PLA-PCL-PEG-PCL-PLA based micelles for improving the ocular permeability of dexamethasone: development, characterization, and in vitro evaluation.

The aim of the present research was to investigate the feasibility of developing polylactide-polycaprolactone-polyethylene glycol-polycaprolactone-polylactide (PLA-PCL-PEG-PCL-PLA) based micelles to improve ocular permeability of dexamethasone (DEX). PLA-PCL-PEG-PCL-PLA copolymers were synthesized by a ring-opening polymerization method. DEX was loaded into the developed copolymers. The DEX-loaded micelles were characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS) methods. Cytotoxicity of the micelles obtained was investigated on L929 cell line. Cellular uptake was followed by fluorescence microscopy and flow cytometry analyses. The release behavior of DEX from the micelles as well as the drug release kinetics was studied. Corneal permeability was also evaluated using an ex vivo bovine model. The pentablock copolymers were successfully synthesized. The TEM results verified the formation of spherical micelles, the sizes of which was approximately 65 nm. The micelles exhibited suitable compatibility on L929 cells. The release profile showed an initial burst release phase followed by a sustained release phase, the kinetic of which was close to the Weibull's distribution model. The micelles showed higher corneal permeability in comparison to a marketed DEX eye drop. Taken together, the results indicated that the PLA-PCL-PEG-PCL-PLA micelles could be appropriate candidates for the ocular delivery of DEX, and probably other hydrophobic drugs.

Biodegradable Pickering emulsions of Lipiodol for liver trans-arterial chemo-embolization.

Water-in-oil (W/O) Lipiodol emulsions remain the preferable choice for local delivery of chemotherapy in the treatment of hepatocellular carcinoma. However, their low stability severely hampers their efficiency. Here, remarkably stable W/O Lipiodol emulsion stabilized by biodegradable particles was developed thanks to Pickering technology. The addition of poly(lactide-co-glycolide) nanoparticles (NPs) into the aqueous-phase of the formulation led to W/O Pickering emulsion by a simple emulsification process through two connected syringes. Influence of nanoparticles concentration and water/oil ratio on emulsion stability and droplet size were studied. All formulated Pickering emulsions were W/O type, stable for at least one month and water droplets size could be tuned by controlling nanoparticle concentration from 24 µm at 25 mg/mL to 69 µm at 5 mg/mL. The potential of these emulsions to efficiently encapsulate chemotherapy was studied through the internalization of doxorubicin (DOX) into the aqueous phase with a water/oil ratio of 1/3 as recommended by the medical community. Loaded-doxorubicin was released from conventional emulsion within a few hours whereas doxorubicin from stable Pickering emulsion took up to 10 days to be completely released. In addition, in vitro cell viability evaluations performed on the components of the emulsion and the Pickering emulsion have shown no significant toxicity up to relatively high concentrations of NPs (3 mg/mL) on two different cell lines: HUVEC and HepG2. STATEMENT OF SIGNIFICANCE: We present an original experimental research in the field of nanotechnology for biomedical applications. In particular, we have formulated, thanks to Pickering technology, a new therapeutic emulsion stabilized with biodegradable PLGA nanoparticles. As far as we know, this is the first therapeutic Pickering emulsion reported in the literature for hepatocellular carcinoma. Such a new emulsion allows to easily prepare a predictable and stable lipiodolized emulsion having all the required characteristics for optimum tumor uptake. As demonstrated throughout our manuscript, emulsions stabilized with these nanoparticles have the advantage of being biodegradable, biocompatible and less toxic compared to usual emulsions stabilized with synthetic surfactants. These findings demonstrate the plausibility of the use of Pickering emulsions for chemoembolization as a therapeutic agent in extended release formulations.

Poly (ε-caprolactone) microspheres for prolonged release of selenium nanoparticles.

Poly (ε-caprolactone) (PCL) microspheres as a carrier for sustained release of antibacterial agent, selenium nanoparticles (SeNPs), were developed. The obtained PCL/SeNPs microspheres were in the range 1-4 µm with the encapsulation efficiency of about 90%. The degradation process and release behavior of SeNPs from PCL microspheres were investigated in five different degradation media: phosphate buffer solution (PBS), a solution of lipase isolated from the porcine pancreas in PBS, 0.1 M hydrochloric acid (HCl), Pseudomonas aeruginosa PAO1 cell-free extract in PBS and implant fluid (exudate) from the subcutaneously implanted sterile polyvinyl sponges which induce a foreign-body inflammatory reaction. The samples were thoroughly characterized by SEM, TEM, FTIR, XRD, PSA, DSC, confocal microscopy, and ICP-OES techniques. Under physiological conditions at neutral pH, a very slow release of SeNPs occurred (3 and 8% in the case of PBS or PBS + lipase, respectively and after 660 days), while in the acidic environment their presence was not detected. On the other hand, the release in the medium with bacterial extract was much more pronounced, even after 24 h (13%). After 7 days, the concentration of SeNPs reached a maximum of around 30%. Also, 37% of SeNPs have been released after 11 days of incubation of PCL/SeNPs in the implant exudate. These results suggest that the release of SeNPs from PCL was triggered by Pseudomonas aeruginosa PAO1 bacterium as well as by foreign body inflammatory reaction to implant. Furthermore, PCL/SeNPs microspheres were investigated in terms of their biocompatibility. For this purpose, cytotoxicity, the formation of reactive oxygen species (ROS), and genotoxicity were evaluated on HepG2 cell line. The interaction of PCL/SeNPs with phagocytic cell line (Raw 264.7 macrophages) was monitored as well. It was found that the microspheres in investigated concentration range had no acute cytotoxic effects. Finally, SeNPs, as well as PCL/SeNPs, showed a considerable antibacterial activity against Gram-positive bacteria: Staphylococcus aureus (ATCC 25923) and Staphylococcus epidermidis (ATCC 1228). These results suggest that PCL/SeNPs-based system could be an attractive platform for a prolonged prevention of infections accompanying implants.

Preparation and in vivo evaluation of anti-plasmodial properties of artemisinin-loaded PCL-PEG-PCL nanoparticles.

PURPOSE: Artemisinin (ART) has anti-inflammatory, antimicrobial, antioxidant, anti-amyloid, and anti-malarial effects, but its application is limited due to its low water solubility and poor oral bioavailability. In this study, the bioavailability, water solubility, and anti-plasmodial property of ART were improved by PCL-PEG-PCL tri-block copolymers. METHODS: The structure of the copolymers was characterized by 1H NMR, FT-IR, DSC, and GPC techniques. ART was encapsulated within micelles by a single-step nano-precipitation method, leading to the formation of ART-loaded PCL-PEG-PCL micelles. The obtained micelles were characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM). The in vivo anti-plasmodial activity of ART-loaded micelles was measured against Plasmodium berghei infected Swiss albino mice. RESULTS: The results showed that the zeta potential of ART-loaded micelles was about -8.37 mV and the average size was 91.87 nm. ART was encapsulated into PCL-PEG-PCL micelles with a loading capacity of 19.33 ± 0.015% and encapsulation efficacy of 87.21 ± 3.32%. In vivo anti-plasmodial results against P. berghei showed that multiple injections of ART-loaded micelles could prolong the circulation time and increase the therapeutic efficacy of ART. CONCLUSION: These results suggested that PCL-PEG-PCL micelles would be a potential carrier for ART for the treatment of malaria.

Nigella sativa oil entrapped polycaprolactone nanoparticles for leishmaniasis treatment.

This study is the first to investigate the antileishmanial activities of Nigella sativa oil (NSO) entrapped poly-ɛ-caprolactone (PCL) nanoparticles on Leishmania infantum promastigotes and amastigotes in vitro. NSO molecules with variable initial doses of 50, 100, 150, and 200 mg were successfully encapsulated into PCL nanoparticles identified as formulations NSO1, NSO2, NSO3, and NSO4, respectively. This process was characterised by scanning electron microscope, dynamic light scattering, Fourier transform infrared, encapsulation efficiency measurements, and release profile evaluations. The resulting synthetised nanoparticles had sizes ranging between 200 and 390 nm. PCL nanoparticles encapsulated 98% to 80% of initial doses of NSO and after incubation released approximately 85% of entrapped oil molecules after 288 h. All investigated formulations demonstrated strong antileishmanial effects on L. infantum promastigotes by inhibiting up to 90% of parasites after 192 h. The tested formulations decreased infection indexes of macrophages in a range between 2.4- and 4.1-fold in contrast to control, thus indicating the strong anti-amastigote activities of NSO encapsulated PCL nanoparticles. Furthermore, NSO-loaded PCL nanoparticles showed immunomodulatory effects by increasing produced nitric oxide amounts within macrophages by 2-3.5-fold in contrast to use of free oil. The obtained data showed significant antileishmanial effects of NSO encapsulated PCL nanoparticles on L. infantum promastigotes and amastigotes.

Biodegradable and Petroleum-Based Microplastics Do Not Differ in Their Ingestion and Excretion but in Their Biological Effects in a Freshwater Invertebrate Gammarus fossarum.

Research on the uptake and effects of bioplastics by aquatic organisms is still in its infancy. Here, we aim to advance the field by comparing uptake and effects of microplastic particles (MPP) of a biodegradable bioMPP (polyhydroxybutyrate (PHB)) and petroleum-based MPP (polymethylmethacrylate (PMMA)) in the freshwater amphipod Gammarus fossarum. Ingestion of both MPP in different particle sizes (32-250 µm) occurred after 24 h, with highest ingestion of particles in the range 32-63 µm and almost complete egestion after 64 h. A four-week effect-experiment showed a significant decrease of the assimilation efficiency in amphipods exposed to the petroleum-based MPP from week two onwards. The petroleum-based PMMA affected assimilation efficiency significantly in contrast to the biodegradable PHB, but overall differences in direct comparison of MPP types were small. Both MPP types led to a significantly lower wet weight gain relative to the control treatments. After four weeks, differences between both MPP types and silica, used as a natural particle control, were detected. In summary, these results suggest that both MPP types provoke digestive constraints on the amphipods, which go beyond those of natural non-palatable particles. This highlights the need for more detailed research comparing environmental effects of biodegradable and petroleum-based MPP and testing those against naturally occurring particle loads.

Multifunctional nanospheres for co-delivery of methotrexate and mild hyperthermia to colon cancer cells.

A multifunctional nanomedicine platform was designed and evaluated for efficient colon cancer therapy by a combinatorial therapeutic approach based on a chemotherapeutic drug and mild hyperthermia. Advantage was taken from the dual role of methotrexate (MTX), as folate receptor-targeting, overexpressed in tumor cells, and as anticancer drug. Incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) allows to heat cancer cells externally through an alternating magnetic field. The developed nanocarrier was based on polyethylene glycol-polylactic acid (PEG-PLA) nanospheres to improve biocompatibility, enhancing their targeting by prolonging blood circulation time. By an emulsion-evaporation method the nanospheres were produced and then characterized for size distribution, zeta-potential, in vitro drug release profile and cellular studies. The co-delivery of MTX and SPIONs on PEG-PLA nanospheres resulted in nanocarriers with a size of 160nm in diameter, a polydispersity index below 0.2 and a zeta potential of ca. -18mV. Multifunctional nanospheres were monodisperse and stable up to 3months. MTX was released preferentially under mild hyperthermia conditions. The multifunctional nanospheres were able to increase the cytotoxicity of MTX towards Caco-2 and SW-480 colon cancer cells, in comparison to free drug. Also, the nanospheres allowed the incorporated MTX to induce greater cell cycle arrest and apoptotic effects than the free MTX. This study provides evidences that MTX-SPIONs-PEG-PLA nanospheres are a promising solution to address colorectal cancer over-expressing folate receptors, by a combinatory approach.

Development and evaluation of nanoparticles based on mPEG-PLA for controlled delivery of vinpocetine: in vitro and in vivo studies.

The aim of present study was to develop VIN-loaded mPEG-PLA nanoparticle systems. The VIN mPEG-PLA nanoparticles were prepared using an emulsion solvent evaporation method, and studied their particle size, morphology, encapsulation efficiency and drug-loading coefficient. Moreover, the nanoparticles were evaluated on the drug release behaviors in vitro and bioavailability in vivo. The results show that the spherical nanoparticles obtained were negatively charged with a zeta potential of about -23.4 mV and characterized ∼110 nm with a narrow size distribution. The encapsulation efficiency and drug loading of prepared NPs were 76.4 ± 6.3 and 9.2 ± 2.2% (n=5), respectively. The in vitro release showed that the percent of accumulated dissolution of VIN NPs in phosphate-buffered saline 6.8 over 24 h was <80%, which was almost 100% of VIN in commercial injections. The in vivo study indicated that systemic absorption of VIN was significantly enhanced by incorporating into mPEG-PLA NPs compared with VIN injection (2.87-fold in AUC0-t). The results suggested that the form of VIN in mPEG-PLA NPs could enter the body circulation to perform sustained release in vitro and in vivo.

Biodegradable nanocomplex from hyaluronic acid and arginine based poly(ester amide)s as the delivery vehicles for improved photodynamic therapy of multidrug resistant tumor cells: An in vitro study of the performance of chlorin e6 photosensitizer.

Photodynamic therapy (PDT), which enables the localized therapeutic effect by light irradiation, provides an alternative and complementary modality for the treatment of tumor. However, the aggregation of photosensitizers in acidic microenvironment of tumor and the non-targeted distribution of photosensitizers in normal tissues significantly affect the PDT efficiency. In this study, we developed a biodegradable nanocomplex HA-Arg-PEA from hyaluronic acid (HA) and arginine based poly(ester amide)s (Arg-PEA) as the nanocarrier for chlorin e6 (Ce6). HA enhanced the tumor-specific endocytosis mediated by the overexpression of CD44 receptor. Arg-PEA not only provide electrostatic interaction with HA to form self-assembled nanostructure, but also improve the monomerization of Ce6 at physiological pH as well as mildly acidic pH. The biodegradable characteristic of HA-Arg-PEA nanocomplex enabled the intracellular delivery of Ce6, in which its release and generation of singlet oxygen can be accelerated by enzymatic degradation of the carrier. The in vitro PDT efficiency of Ce6-loaded HA-Arg-PEA nanocomplex was examined in CD44 positive MDA-MB-435/MDR multidrug resistant melanoma cells. CD44-mediated uptake of Ce6-loaded HA-Arg-PEA nanocomplex significantly improved Ce6 level in MDA-MB-435/MDR cells within short incubation time, and the PDT efficiency in inhibiting multidrug resistant tumor cells was also enhanced at higher Ce6 concentrations. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1487-1499, 2017.

Sequel of MgO nanoparticles in PLACL nanofibers for anti-cancer therapy in synergy with curcumin/ß-cyclodextrin.

Pharmaceutical industries spend more money in developing new and efficient methods for delivering successful drugs for anticancer therapy. Electrospun nanofibers and nanoparticles loaded with drugs have versatile biomedical applications ranging from wound healing to anticancer therapy. We aimed to attempt for fabricating elastomeric poly (l-lactic acid-co-ε-caprolactone) (PLACL) with Aloe Vera (AV), magnesium oxide (MgO) nanoparticles, curcumin (CUR) and ß-cyclodextrin (ß-CD) composite nanofibers to control the growth of MCF-7 cells for breast cancer therapy. The study focused on the interaction of MgO nanoparticle with CUR and ß-CD inhibiting the proliferation of Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. FESEM micrographs of fabricated electrospun PLACL, PLACL/AV, PLACL/AV/MgO, PLACL/AV/MgO/CUR and PLACL/AV/MgO/ß-CD nanofibrous scaffolds achieved bead free, random and uniform nanofibers with fiber diameter in the range of 786±286, 507±171, 334±95, 360±94 and 326±80nm respectively. Proliferation of MCF-7 cells was decreased by 65.92% in PLACL/AV/MgO/CUR with respect to PLACL/AV/MgO nanofibrous scaffolds on day 9. The obtained results proved that 1% CUR interacting with MgO nanoparticles showed higher inhibition of MCF-7 cells among all other nanofibrous scaffolds thus serving as a promising biocomposite material system for the breast cancer therapy.

Lecithin and PLGA-based self-assembled nanocomposite, Lecithmer: preparation, characterization, and pharmacokinetic/pharmacodynamic evaluation.

The present study investigates the drug delivery potential of polymer lipid hybrid nanocomposites (Lecithmer®) composed of poly(D,L-lactide-co-glycolide (PLGA) and soya lecithin. Core-shell structure of Lecithmer was evident from cryo-TEM images. Daunorubicin (DNR) and lornoxicam (LNX)-incorporated Lecithmer nanocomposites were evaluated for anticancer and anti-inflammatory activity. DNR- and LNX-loaded Lecithmer had mean particle size of ∼335 and ∼282.7 nm, respectively. Lecithmer formulated with different cationic lipids resulted in lower particle size (∼120 nm) and positive zeta potential. Entrapment efficiency of DNR and LNX was 93.16 and 88.59 %, respectively. In vitro release of DNR from Lecithmer was slower compared to PLGA nanoparticles. DNR release from Lecithmer was significantly higher at pH 5.5 (80.96 %) as compared to pH 7.4 (55.95 %), providing advantage for selective tumor therapy. Similarly, sustained release of LNX (30 % in 10 h) was observed at pH 7.4. DNR in Lecithmer showed superior cytotoxicity on human erythroleukemic K562 cells. Pharmacokinetic study in Wistar rats with i.v. administered DNR-loaded Lecithmer showed higher volume of distribution, lower elimination rate constant, and longer half-life (81.68 L, 0.3535 h(-1), 1.96 h) as compared to DNR solution (57.46 L, 0.4237 h(-1), 1.635 h). Pharmacodynamic evaluation of orally administered LNX-loaded Lecithmer showed superior anti-inflammatory activity with maximum inhibition of 81.2 % vis-à-vis 53.57 % in case of LNX suspension. In light of these results, Lecithmer can be envisaged as a promising nanosystem for parenteral as well as oral drug delivery.

Preparation, in vitro and in vivo evaluation of mPEG-PLGA nanoparticles co-loaded with syringopicroside and hydroxytyrosol.

This study investigated the therapeutic efficiency of monomethoxy polyethylene glycol-poly(lactic-co-glycolic acid) (mPEG-PLGA) co-loaded with syringopicroside and hydroxytyrosol as a drug with effective targeting and loading capacity as well as persistent circulation in vivo. The nanoparticles were prepared using a nanoprecipitation method with mPEG-PLGA as nano-carrier co-loaded with syringopicroside and hydroxytyrosol (SH-NPs). The parameters like in vivo pharmacokinetics, biodistribution in vivo, fluorescence in vivo endomicroscopy, and cellular uptake of SH-NPs were investigated. Results showed that the total encapsulation efficiency was 32.38 ± 2.76 %. Total drug loading was 12.01 ± 0.42 %, particle size was 91.70 ± 2.11 nm, polydispersity index was 0.22 ± 0.01, and zeta potential was -24.5 ± 1.16 mV for the optimized SH-NPs. The nanoparticle morphology was characterized using transmission electron microscopy, which indicated that the particles of SH-NPs were in uniformity within the nanosize range and of spherical core shell morphology. Drug release followed Higuchi kinetics. Compared with syringopicroside and hydroxytyrosol mixture (SH), SH-NPs produced drug concentrations that persisted for a significantly longer time in plasma following second-order kinetics. The nanoparticles moved gradually into the cell, thereby increasing the quantity. ALT, AST, and MDA levels were significantly lower on exposure to SH-NPs than in controls. SH-NPs could inhibit the proliferation of HepG2.2.15 cells and could be taken up by HepG2.2.15 cells. The results confirmed that syringopicroside and hydroxytyrosol can be loaded simultaneously into mPEG-PLGA nanoparticles. Using mPEG-PLGA as nano-carrier, sustained release, high distribution in the liver, and protective effects against hepatic injury were observed in comparison to SH.

Evaluation of metronidazole-loaded poly(3-hydroxybutyrate) membranes to potential application in periodontitis treatment.

Guided tissue regeneration is a technique used for periodontium reconstruction. This technique uses barrier membranes, which prevent epithelial growth in the wound site and may also be used to release antibiotics, to protect the wound against opportunistic infections. Periodontal poly(3-hydroxybutyrate) membranes containing metronidazole (a drug used to help in infection control) were produced and characterized. The kinetic mechanism of the metronidazole delivery of leached and nonleached membrane as well as its cytotoxicity and structural integrity were evaluated. Poly(3-hydroxybutyrate) membranes containing 0.5-2 wt % of the drug and 20 wt % of the plasticizer were manufactured via compression molding. Based on morphological analysis, membranes loaded with 2% metronidazole were considered for detailed studies. The results revealed that metronidazole delivery by the leached membranes seemed to follow the Fick's law. Membranes were noncytotoxic. The amount of metronidazole delivered was in the range of the minimal inhibitory concentration for Porphyromonas gingivalis, and the membranes inhibited the proliferation of these bacteria. Besides, they maintained their mechanical resistance after 30 days of immersion in phosphate buffer at pH 7.4.

Novel L-lactide-depsipeptide polymeric carrier for enhanced brain uptake of rivastigmine in treatment of Alzheimer's disease.

The present study discusses possibility of targeting an anti-Alzheimer's drug rivastigmine tartarate (RT) to the brain using novel synthesized L-lactide-depsipeptide polymeric nanoparticles (NPs). Single emulsion-solvent evaporation technique was used for preparation of NPs. The mean particle size, zeta potential and entrapment efficiency of drug loaded NPs were found to be 142.2 +/- 21.3 nm, +4.85 mV and 60.72 +/- 3.72% respectively. Pharmacodynamic study showed faster regain of memory loss in amnesic rat with RT loaded NPs as compared to RT solution. In pharmacokinetic study, total concentration and mean residence time was increased up to 3.79 fold and 2 fold respectively while clearance was decreased to 1.91 fold on intravenous administration of RT loaded NPs as compared to RT solution. The biodistribution study demonstrated 5.45 fold and 2 fold increase in brain concentration of drug after administration of RT loaded NPs (i.v; 10.52 +/- 1.31 ng/ml) as compared to plain RT solution by oral (1.93 +/- 1.23 ng/ml) and intravenous (5.34 +/- 1.22 ng/ml) route, respectively. Therefore, RT loaded L-lactide-depsipeptide polymeric NPs might be a potential drug delivery system in treatment of Alzheimer's disease.

An in vitro study of composites of poly(L-lactide-co-ε-caprolactone), ß-tricalcium phosphate and ciprofloxacin intended for local treatment of osteomyelitis.

Osteomyelitis is a bacterial disease that can become chronic, and treatment often includes a surgical operation to remove infected bone. The aim of this study was to develop and investigate in vitro bone filling composite materials that release ciprofloxacin to kill any remaining bacteria and contain bioceramic to help the bone to heal. Three composites of poly(L-lactide-co-ε-caprolactone), ß-tricalcium phosphate and ciprofloxacin were compounded using twin-screw extrusion and sterilized by gamma irradiation. Drug release and degradation of the composites were investigated in vitro for 52 weeks. The composite with 50 wt% of ß-TCP had the most promising ciprofloxacin release profile. The ceramic component accelerated the drug release that occurred in three phases obeying first-order kinetics. Inhibition zone testing using bioluminescence showed that the released ciprofloxacin had effect in eradicating a common osteomyelitis causing bacteria Pseudomonas aeruginosa. During the in vitro degradation test series, molar weight of the polymer matrix of the composites decreased rapidly. Additionally, (1)H-NMR analysis showed that the polymer had blocky structure and the comonomer ratio changed during hydrolysis. The tested composites showed great potential to be developed into bone filler materials for the treatment of osteomyelitis or other bone related infections.

[Sustained release of the antitumor drug paclitaxel from poly(3-hydroxybutyrate)-based microspheres].

Development of systems of medicines with sustained action on the basis of biodegradable polymers is a promising trend in modem pharmacology. Polyhydroxyalkanoates (POA) attract increasing attention due to their biodegradability and high biocompatibility, which make them suitable for development of novel drug dosage forms. We obtained microspheres on the basis of poly(3-hydroxybutyrate) (PHB) loaded with the antitumor drug paclitaxel. Morphology, drug release kinetics and effect on tumor cells in vitro of microspheres were studied. The data on the kinetics of drug release, biocompatibility and biological activity of the biopolymer microspheres in vitro showed that the studied system of prolonged drug release had lower toxicity and higher efficiency compared to the traditional dosage forms of paclitaxel.

Drug evaluation: PB-127, a novel contrast agent for the detection of myocardial perfusion.

Point Biomedical Corp is developing PB-127 (CardioSphere) as an ultrasound imaging agent for assessing myocardial perfusion in patients with coronary artery disease. In January 2006, the company submitted an NDA for the agent; this was accepted for review in February 2006, with a Prescription Drug User Fee Act review and action date of late October 2006. PB-127 is effective for intermittent harmonic power Doppler imaging and may be the first contrast agent to receive FDA approval for myocardial perfusion imaging.

Development and evaluation of novel biodegradable microspheres based on poly(d,l-lactide-co-glycolide) and poly(epsilon-caprolactone) for controlled delivery of doxycycline in the treatment of human periodontal pocket: in vitro and in vivo studies.

This study reports on the development of novel biodegradable microspheres prepared by water-in-oil-water (W/O/W) double emulsion technique using the blends of poly(d,l-lactide-co-glycolide) (PLGA) and poly(epsilon-caprolactone) (PCL) in different ratios for the controlled delivery of doxycycline (DXY). Doxycycline encapsulation of up to 24% was achieved within the polymeric microspheres. Blend placebo microspheres, drug-loaded microspheres and pristine DXY were analyzed by Fourier transform infrared spectroscopy (FT-IR), which indicated no interaction between drug and polymers. Differential scanning calorimetry (DSC) on drug-loaded microspheres confirmed the polymorphism of DXY and indicated a molecular level dispersion of DXY in the microspheres. Scanning electron microscopy (SEM) confirmed the spherical nature and smooth surfaces of the microspheres produced. Mean particle size of the microspheres as measured by dynamic laser light scattering method ranged between 90 and 200 mum. In vitro release studies performed in 7.4 pH media indicated the release of DXY from 7 to 11 days, depending upon the blend ratio of the matrix. Up to 11 days, DXY concentrations in the gingival crevicular fluid were higher than the minimum inhibitory concentration of DXY against most of the periodontal pathogens. One of the developed formulations was subjected to in vivo efficacy studies in thirty sites of human periodontal pockets. Significant results were obtained with respect to both microbiological and clinical parameters up to 3 months even as compared to commercial DXY gel. Statistical analyses of the release data and in vivo results were performed using the analysis of variance (ANOVA) method.

Biodegradable microparticles based on poly(D,L-lactide) as a protective transport system in ruminant digestion.

Despite its abundance in their diet, cattle are unable to directly digest cellulose. The bovine digestive tract overcomes this problem via the rumen, a portion of the stomach containing mixed anaerobic bacteria. These microbes, while breaking down foodstuffs, also perform undesirable processes such as biohydrogenation, in which unsaturated fatty acids become saturated, with deleterious cardiovascular effects. An approach to preventing this saturation entailing the use of polymeric microspheres to encapsulate feed supplements is proposed, with a single emulsion, solvent evaporation method used to formulate poly(D,L-lactide) microparticles for delivery of unsaturated fatty acids to ruminant abomasum.

PLA-PEG particles as nasal protein carriers: the influence of the particle size.

Previous studies have shown that PLA-PEG nanoparticles (NP) are able to enhance the transport of the encapsulated model protein, tetanus toxoid (TT), across the rat nasal mucosa. The aim of this work was to study if the size of PLA-PEG particles affects the nasal transport of the encapsulated protein and, also, the potential contribution of blank nanoparticles to the transport of the free protein. To achieve this purpose, 125I-TT was encapsulated into PLA-PEG particles of different sizes (200 nm, 1.5, 5 and 10 microm) prepared by the water-in-oil-in-water solvent evaporation technique. Firstly, in order to investigate the carrier role of the particles, two series of either conscious or anaesthetized rats were nasally treated with 125I-TT-loaded NP, free 125I-TT, and a physical mixture of blank NP and free 125I-TT. Secondly, the influence of the particle size on the nasal transport of TT encapsulated into PLA-PEG particles was evaluated in conscious rats. The amount of radioactivity recovered in the blood compartment, lymph nodes and other relevant tissues was monitored for up to 24h. Finally, the nasal bioavailability of 125I-TT-loaded PLA-PEG NP was calculated. The results indicated that the use of anaesthesia enhances the transport of 125I-TT and that the physical presence of PLA-PEG NP does not affect the transport of the toxoid. In contrast, when TT was encapsulated into the particles its transport across the nasal mucosa of conscious rats was significantly enhanced. Furthermore, the efficacy of this transport was related to the particle size, reaching the most important transport for the smallest particle size. The intensity of this transport was also illustrated by the high nasal bioavailability of TT encapsulated into nanoparticles (200 nm) (F = 70-80%). These results led us to conclude that PLA-PEG NP can be accepted as nasal protein carriers for nasal administration.