5-Fluorouracil plasma levels and biodegradation of subcutaneously injected drug-loaded microspheres prepared by spray-drying poly( d, l-lactide) and poly( d, l-lactide-co-glycolide) polymers

The purpose of this research was to encapsulate superoxide dismutase (SOD) and catalase (CAT) in biodegradable microspheres (MS) to obtain suitable sustained protein delivery. A modified water/oil/water double emulsion method was used for poly(D,L-lactide-co-glycolide) (PLGA) and poly(D,L-lactide) PLA MS preparation co-encapsulating mannitol, trehalose, and PEG400 for protein stabilization. Size, morphology, porosity, mass loss, mass balance, in vitro release and in vitro activity were assessed by using BCA protein assay, scanning electron microscopy, BET surface area, and particle-sizing techniques. In vitro activity retention within MS was evaluated by nicotinammide adenine dinucleotide oxidation and H2O2 consumption assays. SOD encapsulation efficiency resulted in 30% to 34% for PLA MS and up to 51% for PLGA MS, whereas CAT encapsulation was 34% and 45% for PLGA and PLA MS, respectively. All MS were spherical with a smooth surface and low porosity. Particle mean diameters ranged from 10 to 17 mum. CAT release was prolonged, but the results were incomplete for both PLA and PLGA MS, whereas SOD was completely released from PLGA MS in a sustained manner after 2 months. CAT results were less stable and showed a stronger interaction than SOD with the polymers. Mass loss and mass balance correlated well with the release profiles. SOD and CAT in vitro activity was preserved in all the preparations, and SOD was better stabilized in PLGA MS. PLGA MS can be useful for SOD delivery in its native form and is promising as a new depot system.

In the present paper, monodisperse poly(lactic acid) (PLA) microspheres (MS) containing the enrofloxacin (ENRO), were manufactured by using a modified solid in oil in water (S/O/W) emulsion solvent evaporation method. In order to prepare PLA microspheres with a higher drug loading efficiency by this modified technique, the test of stability and productivity of the primary emulsion was preliminary examined by change species or concentration of the oil-soluble surfactant and the ratio of water and organic solvent. Firstly, enrofloxacin polylactic acid microspheres (ENRO-PLA-MS) were producted, then the morphology and particle size distribution were estimated by scanning electron microscopy (SEM), its encapsulation efficiency and drug loading efficiency were assessed by High performance liquid chromatography (HPLC). In vivo conditions were simulated by an stable release buffer to obtain a detailed release and polymer degradation profile. Consequently, the ENRO-PLA-MS had a denser structure with a smooth, pore-free surface, the preparation of microspheres was simple, the prepared microspheres had excellent controlled drug release characteristics in vitro.

In vivo distribution of radioactivity in mice after injection of biodegradable polymer microspheres containing 14C-labeled tetanus toxoid

Ketoprofen was encapsulated within poly-epsilon-caprolactone (PCL) and hydroxypropyl methylcellulose phthalate 50 (HPMCP50) microspheres (MS). Scanning electron microscopy (SEM) studies showed spherical particles without surface crystal formation and differential scanning calorimetry (DSC) supported these results. MS of PCL or HPMCP50 had a mean particle size of 10.7 +/- 2.2 and 10.9 +/- 2.0 mu m respectively, whereas a mixture of these polymers increased the MS particle size to 30 mu m. Greater incorporation efficiencies were found for HPMCP50 MS (98.1 +/- 0.7). MS of PCL and HPMCP50 mixtures showed a decreased drug entrapment as the amount of PCL was increased (96.0 +/- 0.2 for 25% PCL, 95.6 +/- 1.8 for 50% PCL, 80.2 +/- 0.7 for 75% PCL and 78.9 +/- 9.0 for 100% PCL). Size exclusion chromatography (SEC) studies revealed a weak interaction between ketoprofen and PCL and some polymer degradation was found during HPMCP50 MS storage, probably by breaking of the phthalic anhydride bond to be anyhydroglucose backbone. Four types of cryoprotectors (glucose, trehalose, mannitol and sorbitol, at 5 and 10% W/V) and two freezing conditions (-196 and -20 degrees C) were evaluated in freeze-drying studies. For HPMCP50, the sizes of MS after reconstitution of liophylizates were nearly the same as the initial ones. For PCL MS only, those formulations with sorbitol or glucose at 10% and frozen at -196 degrees C showed acceptable results. In contrast to the rapid release rate of ketoprofen from PCL MS as a result of carrier porosity (80% released within 15 min), the release from HPMCP50 MS could be controlled by means of pH (40% released in the first 15 min in simulated gastric fluid and nearly 100% ketoprofen delivered in the same time in simulated intestinal fluid).

The aim of this study was to develop polymeric biodegradable microspheres (MSs) of poly(d-l lactide-co-glycolide) (PLGA) and zein capable of delivering amoxicillin (AMX) at significant levels for root canal disinfection. PLGA/zein MSs were prepared using a spray-drying technique. The systems were characterized in terms of particle size, morphology, drug loading and in vitro release. Drug levels were reached to be effective during the intracanal dressing in between visits during the endodontic treatment. In vitro release studies were carried out to understand the release profile of the MSs. Antimicrobial activity of AMX was performed by antibiograms. Enterococcus faecalis was the bacteria selected due to its prevalence in endodontic failure. Drug microencapsulation yielded MSs with spherical morphology and an average particle size of between 5 and 38 µm. Different drug-release patterns were obtained among the formulations. Release features related to the MSs were strongly dependent on drug nature as it was demonstrated by using a hydrophobic drug (indomethacin). Finally, AMX-loaded MSs were efficient against E faecalis as demonstrated by the antibiogram results. In conclusion, PLGA/zein MSs prepared by spray drying may be a useful drug delivery system for root canal disinfection.

Although the pathogenesis of glaucoma is not completely understood yet, all patients diagnosed with this chronic disease are observed with neurodegeneration. Neuroprotective treatment will benefit from joint administration of active substances directed towards several therapeutic targets. Our study focuses on the hypothesis that a combination of anti‐inflammatory and antioxidant drugs, namely dexamethasone (DX), melatonin (MEL) and vitamin E (VE), loaded in biodegradable drug delivery devices (microspheres) can be advantageous as a long‐term therapeutic strategy that can achieve protection of visual function and avoid retinal cells death. We further evaluated whether drugs' stability and release properties changed or not after sterilization, a key process for ophthalmic formulations.Biodegradable poly (lactic‐co‐glycolic) acid (PLGA) microspheres (MS) were elaborated using the oil‐in‐water emulsion solvent evaporation technique. DX and MEL were added in a ratio 1/2:10 (DX/MEL:PLGA)(w/w) and a volume of 40 μl of VE was also included as an oily additive. After lyophilisation, MS were subjected to 60Cobalt radiation at 25 kGy (S‐MS) in dry ice. Before and after gamma‐irradiation, MS were characterized by means of internal and external morphology, particle size, encapsulation efficiency, thermal properties and in vitro release profiles.The chosen 38–20 μm MS exhibited pores inside and at a surface level respectively when observed at transmission and scanning electron microscopes, due to a slow evacuation of organic solvent from the internal to the aqueous phase for the oily nature of VE. MS showed high drug loadings of DX (56.61 ± 2.42 μg/mg MS) and MEL (33.97 ± 2.64 μg/mg MS), which remained unaltered for S‐MS, and followed a unimodal distribution of particle size (30.14 ± 1.03 μm for MS; 32.75 ± 1.46 μm for S‐MS). Differential scanning calorimeter thermograms revealed no endothermic transitions at DX and MEL melting points, thus indicating effective encapsulation. Regarding in vitro release profiles, both drugs in MS were released in a controlled fashion for more than 50 days (0.47 ± 0.03 μg/day for DX; 0.60 ± 0.04 μg/day for MEL). DX was released during a total of 120‐day follow‐up period (94.12 ± 0.68% of total DX encapsulated). Both compounds in S‐MS showed a higher burst release values (p < 0.001) in the first 7‐day period (93.21 ± 0.89% for MEL; 43.16 ± 0.75% for DX) compared to MS ones (81.35 ± 0.85% for MEL; 26.48 ± 1.24% for DX). Similarity factor (f2) statistically confirmed that changes in 35‐day release profiles for both the actives were due to sterilization (f2‐MEL = 40.47; f2‐DX = 39.10).The developed formulation proved potential usefulness as a possible long‐term neuroprotective therapy due to its four‐month in vitro co‐delivery. Additional studies will be performed for assessing in vitro toxicity and in vivo effectiveness of both the sterilized and no‐sterilized biodegradable drug delivery devices.

The magnetic bovine serum albumin (BSA) microspheres (MS) were prepared by emulsification/solidification method. In this experiment, two kinds of magnetic MS, e.g. BSA MS and PEG-incorporated BSA microspheres (PMS) were prepared. The obtained MS were characterized by Malvern laser particle sizer and scanning electron microscopy (SEM). The obtained MS were spherical and about 1.3 μm in size. The magnetic responsivity and in vitro release behavior of these MS were studied in detail. The in vivo distribution and targeting delivery of 5-fluorouracil (5-Fu) magnetic MS after artery administration were studied in rat. The results showed that PMS could efficiently delivery 5-Fu to the targeted site compared with BSA MS without PEG MS and free drug.

polymers of sodium alginate and chitosan (NaAlg/Cs) based pH-Sensitive interpenetrating network (IPN) microspheres (MPs) were prepared by emulsion- crosslinking technique using glutaraldehyde (GA) as a crosslinking agent. Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID) was successfully encapsulated The biodegradable into the MPs by varying the ratio of % Cs, amount of GA and % drug loading. MPs with average particle sizes in the range of 293-372 µm were obtained. MPs were characterized by Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM) and Differential scanning calorimetry (DSC). In Vitro release studies were carried out in simulated gastric fluid of pH 1.2 for 2 h followed by simulated intestinal fluid of pH 7.4 at 37oC. In conclusion, the present study indicates that Ibuprofen was successfully encapsulated into the hydrophilic carbohydrate polymers blend MPs composed of NaAlg and Cs. The encapsulation efficiency up to 84% was obtained. The release of drug from the MPs was dependent upon the pH of medium, % Cs ratio, extent of GA and amount of drug loading. The n values ranged between 0.89 and 1.17, indicating that the drug release from the MPs shifted from anomalous to the super Case-II transport. FTIR confirmed the formations of IPN MPs. DSC have confirmed the amorphous dispersion of the drug in the polymer matrix.

Considering the significance of effective antigen presentation for boosting immune responses, it is essential to develop delivery systems for antigen presenting cells (APCs; dendritic cells and macrophages). As a simple and facile way for improving delivery efficiency of PLGA microspheres (MS) into APCs, we fabricated exosome-conjugated PLGA MS via polydopamine coating in this study. Spherical micro-sized particles were first prepared by conventional water-in oil-in water (W1/O/W2) double emulsion and solvent evaporation methods and were observed by scanning electron microscopy (SEM). With increasing model protein (ovalbumin)/MS weight ratios, higher amounts of ovalbumin (OVA) were immobilized onto MS. After exosome (EXO) conjugation to MS via polydopamine coating, the amount of nitrogen was significantly increased on the surface of MS, indicating that EXO were successfully conjugated onto MS. EXO-coated dopamine MS (EXO-Dopa MS) exhibited significantly improved delivery into DC2.4 cells and RAW264.7 cells, compared with bare MS and Dopa MS. Therefore, EXO-Dopa MS could be used as effective carriers of immune stimulating biomolecules into APCs for cancer immunotherapy.

The current study offers an efficient design of novel nanoparticle microspheres (MCs) using a hydrothermal approach. The Co0.5Ni0.5GaxFe2−xO4 (0.0 ≤ x ≤ 1.0) MCs were prepared by engineering the elements, such as cobalt (Co), nickel (Ni), iron (Fe), and gallium (Ga). There was a significant variation in MCs’ physical structure and surface morphology, which was evaluated using energy dispersive X-ray analysis (EDX), X-ray diffractometer (XRD), high-resolution transmission electron microscopy (HR-TEM), and scanning electron microscope (SEM). The anti-proliferative activity of MCs was examined by MTT assay and DAPI staining using human colorectal carcinoma cells (HCT-116), human cervical cancer cells (HeLa), and a non-cancerous cell line—human embryonic kidney cells (HEK-293). Post 72 h treatment, MCs caused a dose dependent inhibition of growth and proliferation of HCT-116 and HeLa cells. Conversely, no cytotoxic effect was observed on HEK-293 cells. The anti-fungal action was assessed by the colony forming units (CFU) technique and SEM, resulting in the survival rate of Candida albicans as 20%, with severe morphogenesis, on treatment with MCs x = 1.0. These findings suggest that newly engineered microspheres have the potential for pharmaceutical importance, in terms of infectious diseases and anti-cancer therapy.

The purpose of this study is to know the effect of uptake of mycobacteria on the phagocytic activity of alveolar macrophage (Mphi) cells toward poly(lactic-co-glycolic) acid (PLGA) microspheres (MS) loaded with the anti-tuberculosis agent rifampicin (RFP-PLGA MS). Biological functions such as phagocytic activity toward PLGA MS loaded with fluorescent coumarin (cPLGA MS) and toward polystyrene latex MS (PSL MS), and generation of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) were examined using alveolar Mphi cell NR8383 after they had phagocytosed Mycobacterium bovis Calmette-Guérin (BCG), heat-killed BCG (h-kBCG) or Escherichia coli. The ingestion of BCG, h-kBCG, and E. coli did not affect the viability of the Mphi cells within 2 days. The phagocytosis caused generation of TNF-alpha and NO, being more significant with E. coli than with both types of BCGs. The phagocytosis of both types of BCGs stimulated the phagocytic uptake of cPLGA and PSL MS's, which took place prior to the generation of TNF-alpha or NO, but that of E. coli suppressed the uptake of both MS's. Mycobacterial infection stimulated the phagocytic uptake toward cPLGA MS. These results suggest that RFP-PLGA MS is favorable for overcoming tuberculosis.

A novel polymeric microsphere (MS) containing micronized triamcinolone acetonide (TA) in a crystalline state was structured to provide extended drug retention in joints after intra-articular (IA) injection. Microcrystals with a median diameter of 1.7 μm were prepared by ultra-sonication method, and incorporated into poly(lactic-co-glycolic acid)/poly(lactic acid) (PLGA/PLA) MSs using spray-drying technique. Cross-sectional observation and X-ray diffraction analysis showed that drug microcrystals were evenly embedded in the MSs, with a distinctive crystalline nature of TA. In vitro drug release from the novel MSs was markedly decelerated compared to those from the marketed crystalline suspension (Triam inj.®), or even 7.2 μm-sized TA crystals-loaded MSs. The novel system offered prolonged drug retention in rat joints, providing quantifiable TA remains over 28 days. Whereas, over 95% of IA TA was removed from joints within seven days, after injection of the marketed product. Systemic exposure of the steroidal compound was drastically decreased with the MSs, with <50% systemic exposure compared to that with the marketed product. The novel MS was physicochemically stable, with no changes in drug crystallinity and release profile over 12 months. Therefore, the TA microcrystals-loaded MS is expected to be beneficial in patients especially with osteoarthritis, with reduced IA dosing frequency.

Polymeric microspheres (MSs) have received attention for their potential to improve the delivery of drugs with poor oral bioavailability. Although MSs can be absorbed into the absorptive epithelium of the small intestine, little is known about the physiologic mechanisms that are responsible for their cellular trafficking. In these experiments, nonbiodegradable polystyrene MSs (diameter range: 500 nm to 5 µm) were delivered locally to the jejunum or ileum or by oral administration to young male rats. Following administration, MSs were taken up rapidly (≤ 5 min) by the small intestine and were detected by transmission electron microscopy and confocal laser scanning microscopy. Gel permeation chromatography confirmed that polymer was present in all tissue samples, including the brain. These results confirm that MSs (diameter range: 500 nm to 5 µm) were absorbed by the small intestine and distributed throughout the rat. After delivering MSs to the jejunum or ileum, high concentrations of polystyrene were detected in the liver, kidneys, and lungs. The pharmacologic inhibitors chlorpromazine, phorbol 12-myristate 13-acetate, and cytochalasin D caused a reduction in the total number of MSs absorbed in the jejunum and ileum, demonstrating that nonphagocytic processes (including endocytosis) direct the uptake of MSs in the small intestine. These results challenge the convention that phagocytic cells such as the microfold cells solely facilitate MS absorption in the small intestine.

Cartilage regeneration using adipose-derived stem cells and the controlled-released hybrid microspheres

Semi-interpenetrating network of acrylamide-grafted-sodium alginate microspheres for controlled release of diclofenac sodium, preparation and characterization