Accelerated removal of solvent residuals from PLGA microparticles by alcohol vapor-assisted fluidized bed drying.

The removal of residual solvents from biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microparticles by fluidized bed drying was investigated. Microparticles were prepared by the O/W solvent extraction/evaporation method and the influence of various process and formulation parameters on the secondary drying was studied. PLGA microparticles and films were characterized for residual organic solvent and water content, recrystallisation, surface morphology, drug loading and in-vitro release of the drugs dexamethasone and risperidone. While alcohol-free fluidized bed drying decreased the residual dichloromethane content only from about 7 % (w/w) to 6.4 % (w/w) (18 °C) or 3.2 % (w/w) (35 °C) within 24 h, 140 mg/L methanol vapor in purge gas facilitated almost complete removal of dichloromethane or ethyl acetate from microparticles (0-0.11 % (w/w) after 6 h). By controlling the alcohol concentration and temperature of the purge gas, the alcohol absorption and complete removal was controlled. Risperidone increased the methanol absorption enhancing the plasticization. A high initial residual water content was identified to promote aggregation and was eliminated by starting fluidized bed drying without alcohol. Alcohol vapor-assisted fluidized bed drying accelerated microparticle manufacturing without affecting the redispersibility, the drug loading and the in-vitro release of risperidone and dexamethasone.

Cu/Gd co-doped hydroxyapatite/poly lactic-co-glycolic acid composites enhance MRI imaging and bone defect regeneration.

Background: The hydroxyapatite (HA)/poly(lactide-co-glycolide) acid (PLGA) composite material is a widely used orthopedic implant due to its excellent biocompatibility and plasticity. Recent advancements in cation doping have expanded its potential biological applications. However, conventional HA/PLGA composites are not visible under X-rays post-implantation and have limited osteogenic induction capabilities. Copper (Cu) is known to regulate osteoblast proliferation and differentiation, while gadolinium (Gd) can significantly enhance the magnetic resonance imaging (MRI) capabilities of materials. Methods: This study aimed to investigate whether incorporating Cu and Gd into an HA/PLGA composite could enhance the osteogenic properties, in vivo bone defect repair, and MRI characteristics. We prepared a Cu/Gd@HA/PLGA composite and assessed its performance. Results: Material characterization confirmed that Cu/Gd@HA retained the morphology and crystal structure of HA. The Cu/Gd@HA/PLGA composite exhibited excellent nuclear magnetic imaging capabilities, porosity, and hydrophilicity, which are conducive to cell adhesion and implant detection. In vitro experiments demonstrated that the Cu/Gd@HA/PLGA composite enhanced the proliferation, differentiation, and adhesion of MC3T3-E1 cells, and upregulated COL-1 and BMP-2 expression at both gene and protein levels. In vivo studies showed that the Cu/Gd@HA/PLGA composite maintained strong T1-weighted MRI signals and significantly improved the bone defect healing rate in rats. Conclusion: These findings indicate that the Cu/Gd@HA/PLGA composites significantly enhance T1-weighted MRI capabilities, promote osteoblast proliferation and differentiation in vitro, and accelerate bone defect healing in vivo.

Control of encapsulation efficiency and morphology of poly(lactide-co-glycolide) microparticles with a diafiltration-driven solvent extraction process.

The removal of organic solvents during the preparation of biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microparticles by an O/W- solvent extraction/evaporation process was investigated and controlled by diafiltration. Emulsification and steady replacement of the aqueous phase were performed in parallel in a single-vessel setup. During the process, the solidification of the dispersed phase (drug:PLGA:solvent droplets) into microparticles was monitored with video-microscopy and focused beam reflectance measurement (FBRM) and the residual solvent content was analyzed with headspace gas chromatography (organic solvent) and coulometric Karl-Fischer titration (water). Microparticles containing dexamethasone or risperidone were characterized with regard to particle size, morphology, encapsulation efficiency and in-vitro release. Diafiltration-accelerated solvent extraction shortened the process time by accelerating solidification of dispersed phase but reduced the residual dichloromethane content only in combination with increased temperature. Increasing the diafiltration rate increased particle size, porosity, and the encapsulation efficiency of risperidone. The latter effect was particularly evident with increasing lipophilicity of PLGA. A slower and more uniform solidification of end-capped and increased lactide content PLGA grade was identified as the reason for an increased drug leaching. Accelerated solvent extraction by diafiltration did not affect the in-vitro release of risperidone from different PLGA grades. The initial burst release of dexamethasone was increased by diafiltration when encapsulated in concentrations above the percolation threshold. Both porosity and burst release could be reduced by increasing the process temperature during diafiltration. Residual water content was established as an indicator for porosity and correlated with the burst release of dexamethasone.

Acceleration of Final Residual Solvent Extraction From Poly(lactide-co-glycolide) Microparticles.

PURPOSE: The removal of the residual solvent dichloromethane from biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles was investigated by aqueous or alcoholic wet extraction or vacuum-drying. METHODS: Microparticles were prepared by the O/W solvent extraction/evaporation method. The solidified microparticles were separated by filtration and the effect of subsequent drying and wet extraction methods were investigated. The residual solvent content was analysed with gas chromatography (organic solvents) and Karl Fischer titration (water). The effect of extraction conditions on microparticle aggregation, surface morphology and encapsulation of the drugs dexamethasone and risperidone was investigated. RESULTS: Residual dichloromethane was reduced to 2.43% (w/w) (20 °C) or 0.03% (w/w) (35 °C) by aqueous wet extraction. With vacuum-drying, residual dichloromethane only decreased from about 5% (w/w) to 4.34% (w/w) (20 °C) or 3.20% (w/w) (35 °C) due to the lack of the plasticizing effect of water. Redispersion of filtered, wet microparticles in alcoholic media significantly improved the extraction due to an increased PLGA plasticization. The potential of different extractants was explained with the Gordon-Taylor equation and Hansen solubility parameters. Extraction in methanol: or ethanol:water mixtures reduced residual dichloromethane from 4 - 7% (w/w) to 0.5 - 2.3% (w/w) within 1 h and 0.08 - 0.18% (w/w) within 6 h. Higher alcohol contents and higher temperature resulted in aggregation of microparticles and lower drug loadings. CONCLUSION: The final removal of residual dichloromethane was more efficient with alcoholic wet extraction followed by aqueous wet extraction at elevated temperature and vacuum drying of the microparticles.

Hot-Melt Extrusion-Based Dexamethasone-PLGA Implants: Physicochemical, Physicomechanical, and Surface Morphological Properties and In Vitro Release Corrected for Drug Degradation.

Developing bioequivalent (BE) generic products of complex dosage forms like intravitreal implants (IVIs) of corticosteroids such as dexamethasone prepared using hot-melt extrusion (HME), based on biodegradable poly (lactide-co-glycolide) (PLGA) polymers, can be challenging. A better understanding of the relationship between the physicochemical and physicomechanical properties of IVIs and their effect on drug release and ocular bioavailability is crucial to develop novel BE approaches. It is possible that the key physicochemical and physicomechanical properties of IVIs such as drug properties, implant surface roughness, mechanical strength and toughness, and implant erosion could vary for different compositions, resulting in changes in drug release. Therefore, this study investigated the hypothesis that biodegradable ophthalmic dexamethasone-loaded implants with 20% drug and 80% PLGA polymer(s) prepared using single-pass hot-melt extrusion (HME) differ in physicochemical and/or physicomechanical properties and drug release depending on their PLGA polymer composition. Acid end-capped PLGA was mixed with an ester end-capped PLGA to make three formulations: HME-1, HME-2, and HME-3, containing 100%, 80%, and 60% w/w of the acid end-capped PLGA. Further, this study compared the drug release between independent batches of each composition. In vitro release tests (IVRTs) indicated that HME-1 implants can be readily distinguished by their release profiles from HME-2 and HME-3, with the release being similar for HME-2 and HME-3. In the early stages, drug release generally correlated well with polymer composition and implant properties, with the release increasing with PLGA acid content (for day-1 release, R2 = 0.80) and/or elevated surface roughness (for day-1 and day-14 release, R2 ≥ 0.82). Further, implant mechanical strength and toughness correlated inversely with PLGA acid content and day-1 drug release. Drug release from independent batches was similar for each composition. The findings of this project could be helpful for developing generic PLGA polymer-based ocular implant products.

The intensity of subacute local biological effects after the implantation of ALBO-OS dental material based on hydroxyapatite and poly(lactide-co-glycolide): in vivo evaluation in rats.

OBJECTIVES: This study aimed to evaluate the intensity of the subacute local biological effects after implantation and osseoconductive potential of novel hydroxyapatite-based bone substitute coated with poly (lactide-co-glycolide), named ALBO-OS, in comparison to Bio-Oss®. METHODS: Fifteen male Wistar rats, randomly assigned into groups: 10, 20, and 30 days (n꞊5), were subcutaneously implanted with ALBO-OS and Bio-Oss®. Furthermore, artificially made bone defects on both rat's tibias were implanted with experimental materials. Unimplanted defects represented negative control. After the animals' euthanizing, tissue samples were prepared and analyzed histologically and histomorphometrically. RESULTS: Normal healing of the epithelial tissue was observed, with no signs of infection or necrosis. Minimal vascular congestion was noted immediately around the graft, with no signs of tissue oedema, with a minimal capsule thickness. The applied material did not cause an inflammatory response (IR) of significant intensity, and 20 days after implantation, the IR was mainly assessed as minimal. The tibial specimen showed that ALBO-OS has good osseoconductive potential, similar to Bio-Oss®, as well as low levels of acute and subacute inflammation. CONCLUSIONS: The tested material exhibits satisfying biocompatibility, similar to Bio-Oss®.

Porous PLGA microparticles prepared with nanosized/micronized sugar particles as porogens.

The objective of this study was to explore the use of nanosized/micronized sugar particles as porogens for preparing porous poly(lactide-co-glycolide) (PLGA) microparticles by a solid-in-oil-in-water (S/O/W) solvent evaporation method. Porous PLGA microparticles containing dexamethasone were prepared with different nanosized/micronized sugars (sucrose, trehalose and lactose), types of PLGA, and osmogens (NaCl or sucrose) in the external water phase. The microparticles were characterized for morphology, thermal properties, particle size, surface area, encapsulation efficiency and drug release/swelling during release. The addition of nanosized/micronized sugar particles resulted in porous PLGA microparticles with high encapsulation efficiencies. The porosity of the microparticles was caused both by the influx of water into the polymer droplets and the encapsulation and subsequent dissolution of sugar particles during the manufacturing process. The porosity (pore size) of the microparticles and, as a result, the drug release pattern could be well controlled by the particle size and weight fraction of the sugar particles. Because of a larger inner surface area, nanosized sugar particles were more efficient porogen than micronized sugar particles to obtain porous PLGA microparticles with flexible release patterns.

Evaluation of Porous (Poly(lactide-co-glycolide)-co-(ε-caprolactone)) Polyurethane for Use in Orthopedic Scaffolds.

To develop an orthopedic scaffold that could overcome the limitations of implants used in clinics, we designed poly(ester-urethane) foams and compared their properties with those of a commercial gold standard. A degradable poly(ester-urethane) was synthetized by polyaddition between a diisocyanate poly(ε-caprolactone) prepolymer (PCL di-NCO, Mn = 2400 g·mol-1) and poly(lactic-co-glycolic acid) diol (PLGA, Mn = 2200 g·mol-1) acting as a chain extender. The resulting high-molecular-weight poly(ester-urethane) (PEU, Mn = 87,000 g·mol-1) was obtained and thoroughly characterized by NMR, FTIR and SEC-MALS. The porous scaffolds were then processed using the solvent casting (SC)/particle leaching (PL) method with different NaCl crystal concentrations. The morphology, pore size and porosity of the foams were evaluated using SEM, showing interconnected pores with a uniform size of around 150 µm. The mechanical properties of the scaffolds are close to those of the human meniscus (Ey = 0.5~1 MPa). Their degradation under accelerated conditions confirms that incorporating PLGA into the scaffolds greatly accelerates their degradation rate compared to the gold-standard implant. Finally, a cytotoxicity study confirmed the absence of the cytotoxicity of the PEU, with a 90% viability of the L929 cells. These results suggest that degradable porous PLGA/PCL poly(ester-urethane) has potential in the development of meniscal implants.

A Review of the Potential of Poly-(lactide-co-glycolide) Nanoparticles as a Delivery System for an Active Antimycobacterial Compound, 7-Methyljuglone.

7-Methyljuglone (7-MJ) is a pure compound isolated from the roots of Euclea natalensis A. DC., a shrub indigenous to South Africa. It exhibits significant promise as a potential treatment for the highly communicable disease tuberculosis (TB), owing to its effective antimycobacterial activity against Mycobacterium tuberculosis. Despite its potential therapeutic benefits, 7-MJ has demonstrated in vitro cytotoxicity against various cancerous and non-cancerous cell lines, raising concerns about its safety for consumption by TB patients. Therefore, this review focuses on exploring the potential of poly-(lactide-co-glycolic) acid (PLGA) nanoparticles as a delivery system, which has been shown to decrease in vitro cytotoxicity, and 7-MJ as an effective antimycobacterial compound.

Development of in situ forming implants for controlled delivery of punicalagin.

Due to efficient drainage of the joint, the development of intra-articular depots for long-lasting drug release is a difficult challenge. Moreover, a disease-modifying osteoarthritis drug (DMOAD) that can effectively manage osteoarthritis has yet to be identified. The current study was undertaken to explore the potential of injectable, in situ forming implants to create depots that support the sustained release of punicalagin, a promising DMOAD. In vitro experiments demonstrated punicalagin's ability to suppress production of interleukin-1ß and prostaglandin E2, confirming its chondroprotective properties. Regarding the entrapment of punicalagin, it was demonstrated by LC-MS/MS to be stable within PLGA in situ forming implants for several weeks and capable of inhibiting collagenase upon release. In vitro punicalagin release kinetics were tunable through variation of solvent, PLGA lactide:glycolide ratio, and polymer concentration, and an optimized formulation supported release for approximately 90 days. The injection force of this formulation steadily increased with plunger advancement and higher rates of advancement were associated with greater forces. Although the optimal formulation was highly cytotoxic to primary chondrocytes if cells were exposed immediately or shortly after implant formation, upwards of 70 % survival was achieved when the implants were first allowed to undergo a 24-72 h period of phase inversion prior to cell exposure. This study demonstrates a PLGA-based in situ forming implant for the controlled release of punicalagin. With modification to address cytotoxicity, such an implant may be suitable as an intra-articular therapy for OA.

Long-Acting Microparticle Formulation of Griseofulvin for Ocular Neovascularization Therapy.

Neovascular age-related macular degeneration (nAMD) is a leading cause of vision loss in older adults. nAMD is treated with biologics targeting vascular endothelial growth factor; however, many patients do not respond to the current therapy. Here, a small molecule drug, griseofulvin (GRF), is used due to its inhibitory effect on ferrochelatase, an enzyme important for choroidal neovascularization (CNV). For local and sustained delivery to the eyes, GRF is encapsulated in microparticles based on poly(lactide-co-glycolide) (PLGA), a biodegradable polymer with a track record in long-acting formulations. The GRF-loaded PLGA microparticles (GRF MPs) are designed for intravitreal application, considering constraints in size, drug loading content, and drug release kinetics. Magnesium hydroxide is co-encapsulated to enable sustained GRF release over >30 days in phosphate-buffered saline with Tween 80. Incubated in cell culture medium over 30 days, the GRF MPs and the released drug show antiangiogenic effects in retinal endothelial cells. A single intravitreal injection of MPs containing 0.18 µg GRF releases the drug over 6 weeks in vivo to inhibit the progression of laser-induced CNV in mice with no abnormality in the fundus and retina. Intravitreally administered GRF MPs prove effective in preventing CNV, providing proof-of-concept toward a novel, cost-effective nAMD therapy.

Towards rational design of API-poly(D, L-lactide-co-glycolide) based micro- and nanoparticles: The role of API-polymer compatibility prediction.

Due to their unique properties, such as controlled drug release and improved bioavailability, polymeric microparticles and nanoparticles (MPs and NPs) have gained considerable interest in the pharmaceutical industry. Nevertheless, the high costs associated with biodegradable polymers and the active pharmaceutical ingredients (APIs) used for treating serious diseases, coupled with the vast number of API-polymer combinations, make the search for effective API-polymer MPs and NPs a costly and time-consuming process. In this work, the correlation between the compatibility of selected model APIs (i.e., ibuprofen, naproxen, paracetamol, and indomethacin) with poly(lactide-co-glycolide) (PLGA) derived from respective binary phase diagrams and characteristics of prepared MPs and NPs, such as the drug loading and solid-state properties, was investigated to probe the possibility of implementing the modeling of API-polymer thermodynamic and kinetic phase behavior as part of rational design of drug delivery systems based on MPs and NPs. API-PLGA-based MPs and NPs were formulated using an emulsion-solvent evaporation technique and were characterized for morphology, mean size, zeta potential, drug loading, and encapsulation efficiency. The solid-state properties of the encapsulated APIs were assessed using differential scanning calorimetry and X-ray powder diffraction. The evaluated compatibility was poor for all considered API-PLGA pairs, which is in alignment with the experimental results showing low drug loading in terms of amorphous API content. At the same time, drug loading of the studied APIs in terms of amorphous content was found to follow the same trend as their solubility in PLGA, indicating a clear correlation between API solubility in PLGA and achievable drug loading. These findings suggest that API-polymer phase behavior modeling and compatibility screening can be employed as an effective preformulation tool to estimate optimum initial API concentration for MP and NP preparation or, from a broader perspective, to tune or select polymeric carriers offering desired drug loading.

Time-Sequential and Multi-Functional 3D Printed MgO2 /PLGA Scaffold Developed as a Novel Biodegradable and Bioactive Bone Substitute for Challenging Postsurgical Osteosarcoma Treatment.

Osteosarcoma (OS) is the most commonly occurring primary bone malignant tumor. The clinical postsurgical OS treatment faces big challenges for the staged therapeutic requirements of early anti-tumor, anti-bacterial, and long-lasting osteogenesis. Herein, multi-functional bioactive scaffolds with time-sequential functions of preventing tumor recurrence, inhibiting bacterial infection, and promoting bone defect repair are designed as a novel strategy. Nanocomposite scaffold magnesium peroxide (MgO2 )/poly (lactide-co-glycolide) is prepared by low-temperature 3D printing for controllable releasing magnesium ions (Mg2+ ) and reactive oxygen species in a time-sequential manner. The scaffold with 20 wt% MgO2 (20MP) is verified with desired mechanical properties, as well as exhibits staged release behavior of bioactive elements with hydrogen peroxide (H2 O2 ) release for the first 3 weeks, and long-lasting Mg2+ release for 12 weeks. The released H2 O2 initiates chemodynamic therapy to induce apoptosis and ferroptosis in tumor cells, along with activating the anticancer immune microenvironment by M1 polarization of macrophages. The released Mg2+ subsequently enhances bone repair by activating the Wnt3a/GSK-3ß/ß-catenin signaling pathway to promote osteogenic differentiation of bone marrow mesenchymal stem cells and create osteopromotive immune microenvironment by M2 polarization of macrophages. In conclusion, the multi-functional 20MP scaffold demonstrates time-sequential therapeutic properties as an innovative strategy for OS-associated bone defect treatment.

Role of the Lactide:Glycolide Ratio in PLGA Nanoparticle Stability and Release under Lysosomal Conditions for Enzyme Replacement Therapy of Lysosomal Storage Disorders.

Prior studies demonstrated that encapsulation in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) enhanced the delivery of enzymes used for replacement therapy (ERT) of lysosomal storage disorders (LSDs). This study examined how the copolymer lactide:glycolide ratio impacts encapsulation, physicochemical characteristics, stability, and release under lysosomal conditions. Hyaluronidase, deficient in mucopolysaccharidosis IX, was encapsulated in NPs synthesized using 50:50, 60:40, or 75:25 lactide:glycolide copolymers. All NPs had diameters compatible with cellular transport (≤168 nm) and polydispersity indexes (≤0.16) and ζ-potentials (≤-35 mV) compatible with colloidal stability. Yet, their encapsulation efficiency varied, with 75:25 NPs and 60:40 NPs having the lowest and highest EE, respectively (15% vs. 28%). Under lysosomal conditions, the 50:50 copolymer degraded fastest (41% in 1 week), as expected, and the presence of a targeting antibody coat did not alter this result. Additionally, 60:40 NPs destabilized fastest (<1 week) because of their smaller diameter, and 75:25 NPs did not destabilize in 4 weeks. All formulations presented burst release under lysosomal conditions (56-78% of the original load within 30 min), with 50:50 and 60:40 NPs releasing an additional small fraction after week 1. This provided 4 weeks of sustained catalytic activity, sufficient to fully degrade a substrate. Altogether, the 60:40 NP formulation is preferred given its higher EE, and 50:50 NPs represent a valid alternative, while the highest stability of 75:25 NPs may impair lysosomes. These results can guide future studies aiming to translate PLGA NP-based ERT for this and other LSDs.

Direct drug milling in organic PLGA solution facilitates the encapsulation of nanosized drug into PLGA microparticles.

The objective of this study was to prepare poly(lactide-co-glycolide) (PLGA) microparticles loaded with nanosized drug by combining non-aqueous wet bead milling and microencapsulation. 200-300 nm dexamethasone, hydrocortisone and dexamethasone sodium phosphate nanosuspensions were successfully prepared by wet bead milling the drug in dichloromethane using PLGA as a stabilizer. PLGA microparticles loaded with nanosized drugs were then prepared by a solid-in-oil-in-water (S/O/W) solvent evaporation method or solid-in-oil-in-oil (S/O/O) organic phase separation method. The microparticles were characterized by laser diffraction (LD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and in vitro drug release. The nanosized drugs were homogeneously distributed within the microparticle matrix and remained crystalline, however, with a decrease in crystallinity. High drug encapsulation efficiencies >80 % were achieved at theoretical drug loadings between 5 and 30 %. Drug release profiles could be controlled by varying PLGA grades/blends, microparticle size and drug loadings. Quasi-linear release profiles without the PLGA-typical slow release phase were achieved with PLGA encapsulated nanosized drug.

In situ forming risperidone implants: Effect of PLGA attributes on product performance.

Despite the unique advantages of injectable, long-acting in situ forming implant formulations based on poly(lactide-co-glycolide) (PLGA) and N-Methyl-2-Pyrrolidone (NMP), only six products are commercially available. A better understanding of PLGA will aid in the development of more in situ forming implant innovator and generic products. This article investigates the impact of slight changes in PLGA attributes, i.e., molecular weight (MW), lactide:glycolide (L/G) ratio, blockiness, and end group, on the in vitro and in vivo performance of PLGA-based in situ forming implant formulations. Perseris (risperidone) for extended-release injectable suspension was selected as the reference listed drug (RLD). A previously developed adapter-based USP 2 method was used for the in vitro release testing of various risperidone implant formulations. A rabbit model was used to determine the in vivo pharmacokinetic profiles of the formulations (subcutaneous administration) and deconvolution (Loo-Riegelman method) was conducted to obtain the in vivo release profiles. The results showed that a 5 KDa difference in the MW (19.2, 24.2, 29.2 KDa), a 5% variation in the L/G ratio (85/15, 80/20, 75/25) and the end-cap (acid vs ester) all significantly impacted the formulation behavior both in vitro and in vivo. Higher MW, higher L/G ratio and ester end-cap PLGA all resulted in longer release durations. The formulations prepared with polymers with different blockiness values (within the blockiness range tested) did not show differences in in vitro and in vivo release. An in vitro-in vivo correlation (IVIVC) was not developed due to the different in vitro and in vivo phase separation rates, swelling tendencies and consequent significantly different release profiles. This is the first report evaluating the impact of PLGA property variation (over a narrow range) on the performance of in situ forming implants. The knowledge gained will provide a better understanding of the mechanisms underlying risperidone in situ forming implant performance and will aid the development of future products.

CNT incorporation improves the resolution and stability of porous 3D printed PLGA/HA/CNT scaffolds for bone regeneration.

In this study, 3D printed porous poly(lactide-co-glycolide) (PLGA) and its nanocomposites with 5 wt. % hydroxyapatite (HA) and 0.5, 1 and 2 wt. % carboxyl-functionalized multi-walled carbon nanotube (CNT) scaffolds were fabricated by using extrusion-based printing. The printing parameters were optimized by rheological studies. The rheological studies demonstrated shear thinning properties for all compositions and an increase in storage modulus was observed after the addition of CNT. Porous PLGA/HA/CNT scaffolds were printed by applying a pressure of 4.76 bar at 125 °C. The addition of 0.5 wt. % of CNT reduced the strut size and increased the porosity from 42% to 60%. The increase in storage modulus and decrease in strut size were related to hydrogen bonding between CNT, HA and PLGA which ultimately improved shape fidelity. The scaffolds were characterized by analysis of their chemical structure, water contact angle measurement,in vitrobioactivity test, biodegradation test, mechanical analysis, andin vitrocell studies. The scaffolds were found to be more hydrophilic by the incorporation of CNTs. Also, degradation studies showed that the microstructure of the scaffold became more stable with the addition of HA and CNT. The compressive modulus of PLGA/HA/CNT2 scaffold was found to be 548.5 MPa, which is found suitable to replace cancellous bone. The scaffolds were found to be highly biocompatible which is possibly due to alignment of CNT and PLGA during 3D printing process. Alizarin red staining indicated improvement of mineralization of MC3T3-E1 cells on the CNT incorporated porous 3D scaffolds. The results suggest that the produced porous 3D printed PLGA/HA/CNT scaffolds are promising for bone regeneration applications.

Degradation Behavior of Poly(Lactide-Co-Glycolide) Monolayers Investigated by Langmuir Technique: Accelerating Effect.

Among biodegradable polymers, polylactides (PLAs) have attracted considerable interest because the monomer can be produced from renewable resources. Since their initial degradability strongly affects commercial application fields, it is necessary to manage the degradation properties of PLAs to make them more commercially attractive. To control their degradability, poly(lactide-co-glycolide) (PLGA) copolymers of glycolide and isomer lactides (LAs) were synthesized, and their enzymatic and alkaline degradation rates of PLGA monolayers as functions of glycolide acid (GA) composition were systematically investigated by the Langmuir technique. The results showed that the alkaline and enzymatic degradations of PLGA monolayers were faster than those of l-polylactide (l-PLA), even though proteinase K is selectively effective in the l-lactide (l-LA) unit. Alkaline hydrolysis was strongly affected by their hydrophilicity, while the surface pressure of monolayers for enzymatic degradations was a major factor.

In vivo characterization of Perseris and compositionally equivalent formulations.

Perseris is asubcutaneous extended-release risperidone in situ forming implant (suspension) indicated for the treatment of adult schizophrenia. Owing to the release rate controlling polymer poly(lactide-co-glycolide) (PLGA), one injection of Perseris can deliver risperidone for one month, which significantly reduces the administration frequency and improves patient compliance. The PLGA and drug used in Perseris was previously identified through reverse engineering and two compositionally equivalent formulations (F-1 and F-2) showing similar in vitro drug release were developed. The current work focuses on in vivo exploration of Perseris and the developed compositionally equivalent formulations using a rabbit model and further evaluate the sameness of the developed formulations compared to Perseris. The in vivo pharmacokinetic (PK) profiles, drug absorption rate, phase separation rate, macro appearance, weight loss as well as the water uptake of the solidified drug depots at different time points were investigated and compared with the in vitro release data as well as with dog and human in vivo data available in literature. Results show that the rabbit PK profile of Perseris was relevant with those obtained from both the dog model and the clinical data, indicating that the rabbit model is appropriate for investigation of the in vivo performance of risperidone implants. Consistent with their similar in vitro drug release, the two compositionally equivalent formulations demonstrated similar PK profiles, drug absorption rates, weight loss and swelling in vivo compared to Perseris. Although the erosion mechanism appeared to be similar between in vitro and in vivo, there were in vitro-in vivo differences concerning the drug release kinetics, phase separation rates and swelling behavior. This work provides a comprehensive in vitro/in vivo understanding of Perseris and the developed compositionally equivalent formulations, which will be beneficial for future development of generic as well as novel PLGA in situ forming implant products.

Dual receptor specific nanoparticles targeting EGFR and PD-L1 for enhanced delivery of docetaxel in cancer therapy.

Dual-receptor targeted (DRT) nanoparticles which contain two distinct targeting agents may exhibit higher cell selectivity, cellular uptake, and cytotoxicity toward cancer cells than single-ligand targeted nanoparticle systems without additional functionality. The purpose of this study is to prepare DRT poly(lactic-co-glycolic acid) (PLGA) nanoparticles for targeting the delivery of docetaxel (DTX) to the EGFR and PD-L1 receptor positive cancer cells such as human glioblastoma multiform (U87-MG) and human non-small cell lung cancer (A549) cell lines. Anti-EGFR and anti-PD-L1 antibody were decorated on DTX loaded PLGA nanoparticles to prepare DRT-DTX-PLGA via. single emulsion solvent evaporation method. Physicochemical characterizations of DRT-DTX-PLGA, such as particle size, zeta-potential, morphology, and in vitro DTX release were also evaluated. The average particle size of DRT-DTX-PLGA was 124.2 ± 1.1 nm with spherical and smooth morphology. In the cellular uptake study, the DRT-DTX-PLGA endocytosed by the U87-MG and A549 cells was single ligand targeting nanoparticle. From the in vitro cell cytotoxicity, and apoptosis studies, we reported that DRT-DTX-PLGA exhibited high cytotoxicity and enhanced the apoptotic cell compared to the single ligand-targeted nanoparticle. The dual receptor mediated endocytosis of DRT-DTX-PLGA showed a high binding affinity effect that leads to high intracellular DTX concentration and exhibited high cytotoxic properties. Thus, DRT nanoparticles have the potential to improve cancer therapy by providing selectivity over single-ligand-targeted nanoparticles.