Scanning electron micrographs (SEMs) of the monolithic rods revealed erosion of the rods and the removal of drug crystals from the rod structure.

Bioerosion and biocompatibility of poly( d, l-lactic-co-glycolic acid) implants in brain

Brain delivery of neurotrophic factors via the systemic route is limited by the presence of blood brain barrier. Direct infusion into the intraventricular space is currently the mode of administration available clinically. Alternatively, controlled release systems can be the delivery system of choice using bioerodible polymers such as poly( d, l-lactic-co-glycolic acid) (PLGA). To utilize this concept, one has to establish the safety profile of the polymer and degradation products in brain. This report presents the results on the brain biocompatibility of PLGA implant using a rat model. In vitro erosion studies showed that the test PLGA rods eroded almost completely over a period of one month. Upon implantation into the rats' brains, these polymer rods and their breakdown products were well tolerated by the brain tissue. The overall presentation suggested that the brain tissue response to the implanted polymer was typical of those following mechanical trauma and exposure to foreign body. Tissue reaction was more pronounced around 14 days after implantation and largely subsided by day 28 when polymer erosion was near completion. There was no adverse cellular reactions in the parenchymal tissue adjacent to the implanted polymer. These results suggest that the PLGA materials are biocompatible and can be used to construct drug delivery devices for brain implantation.