Poly(lactic-co-glycolic) Acid Concentrations Research Articles

Modeling electrospun PLGA nanofibers’ diameter using response surface methodology and artificial neural networks

The present work is an attempt to model the diameter of Poly Lactic-co-Glycolic Acid (PLGA) nanofibers by utilizing response surface methodology (RSM) and artificial neural networks (ANNs). Hence, determining the optimal electrospinning process conditions to produce a minimum fiber diameter. For modelling the average diameter of nanofibers, RSM approach based on four parameters (polymer concentration, high voltage and needle tip to collector distance and spinning angle) with five-level was compared to ANN technique. In the RSM approach, central composite design (CCD) was used to determine the individual and interaction impacts of the parameters on the average diameter of nanofibers. Several ANNs of single and double hidden layers with different number of cells for each were tried to obtain the best network structure. The experimental and predicted PLGA fiber diameters using an ANN showed a strong correlation, indicating that the network topology of 4-14-1 has good predictability for analyzing factors impacting PLGA fiber diameter. The average absolute relative error for predicting PLGA nanofibers’ diameter using ANN (2.24%) is slightly less than that obtained from RSM (2.59%). The high regression coefficient between the variables and the response (R2 = 0.9636) shows a good second-order polynomial regression model for evaluating experimental data. The R2 value was 0.945, indicating that the ANN model was good fitting with the experimental results. The optimum combinations (PLGA concentration of 26 wt.%, high voltage 22 kV, needle tip to collector distance 20 cm, and spinning angle 60o) were developed by RSM model for electrospinning PLGA nanofiber that can produce fine, consistent, and high-quality nanofibers.

PROCESS OPTIMIZATION USING QUALITY BY DESIGN (QBD) APPROACH OF A GENTAMICIN LOADED PLGA BIOCOMPOSITE

Osteomyelitis continues to be a major concern when orthopedic surgery is performed. Orthopedic infections have an incidence of 5% to 10% but their management proves to be quite difficult due to both biofilm formation and limited access of the drug to the infected area when systemic treatment is employed. The aim of the study was to optimize the synthesis process of a gentamicin loaded poly(-lactic-co-glycolic) acid (PLGA) based biodegradable composite by varying parameters that affect both efficiency encapsulation and nanoparticle size. Furthermore, a kinetic study was conducted to study the biodegradation process of the polymer. Gentamicin loaded PLGA nanoparticles were obtained using the double emulsion technique which allows the variation of several factors such as gentamycin concentration, PLGA concentration, buffer concentration and stirring speed. Out of the four factors evaluated, gentamicin concentration had the highest impact on both encapsulation efficiency and nanoparticle size. A few relevant interactions between factors were also registered.

In vitro characterization of hierarchical 3D scaffolds produced by combining additive manufacturing and thermally induced phase separation

This paper reports on the hybrid process we have used for producing hierarchical scaffolds made of poly(lactic-co-glycolic) acid (PLGA) and nanohydroxyapatite (nHA), analyzes their internal structures via scanning electron microscopy, and presents the results of our in vitro proliferation of MC3T3-E1 cells and alkaline phosphatase activity (ALP) for 0 and 21 days. These scaffolds were produced by combining additive manufacturing (AM) and thermally induced phase separation (TIPS) techniques. Slow cooling at a rate of 1.5 °C/min during the TIPS process was used to enable a uniform temperature throughout the scaffolds, and therefore, a relatively uniform pore size range. We produced ten different scaffold compositions and topologies in this study. These scaffolds had macrochannels with diameters of ∼300 µm, ∼380 µm, and ∼460 µm, generated by the extraction of embedded porous 3D-plotted polyethylene glycol (PEG) matrices. The other experimental factors included different TIPS temperatures (−20 °C, −10 °C, and 0 °C), as well as varying PLGA concentrations (8%, 10%, and 12% w/v) and nHA content (0%, 10%, and 20% w/w). Our results indicated that almost all these macro/microporous scaffolds supported cell growth over the period of 21 days. Nevertheless, significant differences were observed among some scaffolds in terms of their support of cell proliferation and differentiation. This paper presents the results of our in vitro cell culture for 0 and 21 days. Our optimal scaffold with a porosity of ∼90%, a modulus of ∼5.2 MPa, and a nHA content of 20% showed a cell adhesion of ∼29% on day 0 and maintained cell proliferation and ALP activity over the 21-day in vitro culture. Hence, the use of additive manufacturing and designed experiments to optimize the scaffold fabrication parameters resulted in superior mechanical properties that most other studies using TIPS.

Factors affecting preparation and evaluation of Kitorolac tromethamine microsponges for ocular use

Ketorolac Tromethamine (KT) is prepared for the first time by double emulsion procedure. The current research involves preparation and evaluation of microsponges for ocular applications. This work included preparation of sixteen formulas of KT-microsponges by double
 emulsion (w/o/w) method using poly lactic-co-glycolic acid (PLGA) as a polymer and poly vinyl alcohol (PVA) as a stabilizer, with different mixer types for different time and power. The prepared microsponges were characterized by Scanning Electron Microscopy (SEM) to investigate the morphology and particle size, the entrapment efficacy and percentage yield were calculated as well as in vitro drug release. Best formula (F14) of KT-microsponges had EE (74%), % yield (83%) with initial drug release (approximately 21% within the first fifteen days) which continued to reach (approximately 86% within 90 days) by using 30% of PLGA concentration with 0.05% of PVA and 200 ml of the external aqueous phase using a probe sonicator for 4 minutes at 200 Watt power. This formulation technique will be the interest of pharmaceutical company.

Low-temperature solvent-based 3D printing of PLGA: a parametric printability study

In this paper, a novel low-temperature 3 D printing technique is introduced and characterized through a parametric printability study to fabricate poly-lactic-co-glycolic acid (PLGA) constructs using methyl ethyl ketone (MEK) as a solvent. The effects of varying concentrations of PLGA in MEK solvent, lactic to glycolic ratio of PLGA, the molecular weight of PLGA, and the scaling of PLGA constructs on the printability are investigated. PLGA concentrations of higher than 80% w/v, lactic to glycolic ratio more than 75%, molecular weight more than 100 kDa, and printing through nozzles smaller than 0.96 mm internal diameter are recommended for 3 D printing of PLGA constructs with high shape fidelity. Ultimately, a vacuum drying solvent removal process is implemented, and Proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy is used to confirm complete removal of the solvent from PLGA constructs. The results of this study can be used for the development of drug-eluting implants.

I-Optimal design of poly(lactic-co-glycolic) acid/hydroxyapatite three-dimensional scaffolds produced by thermally induced phase separation.

In bone tissue engineering, 3D scaffolds are often designed to have adequate modulus while taking into consideration the requirement for a highly porous network for cell seeding and tissue growth. This paper presents the design optimization of 3D scaffolds made of poly(lactic-co-glycolic) acid (PLGA) and nanohydroxyapatite (nHA), produced by thermally induced phase separation (TIPS). Slow cooling at a rate of 1°C/min enabled a uniform temperature and produced porous scaffolds with a relatively uniform pore size. An I-optimal design of experiments (DoE) with 18 experimental runs was used to relate four responses (scaffold thickness, density, porosity, and modulus) to three experimental factors, namely the TIPS temperature (-20°C, -10°C, and 0°C), PLGA concentration (7%, 10%, and 13% w/v), and nHA content (0%, 15%, and 30% w/w). The response surface analysis using JMP® software predicted a temperature of -18.3°C, a PLGA concentration of 10.3% w/v, and a nHA content of 30% w/w to achieve a thickness of 3 mm, a porosity of 83%, and a modulus of ~4 MPa. The set of validation scaffolds prepared using the predicted factor levels had a thickness of 3.05 ± 0.37 mm, a porosity of 86.8 ± 0.9 %, and a modulus of 3.57 ± 2.28 MPa.

Preparation of a reproducible long-acting formulation of risperidone-loaded PLGA microspheres using microfluidic method

The aim of the present study is to prepare risperidone-loaded poly lactic-co-glycolic acid (PLGA) microspheres within microfluidic system and to achieve a formulation with uniform size and monotonic and reproducible release profile. In comparison to batch method, T-junction and serpentine chips were utilized and optimizing study was carried out at different processing parameters (e.g. PLGA and surfactant concentration and flow rates ratio of outer to inner phase). The computational fluid dynamic (CFD) modeling was performed, and loading and release study were carried out. CFD simulation indicates that increasing the flow rate of aqueous phase cause to decrease the droplet size, while the change in size of microspheres did not follow a specific pattern in the experimental results. The most uniform microspheres and narrowest standard deviation (66.79 μm ± 3.32) were achieved using T-junction chip, 1% polyvinylalcohol, 1% PLGA and flow rates ratio of 20. The microfluidic-assisted microspheres were more uniform with narrower size distribution. The release of risperidone from microspheres produced by the microfluidic method was more reproducible and closer to zero-order kinetic model. The release profile of formulation with 2:1 drug-to-polymer ratio was the most favorable release, in which 41.85% release could be achieved during 24 days.

Research of amoxicillin microcapsules preparation playing micro-jetting technology.

With polylactic-co-glycolic acid(PLGA) as shell material of microcapsule, amoxicillin as the model, poly(vinyl alcohol) and twain as surfactant, amoxicillin-PLGA microcapsules were manufactured using digital micro-jetting technology and a glass nozzle of 40μm diameter. The influences of the parameters of micro-jetting system on the mean grain size and size distribution of amoxicillin-PLGA microcapsules were studied with single factor analysis and orthogonal experiment method, namely, PLGA solution concentration, driving voltage, jetting frequency, stirrer speed, etc. The optimal result was obtained; the form representation of microcapsule was analyzed as well. The results show that, under certain conditions of experimental drug prescription, driving voltage was proportional to the particle size; jetting frequency and stirrer speed were inversely proportional. When the PLGA concentration for 3%, driving voltage for 80V, the jetting frequency for 10000Hz and the stirrer speed for 750rpm, the particles were in an ideal state with the mean grain size of 60.246μm, the encapsulation efficiency reached 62.39％ and 2.1％ for drug loading.

Novel flavonoid-based biodegradable nanoparticles for effective oral delivery of etoposide by P-glycoprotein modulation: an in vitro, ex vivo and in vivo investigations

A receptor level interaction of etoposide with P-glycoprotein (P-gp) and subsequent intestinal efflux has an adverse effect on its oral absorption. The present work is aimed to enhance the bioavailability of etoposide by co-administering it with quercetin (a P-gp inhibitor) in dual-loaded polymeric nanoparticle formulation. Poly-lactic-co-glycolic acid (PLGA) nanoparticles were optimized for various parameters like o/w phase volume ratio, poly-vinyl alcohol concentration, PLGA concentration and sonication time. The cytotoxicity studies (MTT assay) revealed a 9- and 11-fold decrease in the IC 50 values for etoposide-loaded nanoparticles (ENP) and etoposide + quercetin dual-loaded nanoparticles (EQNP) when compared to that of free etoposide, respectively, and the results were further supported by florescent-activated cell sorter studies. The confocal imaging of the intestinal sections treated with ENP and EQNP containing fluorescent probe (rhodamine) showed the superiority of the EQNP to permeate deeper. Furthermore, pharmacokinetic studies on rats revealed that EQNP exhibited a 2.4-fold increase in bioavailability of etoposide than ENP with no quercetin. The developed loaded nanoparticles have the high potential to enhance the bioavailability of the etoposide and sensitize the resistant cells.

Biodegradable Injectable In Situ Implants and Microparticles for Sustained Release of Montelukast: In Vitro Release, Pharmacokinetics, and Stability

The objective of this study was to investigate the sustained release of a hydrophilic drug, montelukast (MK), from two biodegradable polymeric drug delivery systems, in situ implant (ISI) and in situ microparticles (ISM). N-Methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), triacetin, and ethyl acetate were selected as solvents. The release of 10% (w/v) MK from both systems containing poly-lactic-co-glycolic acid (PLGA) as the biodegradable polymer was compared. Upon contact with the aqueous medium, the PLGA in ISI and ISM systems solidified resulting in implants and microparticles, respectively. The in vitro drug release from the ISI system showed marked difference from miscible solvents (NMP and DMSO) than the partially miscible ones (triacetin and ethyl acetate), and the drug release decreased with increased PLGA concentration. In the ISM system, the initial in vitro drug release decreased with decreased ratio of polymer phase to external oil phase. In vivo studies in rats showed that ISM had slower drug release than the drug release from ISI. Also, the ISM system when compared to ISI system had significantly reduced initial burst effect. In vitro as well as the in vivo studies for both ISI and ISM systems showed sustained release of MK. The ISM system is suitable for sustained release of MK over 4-week period with a lower initial burst compared to the ISI system. Stability studies of the ISI and ISM formulations showed that MK is stable in the formulations stored at 4°C for more than 2 years.

Production of PLGA micro- and nanocomposites by supercritical fluid extraction of emulsions: I. Encapsulation of lysozyme

Micro- and nanoparticles of bio-compatible and bio-degradable polymers such as poly-lactic-co-glycolic acid (PLGA) are widely used as delivery devices for the administration of sensitive biopharmaceuticals such as proteins, peptides and genes. The purpose of this study is the investigation of supercritical fluid extraction of emulsions (SFEE) as a novel process for the production of such particles. By variation of PLGA concentration and stirring rate during emulsion preparation, particles of pure PLGA with average sizes ranging between 100 nm and a few μ m with very narrow size distributions have been produced in controlled and reproducible manner. Moreover, lysozyme has been used for the formation of composite particles with PLGA. Three different encapsulation methods have been investigated and evaluated by determining the corresponding encapsulation efficiencies. With the method of in situ suspension emulsions, an encapsulation efficiency of up to 48.5% has been achieved. The current study highlights the potential of SFEE as an attractive and scalable process for the manufacturing of drug–PLGA composite particles for pharmaceutical applications.

Elucidation of the physicomechanical and ab initio quantum energy transitions of a crosslinked PLGA scaffold

This study elucidated the in vitro physicomechanical transitions of a crosslinked polylactic- co-glycolic acid (PLGA) scaffold, utilizing quantum mechanics to compute the ab initio energy requirements of a salted-out and subsequently crosslinked PLGA scaffold interacting with simulated physiological fluid, phosphate buffered saline (PBS) (pH 7.4, 37 °C) at a molecular level. Twenty-six salted-out PLGA scaffolds were formulated using a four factor, two centerpoint quadratic Face-Centered Central Composite Design (FCCD). PLGA molecular mass, PLGA concentration, water volume and salting-out reaction time were the dependant formulation variables. Subsequent to PLGA solubilization in dimethyl formamide (DMF), protonated water was added to induce salting-out of PLGA into a scaffolds that were immersed in PBS, oscillated at 100 rpm, and analyzed at pre-determined time intervals for their physicomechanical and ab initio quantum energy transitions. Results indicated that the matrix resilience (MR) decreased with longer incubation periods (MR=35–45%) at day 30. Scaffolds salted-out using higher PLGA concentrations exhibited minimal changes in MR and the matrix ability to absorb energy was found to closely correlate with the scaffold residence time in PBS. Spartan-based ab initio quantum energy predictions elucidated the potential scaffold stability from a molecular viewpoint and its suitability for use in rate-modulated drug delivery.