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      Increased localized delivery of piroxicam by cationic nanoparticles after intra-articular injection

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          Abstract

          Piroxicam (PRX), a potent nonsteroidal anti-inflammatory drug, is prescribed to relieve postoperative and/or chronic joint pain. However, its oral administration often results in serious gastrointestinal adverse effects including duodenal ulceration. Thus, a novel cationic nanoparticle (NP) was explored to minimize the systemic exposure and increase the retention time of PRX in the joint after intra-articular (IA) injection, by forming micrometer-sized electrostatic clusters with endogenous hyaluronic acid (HA) in the synovial cavity. PRX-loaded NPs consisting of poly(lactic- co-glycolic acid), Eudragit RL, and polyvinyl alcohol were constructed with the following characteristics: particle size of 220 nm, zeta potential of 11.5 mV in phosphate-buffered saline, and loading amount of 4.0% (w/w) of PRX. In optical and hyperspectral observations, the cationic NPs formed more than 50 μm-sized aggregates with HA, which was larger than the intercellular gaps between synoviocytes. In an in vivo pharmacokinetic study in rats, area under the plasma concentration–time curve (AUC 0–24 h) and maximum plasma concentration ( C max) of PRX after IA injection of the cationic NPs were <70% ( P<0.05) and 60% ( P<0.05), respectively, compared to those obtained from drug solution. Moreover, the drug concentration in joint tissue 24 h after dosing with the cationic NPs was 3.2-fold ( P<0.05) and 1.8-fold ( P<0.05) higher than that from drug solution and neutrally charged NPs, respectively. Therefore, we recommend the IA cationic NP therapy as an effective alternative to traditional oral therapy with PRX, as it increases drug retention selectively in the joint.

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          Most cited references 29

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          Intraarticular drug delivery in osteoarthritis.

          Osteoarthritis (OA) is a primarily non-inflammatory, degenerative joint disease characterized by progressive loss of articular cartilage, subchondral bone sclerosis, osteophyte formation, changes in the synovial membrane, and an increased volume of synovial fluid with reduced viscosity and hence changed lubrication properties. As OA is the most common type of arthritis and a leading cause of disability, there is a largely unmet medical need for disease-modifying and symptomatic treatment. Due to the localized nature of the disease, intraarticular (IA) drug injection is an attractive treatment approach for OA. The various glucocorticoid and hyaluronic acid (HA) formulations, which are currently available on the market for IA treatment, provide only short-term pain relief or/and often do not provide adequate pain relief. The available oral drugs for symptomatic treatment also have shortcomings, most notably side effects. Therefore, there is still a large unmet need for novel OA drugs, which provide effective long-term pain relief and/or have disease-modifying properties. To achieve long-term drug exposure, different established formulations such as suspensions and hydrogels, and also novel approaches such as lipid based formulations and nano- or microparticles are currently in development. The development of novel drugs in combination with new formulations for IA treatment of OA, represents a promising approach in this challenging area of research.
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            Effects of emulsifiers on the controlled release of paclitaxel (Taxol) from nanospheres of biodegradable polymers.

            Paclitaxel (Taxol) is an antineoplastic drug effective for various cancers especially ovarian and breast cancer. Due to its high hydrophobicity, however, an adjuvant such as Cremophor EL has to be used in its clinical administration, which causes serious side-effects. Nanospheres of biodegradable polymers could be an ideal solution. This study investigates the effects of various emulsifiers on the physical/chemical properties and release kinetics of paclitaxel loaded nanospheres fabricated by the solvent extraction/evaporation technique. It is shown that phospholipids could be a novel type of emulsifiers. The nanospheres manufactured with various emulsifiers were characterized by laser light scattering for their size and size distribution; scanning electron microscopy (SEM) and atomic force microscopy (AFM) for their surface morphology; zeta potential analyser for their surface charge; and, most importantly, X-ray photoelectron spectroscopy (XPS) for their surface chemistry. The encapsulation efficiency and in vitro release profile were measured by high performance liquid chromatography (HPLC). It is found that dipalmitoyl-phosphatidylcholine (DPPC) can provide more complete coating on the surface of the products which thus results in a higher emulsifying efficiency compared with polyvinyl alcohol (PVA). Our result shows that the chain length and unsaturation of the lipids have a significant influence on the emulsifying efficiency. Phospholipids with short and saturated chains have excellent emulsifying effects.
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              Intra-articular delivery of kartogenin-conjugated chitosan nano/microparticles for cartilage regeneration.

              We developed an intra-articular (IA) drug delivery system to treat osteoarthritis (OA) that consisted of kartogenin conjugated chitosan (CHI-KGN). Kartogenin, which promotes the selective differentiation of mesenchymal stem cells (MSCs) into chondrocytes, was conjugated with low-molecular-weight chitosan (LMWCS) and medium-molecular-weight chitosan (MMWCS) by covalent coupling of kartogenin to each chitosan using an ethyl(dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) catalyst. Nanoparticles (NPs, 150 ± 39 nm) or microparticles (MPs, 1.8 ± 0.54 μm) were fabricated from kartogenin conjugated-LMWCS and -MMWCS, respectively, by an ionic gelation using tripolyphosphate (TPP). The in vitro release profiles of kartogenin from the particles showed sustained release for 7 weeks. When the effects of the CHI-KGN NPs or CHI-KGN MPs were evaluated on the in vitro chondrogenic differentiation of human bone marrow MSCs (hBMMSCs), the CHI-KGN NPs and CHI-KGN MPs induced higher expression of chondrogenic markers from cultured hBMMSCs than unconjugated kartogenin. In particular, hBMMSCs treated with CHI-KGN NPs exhibited more distinct chondrogenic properties in the long-term pellet cultures than those treated with CHI-KGN MPs. The in vivo therapeutic effects of CHI-KGN NPs or CHI-KGN MPs were investigated using a surgically-induced OA model in rats. The CHI-KGN MPs showed longer retention time in the knee joint than the CHI-KGN NPs after IA injection in OA rats. The rats treated with CHI-KGN NPs or CHI-KGN MPs by IA injection showed much less degenerative changes than untreated control or rats treated with unconjugated kartogenin. In conclusion, CHI-KGN NPs or CHI-KGN MPs can be useful polymer-drug conjugates as an IA drug delivery system to treat OA.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                16 November 2016
                : 10
                : 3779-3787
                Affiliations
                [1 ]Division of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, Seoul
                [2 ]College of Pharmacy, Dankook University, Cheonan, Chungnam, South Korea
                Author notes
                Correspondence: Young Wook Choi, Division of Pharmaceutical Sciences, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 156-756, South Korea, Tel +82 2 820 5609, Fax +82 2 826 3781, Email ywchoi@ 123456cau.ac.kr
                Myung Joo Kang, Division of Pharmaceutical Sciences, College of Pharmacy, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan, Chungnam 330-714, South Korea, Tel +82 41 550 1446, Fax +82 41 550 7899, Email kangmj@ 123456dankook.ac.kr
                Article
                dddt-10-3779
                10.2147/DDDT.S118145
                5117887
                © 2016 Kim et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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