Combination of Indomethacin with Nanostructured Lipid Carriers for Effective Anticancer Therapy.

Purpose: The anticancer potential of indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, in vivo, and in clinical trials is well known and widely reported in the literature, along with their side effects, which are mainly observed in the gastrointestinal tract. Here, we present a strategy for the application of the old drug indomethacin as an anticancer agent by encapsulating it in nanostructured lipid carriers (NLC). We describe the production method of IND-NLC, their physicochemical parameters, and the results of their antiproliferative activity against selected cancer cell lines, which were found to be higher compared to the activity of free indomethacin. Methods: IND-NLC were fabricated using the hot high-pressure homogenization method. The nanocarriers were physicochemically characterized, and their biopharmaceutical behaviour and therapeutic efficacy were evaluated in vitro. Results: Lipid nanoparticles IND-NLC exhibited a particle size of 168.1 nm, a negative surface charge (-30.1 mV), low polydispersity index (PDI of 0.139), and high encapsulation efficiency (over 99%). IND-NLC were stable for over 60 days and retained integrity during storage at 4 °C and 25 °C. The potential therapeutic benefits of IND-NLC were screened using in vitro cancer models, where nanocarriers with encapsulated drug effectively inhibited the growth of breast cancer cell line MDA-MB-468 at dosage 15.7 µM. Conclusion: We successfully developed IND-NLC for delivery of indomethacin to cancer cells and confirmed their antitumoral efficacy in in vitro studies. The results suggest that indomethacin encapsulated in lipid nanoparticles possesses high anticancer potential. Moreover, the presented strategy is highly promising and may offer a new alternative for future therapeutic drug innovations.

Chitosan - dextran phosphate carbamate hydrogels for locally controlled co-delivery of doxorubicin and indomethacin: From computation study to in vivo pharmacokinetics.

The development of synergistic drug combinations is a promising strategy for effective cancer suppression. Here, we report all-polysaccharide biodegradable polyelectrolyte complex hydrogels (DPCS) based on dextran phosphate carbamate (DP) and chitosan (CS) for controlled co-delivery of the anticancer drug doxorubicin (DOX) and the non-steroidal anti-inflammatory drug indomethacin (IND). IND can induce more apoptosis in tumor cells by reducing the level of multidrug resistance-associated protein 1. Based on calculations using density functional theory and zeta potential analysis data, carriers with high drug loading were obtained. The release profile of both drugs from the hydrogels was tuned by changing the molecular weight and functional groups content of the polysaccharides. The optimized DPCS showed a steady release of DOX both in vitro and in vivo, and a gradual release of IND, which constantly induced the action of DOX. Considering all of these benefits, DOX- and IND-loaded DPCS offer a promising long-acting polysaccharide-based antitumor platform.

Lipid Formulations and Bioconjugation Strategies for Indomethacin Therapeutic Advances.

Indomethacin (IND) is a drug which after successful clinical trials became available for general prescription in 1965 and from that time is one of the most widely used anti-inflammatory drug with the highest potencies in the in vitro and in vivo models. However, despite its high therapeutic efficacy in relieving the symptoms of certain arthritis and in treating gout or collagen diseases, administration of IND causes a number of adverse effects, such as gastrointestinal ulceration, frequent central nervous system disorders and renal toxicity. These obstacles significantly limit the practical applications of IND and make that 10-20% of patients discontinue its use. Therefore, during the last three decades many attempts have been made to design novel formulations of IND aimed to increase its therapeutic benefits minimizing its adverse effects. In this review we summarize pharmacological information about IND and analyze its new lipid formulations and lipid bioconjugates as well as discuss their efficacy and potential application.

Polymer/lipid interplay in altering in vitro supersaturation and plasma concentration of a model poorly soluble drug.

Supersaturation drug delivery system (SDDS) based on amorphous solid dispersion (ASD) is a widely used strategy to improve oral absorption of poorly water-soluble drugs by achieving a supersaturated state where drug concentration is significantly higher than drug solubility. However, dissolved drugs tend to recrystallize in gastrointestinal (GI) tract if without effective stabilizing excipients. In this paper, well-recognized polymer (polyvinylpyrrolidone, PVP) and lipid (phosphatidylcholine, PC) excipients are combined as ASD carrier, aiming at investigating the effects on evolution of in vitro supersaturation and in vivo plasma concentration of a model poorly soluble drug indomethacin (IND). Fundamental aspects including polymer/lipid composition ratio, drug loading (DL) degree and administration dose were investigated. The in vitro dissolution profiles of ASDs were assessed by supersaturation degree, duration, maximum achievable drug concentration and dose-normalized efficiency, and correlated with in vivo pharmacokinetic data. Results showed that both in vitro and in vivo concentration-time profiles of IND were significantly varying with abovementioned factors. Solution viscosity, solid-state properties and morphology of ASDs were related to the results. This study revealed fundamental mechanisms of PVP/PC mixture effect on IND supersaturation and oral bioavailability, demonstrating that polymer/lipid mixture could be used as a promising carrier to alter supersaturation profile and oral bioavailability of SDDS products.

Pharmacokinetics-based analysis of indomethacin's anti-tumor effect and drug efficacy.

Non-steroidal anti-inflammatory drugs are commonly used anti-inflammatory analgesics in clinic. Indomethacin is a kind of NSAIDs and has anti-tumor effect. It can significantly change the growth cycle of cancer cells, inhibit their proliferation. In this paper, the antineoplastic effect of indomethacin and its pharmacokinetic effect were analysed. The result showed that indomethacin had more metabolic distribution in tumor tissues and reached its peak at 4 hours, after that, the clearance rate was slower than that in the blood, with the clearance rate slowest at 6-12 hours. At the same time, the expression of Bcl-2 protein in cancer cells was significantly reduced and weakened, while the expression of Bax protein did not change significantly. Pharmacodynamic studies have proved that IN (Indomethacin) has a strong anti-tumor effect. It can enter into tumor cells through cell membrane and nuclear membrane to have an anti-tumor effect.

VITREOUS PROSTAGLANDIN E2 CHANGES AFTER TOPICAL ADMINISTRATION OF DICLOFENAC 0.1%, INDOMETHACIN 0.5%, NEPAFENAC 0.3%, AND BROMFENAC 0.09.

PURPOSE: To evaluate the vitreous concentration of different nonsteroidal anti-inflammatory drugs (NSAIDs) after topical administration and the related prostaglandin E2 (PGE2) levels in patients undergoing pars plana vitrectomy. METHODS: A prospective, randomized, investigator-masked study was performed. One hundred four patients scheduled for a pars plana vitrectomy for an epiretinal membrane or a macular hole were randomized to receive topical diclofenac 0.1%, indomethacin 0.5%, nepafenac 0.3%, bromfenac 0.09%, or placebo 3 days before surgery. At the beginning of surgery, a sample of undiluted vitreous was collected in each patient to assess NSAIDs concentration and PGE2 levels. RESULTS: The median vitreous concentrations were 203.35 (interquartile range 146.54-264.18) pg/mL for diclofenac, 243.45 (interquartile range 156.96-365.37) pg/mL for nepafenac, 438.21 pg/mL (interquartile range, 282.52-645.87) for its active metabolite amfenac, 350.14 (interquartile range, 290.88-481.95) pg/mL for indomethacin, and 274.59 (245.43-358.25) pg/mL for bromfenac. Vitreous PGE2 levels were significantly lower for all the NSAIDs groups compared with the control group (P < 0.001). A statistically significant higher vitreous PGE2 level was found in the diclofenac group compared with the other NSAIDs groups (P < 0.05). CONCLUSION: Topical NSAIDs achieve sufficient vitreous concentration to decrease vitreous PGE2 levels compared with the control group. The different efficacy in reducing PGE2 concentration may affect the management of posterior segment inflammation.

Computer-assisted engineering of programmed drug releasing multilayer nanomedicine via indomethacin-mediated ternary complex for therapy against a multidrug resistant tumor.

Nanomedicine with programmed drug release can give full play to the synergistic effect of multi-component system in complicated tumor environment. However, the construction of these programmed drug delivery systems often depends on the sophisticated materials design and synthesis. In this study, we successfully designed an indomethacin (IND)-mediated ternary complex system based on a PEG cleavable polyethyleneimine (PEI), indomethacin (IND) and benzene ring containing chemotherapeutic drugs (such as paclitaxel (PTX), doxorubicin and docetaxel). Based on the difference of hydrophobicity in these components, these components were one-pot self-assembled into drug-loaded IND mediated PEGylation cleavable nanoassemblies (IPCNs) in multilayer structure. In drug-loaded IPCNs, PEG fragments, PEI/IND, and chemotherapeutic drug were respectively distributed from the out layer to core of nanomedicine. When drug-loaded IPCNs reached tumor site through EPR effect, the PEG fragment would firstly responsively release to the acidic tumor microenvironment to expose the intermediate layer of drug-loaded IPCNs that composed by mixture of PEI and IND for increasing the surface potential to promote the uptake by tumor cells. After entering cells, IND would be released faster than chemotherapeutic drug encapsulated in core to efficiently inhibit the expression of multidrug resistance protein 1 to reverse MDR of tumor cells before chemotherapeutic drug releasing. Contributed by the staged responsively releasing of PEG fragments, IND and encapsulated chemotherapeutic drug, the drug-loaded IPCNs exhibited a superior antitumor efficacy against A549/MDR tumor cells both in vitro and in vivo. STATEMENT OF SIGNIFICANCE: The way to develop programmed released drug delivery system is commonly relied on complicated material design and synthesis. Herein, under the computer-assist design, we successfully designed a ternary complex derived from indomethacin (IND), paclitaxel (PTX) and a pH-responsive PEGylated polyethyleneimine (PEG-s-PEI), and employed this ternary complex to successfully prepare a high drug loading and multilayer structured nanomedicine of PTX (PTX IPCNs). Contribute by the different location of PTX, IND and PEG-s-PEI in PTX IPCNs, PEG fragments, IND and PTX molecules could programmed release after reaching tumor for perfectly realizing the synergistic anti-tumor effect of tumor targeting, reversal of MDR and chemotherapy. Based on a fusion of these multiple mechanisms, PTX IPCNs showed a superior antitumor efficacy in mice loading A549/MDR tumor.

Self-Assembled Indomethacin Dimer Nanoparticles Loaded with Doxorubicin for Combination Therapy in Resistant Breast Cancer.

An ortho-ester-linked indomethacin (IND) dimer-based nanodrug delivery system was prepared to improve the therapeutic effect of doxorubicin (DOX) by reversing the multidrug resistance. The synthesized dimer (IND-OE) could form stable nanoparticles (IND-OE/DOX) loaded with DOX via the single-emulsion method. Compare to insensitive nanoparticles (IND-C12/DOX), IND-OE/DOX showed a rapid degradation behavior and accelerated drug release at mildly acidic environments. In vitro cell experiments verified that IND-OE nanoparticles could increase DOX concentration due to the efficient intracellular drug release by the degradation of the ortho ester as well as reduced DOX efflux by IND-mediated P-gp downregulation. In vivo studies further demonstrated that IND-OE/DOX displayed the maximized synergetic antitumor efficacy than free DOX or IND-C12/DOX, and the tumor inhibition rates versus saline were 46.78% (free DOX), 60.23% (IND-C12/DOX), and 80.62% (IND-OE/DOX). Overall, this strategy of combination with chemosensitizers and ortho ester linkage has great potential to serve as an amplifying chemotherapy platform against various drug-resistant tumors.

Impacts of Polymeric Additives on Nucleation and Crystal Growth of Indomethacin from Supersaturated Solutions.

Three polymers, polyvinylpyrrolidone (PVP K30), hydroxypropyl methyl cellulose (HPMC E5), and Kollidone VA64 (PVP-VA64), have been assessed for their impact on the nucleation and crystal growth of indomethacin (IND) from supersaturation solutions. PVP was the most effective inhibitor on IND nucleation among three polymers, but the effect of three polymers on inhibiting nucleation is quite limited when the degree of supersaturation S is higher than about 9. Analysis of the nucleation data by classical nucleation theory model generally afforded good data fitting with the model and showed that addition of polymers may affect the crystal/solution interfacial free energy γ and also the pre-exponential kinetic factor. PVP-VA showed better inhibitory effects on crystal growth of IND when the polymer concentration is high (0.1%, w/w) as reflected by the crystal growth inhibition factor R, and PVP exhibited relatively stronger effects on inhibiting crystal growth at low polymer concentrations (0.005%, w/w). The crystal growth inhibitory effect of polymers should be attributable to the retardation of the surface integration of the drug, and such effect should also be polymer and drug dependent. The enhancement of supersaturation level of IND should be attributable to both nucleation and crystal growth inhibition by polymers. The nucleation and crystal growth rate of α-polymorph IND is higher than that of γ-polymorph, and α-polymorph is the predominant form appeared in supersaturated solutions. A rational selection of the appropriate polymer for specific drug is critical for developing supersaturated drug delivery formulations.

Energy-dependent endocytosis is responsible for drug transcorneal penetration following the instillation of ophthalmic formulations containing indomethacin nanoparticles.

PURPOSE: We previously found that ophthalmic formulations containing nanoparticles prepared by a bead mill method lead to an increase in bioavailability in comparison with traditional formulations (solution type). However, the transcorneal penetration pathway for ophthalmic formulations has not been explained yet. In this study, we investigated the mechanism of transcorneal penetration in the application of ophthalmic formulations containing indomethacin nanoparticles (IMC-NPs). MATERIALS AND METHODS: IMC-NPs was prepared by the bead mill method. For the analysis of energy-dependent endocytosis, corneal epithelial (HCE-T) cell monolayers and removed rabbit cornea were thermoregulated at 4°C, where energy-dependent endocytosis is inhibited. In addition, for the analysis of different endocytosis pathways using pharmacological inhibitors, inhibitors of caveolae-mediated endocytosis (54 µM nystatin), clathrin-mediated endocytosis (40 µM dynasore), macropinocytosis (2 µM rottlerin) or phagocytosis (10 µM cytochalasin D) were used. RESULTS: The ophthalmic formulations containing 35-200 nm sized indomethacin nanoparticles were prepared by treatment with a bead mill, and no aggregation or degradation of indomethacin was observed in IMC-NPs. The transcorneal penetration of indomethacin was significantly decreased by the combination of nystatin, dynasore and rottlerin, and the decreased penetration levels were similar to those at 4°C in HCE-T cell monolayers and rabbit cornea. In the in vivo experiments using rabbits, dynasore and rottlerin tended to decrease the transcorneal penetration of indomethacin (area under the drug concentration - time curve in the aqueous humor [AUCAH]), and the AUCAH in the nystatin-treated rabbit was significantly lower than that in non-treatment group. In addition, the AUCAH in rabbit corneas undergoing multi-treatment was obviously lower than that in rabbit corneas treated with each individual endocytosis inhibitor. CONCLUSION: We found that three energy-dependent endocytosis pathways (clathrin-dependent endocytosis, caveolae-dependent endocytosis and macropinocytosis) are related to the trans-corneal penetration of indomethacin nanoparticles. In particular, the caveolae-dependent endocytosis is strongly involved.

Transdermal delivery system of nanostructured lipid carriers loaded with Celastrol and Indomethacin: optimization, characterization and efficacy evaluation for rheumatoid arthritis.

Co-encapsulation of drugs provides a convenient means for treating different symptoms of a disease. Celastrol (Cel) shows potent anti-arthritic activity and Indomethacin (Indo) is effective in relieving inflammatory pain. Nanostructured lipid carriers loaded with Celastrol and Indomethacin (Cel-Indo-NLCs) were prepared by emulsification evaporation-solidification method, optimized by the Box-Behnken design and characterized by transmission electron microscopy (TEM), Fourier transform infrared (FTIR) and powder X-ray diffraction analysis (PXRD). Visualization of transdermal translocation of Cel-Indo-NLCs was achieved by confocal laser scanning microscope (CLSM). Further, Cel-Indo-NLCs were incorporated into Carbopol 940 for transdermal delivery. The in vitro studies were evaluated by using the Franz diffusion cells. Cel-Indo-NLCs depicted small particle size (26.92 ± 0.62 nm) and PDI (0.201 ± 0.01), high entrapment efficiency (96.56 ± 1.41%) and drug load (3.65 ± 0.05%). Moreover, Cel-Indo-NLCs showed prominent effect of decreasing paw oedema, inhibiting inflammation and pain by regulating the levels of IL-1ß, TNF-α, ß-endorphin and Substance P. After the administration of Cel-Indo-NLCs-gel, no skin irritation was observed in rats. There was no difference of gastrointestinal tract between different groups of rats when they were sacrificed. The histological analysis showed no renal and reproductive toxicity. Therefore, it can be concluded that co-encapsulation strategy based NLCs have the potential to provide safe transdermal delivery and are promising in treatment of pain and inflammation associated with rheumatoid arthritis.

Improvement of the skin penetration of hydrophobic drugs by polymeric micelles.

Polymeric micelles, which form through the self-assembly of poly(ethylene glycol)-poly(amino acid) block copolymers, are systemic nanocarriers in targeted cancer therapy. These micelles can encapsulate therapeutic compounds, such as lipophilic substances, charged compounds, and metal complexes, that have characteristics of increased solubility, sustained release, and improved tissue distribution. However, few studies have been conducted on the local distribution of polymeric micelles. Thus, we evaluated the skin penetration pattern of hydrophobic drugs in polymeric micelles. We revealed that improved water solubility by the encapsulation of the hydrophobic drugs indomethacin and resveratrol in polymeric micelles significantly increased the amount of drugs penetrating into the skin. Moreover, polymeric micelles did not enhance the permeability of drugs. Furthermore, although the polymers remained on or in the stratum corneum, the encapsulated drugs gradually moved deeper into the skin. These results indicate that encapsulated hydrophobic drugs in polymeric micelles can penetrate the living cell layer of the skin without bringing about unexpected side effects associated with other ingredients in the formulation. Thus, polymeric micelles for encapsulating hydrophobic drugs can be used for skin applications.

Biotin-Pt (IV)-indomethacin hybrid: A targeting anticancer prodrug providing enhanced cancer cellular uptake and reversing cisplatin resistance.

A Pt(IV) prodrug (2) composed of cancer-targeting biotin and nonsteroidal anti-inflammatory drug indomethacin in the axial positions of the six-coordinated octahedral geometry derived from cisplatin was developed, which could be highly accumulated in cancer cells more than normal ones and activated by endogenous reducing molecules to release cisplatin and indomethacin moieties simultaneously to inhibit tumor progression synergistically. In vitro assays revealed that 2 exhibited significantly selective inhibition to the tested cancer cell lines and sensitivity to cisplatin resistant cancer cells. Moreover, 2 presented cyclooxygenases inhibition properties to reduce tumor-associated inflammation, reduced the invasiveness of the highly aggressive PC-3 cells, and disrupted capillary-like tube formation in EA.hy926 cells. In all, this study offers a new strategy to enhance sensitivity and reduce toxicity of cisplatin.

Smart pH-sensitive nanoassemblies with cleavable PEGylation for tumor targeted drug delivery.

A new acidly sensitive PEGylated polyethylenimine linked by Schiff base (PEG-s-PEI) was designed to render pH-sensitive PEGylation nanoassemblies through multiple interactions with indomethacin and docetaxel (DTX). DTX nanoassemblies driven by PEG-s-PEI thus formulated exhibited an excellent pH-sensitivity PEGylation cleavage performance at extracellular pH of tumor microenvironment, compared to normal tissues, thereby long circulated in blood but were highly phagocytosed by tumor cells. Consequently, this smart pH-sensitive PEGylation cleavage provided an efficient strategy to target tumor microenvironment, in turn afforded superior therapeutic outcome in anti-tumor activity.

Chemosensitizing indomethacin-conjugated chitosan oligosaccharide nanoparticles for tumor-targeted drug delivery.

A chitosan oligosaccharide (CSO)-indomethacin (IDM) conjugate (CI) was synthesized to fabricate chemosensitizing nanoparticles (NPs) for tumor-targeted drug delivery. IDM was conjugated to a CSO backbone via amide bond formation, of which successful synthesis was confirmed by proton-nuclear magnetic resonance analyses. Doxorubicin (DOX)-loaded CI (CI10/DOX; CI:DOX=10:1 [w/w]) NPs with <75nm of mean diameter, polydispersity index of ∼0.2, and positive zeta potential were prepared. The release of DOX from the NPs was enhanced at acidic pH (pH 5.5 and 6.8) compared to physiological pH (pH 7.4). The release of IDM increased in the presence of A549 cell lysates. In A549 cells (human lung carcinoma cells), more efficient cellular uptake of CI10/DOX NPs than that of free DOX was observed by using confocal laser scanning microscopy and flow cytometry. The in vitro cytotoxicity of CI10/DOX NPs in A549 cells was higher than those of free DOX and CI NPs with free DOX groups. In vivo pharmacokinetic studies after intravenous administration in rats showed significantly lower clearance of DOX from NPs compared with the free DOX group. Tumor targetability of the developed CI NPs was also verified by a real-time optical imaging study. In summary, the chemosensitizing CI/DOX NP with enhanced anticancer activity, prolonged blood circulation, and passive tumor targeting can be a promising anticancer drug delivery system for tumor-targeted therapy. STATEMENT OF SIGNIFICANCE: Chemosensitizing nanoparticles (NPs) based on amphiphilic chitosan oligosaccharide-indomethacin (CSO-IDM; CI) conjugate were developed for tumor-targeted delivery of doxorubicin (DOX). IDM was introduced to the CSO backbone as a hydrophobic residue to synthesize an amphiphilic conjugate and a chemosenstizer of DOX for improving antitumor efficacies. IDM, conjugated to CSO, may inhibit the efflux of cellular uptaken DOX via multidrug resistance-associated protein (MRP) and subsequently augment the anti-proliferation potentials of DOX in A549 cells (MRP-expressed human lung cancer cells). Chemosensitizing properties of developed CI NPs were assessed in cell culture models and the tumor targetability of CI/DOX NPs was demonstrated in A549 tumor-xenografted mouse model by a real-time optical imaging. Developed CI NPs can be used as a multifunctional nanosystem for the therapy of MRP-expressed cancers.

Poly(ε-benzyloxycarbonyl-L-lysine)-grafted branched polyethylenimine as efficient nanocarriers for indomethacin with enhanced oral bioavailability and anti-inflammatory efficacy.

Star-block copolymers PEI-g-PZLL with a branched polyethylenimine (PEI) core and multiple grafted poly(ε-benzyloxycarbonyl-L-lysine) (PZLL) peripheral chains were designed, synthesized, and evaluated as nanocarriers for indomethacin (IND). In an aqueous solution, PEI-g-PZLL self-assembled into spherical nanoparticles capable of encapsulating IND at high loading capacity and loading efficiency. Differential scanning calorimetry and X-ray diffraction measurements indicated that IND was molecularly or amorphously dispersed in the nanoparticles. Fourier transform infrared spectra revealed the presence of multiple intermolecular interactions, including hydrogen bonding, electrostatic forces, π-π stacking and hydrophobic interactions, between the block copolymer and the IND molecules. IND-loaded nanoparticles exhibited fast release under intestinal pH. Compared with raw IND, the utilization of PEI-g-PZLL as a carrier significantly enhanced the oral bioavailability of IND and improved its protective effect on renal ischemia-reperfusion injury, as evidenced by in vivo pharmacokinetic and pharmacodynamic studies. Cytotoxicity assay, histological observation and cellular uptake study suggested that PEI-g-PZLL was fairly biocompatible. All these results indicated that star-block copolymers PEI-g-PZLL could be used as efficient nanocarriers for IND and other poorly water-soluble drugs. STATEMENT OF SIGNIFICANCE: The use of polyethylenimine (PEI) as an oral drug delivery carrier is limited because it is not biodegradable and the use of higher molecular weight PEI leads to improved efficiency but also increased cytotoxicity. The design of functionalized PEIs with low cytotoxicity and high efficiency is crucial for developing a successful oral drug delivery system. In our study, poly(ε-benzyloxycarbonyl-L-lysine) (PZLL)-grafted branched PEI (PEI-g-PZLL) was reported as an oral nanocarrier for indomethacin (IND). The low cytotoxicity and biodegradability, well-defined self-assembled nano-sized polymeric micelles, high loading capacity and loading efficiency, amorphous state of the encapsulated IND, as well as the enhanced oral bioavailability of IND, makes the copolymer PEI-g-PZLL a promising nanocarrier for the oral administration of IND and possibly other poorly water-soluble drugs.

Amphiphilic poly-N-vinylpyrrolidone nanoparticles as carriers for non-steroidal, anti-inflammatory drugs: In vitro cytotoxicity and in vivo acute toxicity study.

Polymeric nanoparticles were prepared from self-assembled amphiphilic N-vinylpyrrolidone polymers in aqueous media and evaluated as novel carriers of indomethacin, a non-steroidal, anti-inflammatory drug. It was determined that these nanoparticles could be created in spherical morphologies with sizes less than 100nm, narrow size distributions and high indomethacin contents(up to 35%) combined with high drug loading efficiencies(up to 95%). In cytotoxicity tests using the human embryonic stem cell derived fibroblasts (EBF-H9) and hepatocellular carcinoma cells (HepG2), the indomethacin-loaded polymeric nanoparticles showed higher cell viability compared to that of free indomethacin at the same concentration. The median LD50 values, determined by the Litchfield-Wilcoxon method, were 55-70mg/kg body weight depending on the polymer molecular design in both mice and rats. Based on the acquired results, these novel amphiphilic poly-N-vinylpyrrolidone nanoparticles can be considered as potential carriers for new, highly efficient, injectable drug delivery systems for hydrophobic drugs such as indomethacin.

REDUCTION OF VITREOUS PROSTAGLANDIN E2 LEVELS AFTER TOPICAL ADMINISTRATION OF INDOMETHACIN 0.5%, BROMFENAC 0.09%, AND NEPAFENAC 0.1.

PURPOSE: To assess vitreous concentrations of nonsteroidal anti-inflammatory drugs (NSAIDs) and prostaglandin E2 (PGE2) in patients treated with NSAIDs before vitrectomy for macular pucker. METHODS: A prospective, investigator-masked, randomized study was performed in 64 patients scheduled to undergo vitrectomy. The patients were randomized 1:1:1:1 to receive indomethacin 0.5%, bromfenac 0.09%, nepafenac 0.1%, or placebo three times a day. NSAIDs and PGE2 levels were evaluated in vitreous samples collected at the beginning of surgery. RESULTS: Mean (SD) vitreous concentrations of the study drugs were 503.13 (241.1) pg/mL for indomethacin, 302.5 (91.03) pg/mL for bromfenac, and 284.38 (128.2) pg/mL for nepafenac. Mean (SD) vitreous PGE2 levels were 247.9 (140.9) pg/mL for indomethacin, 322.12 (228.1) pg/mL for bromfenac, 448.8 (261.1) pg/mL for nepafenac, and 1,133 (323.9) pg/mL for placebo. All three NSAIDs reduced vitreous PGE2 levels to a statistically significant extent, without a significant difference among them. CONCLUSION: All assessed NSAIDs penetrated the vitreous and lowered basal PGE2 levels. A greater penetration was associated with pseudophakic eyes. The important inhibition of prostaglandins in the retina may have a clinical effect on the management of inflammatory retina diseases.

Tamoxifen is a potent antioxidant modulator for sperm quality in patients with idiopathic oligoasthenospermia.

OBJECTIVE: To explore the new mechanisms of tamoxifen (TAM) in the treatment for patients with idiopathic oligoasthenospermia-antioxidation. METHODS: In a prospective, randomized, controlled clinical trial, 120 cases of idiopathic oligoasthenospermia were enrolled and randomly assigned to the indomethacin group (n = 60) treated with indomethacin (25 mg, bid) and TAM group (n = 60) treated with TAM (10 mg, bid) for 3 months. Before and after treatment, we evaluated semen parameters, serum malondialdehyde (MDA) and total antioxidant capacity (TAC), seminal plasma MDA and TAC, spermatozoa intracellular reactive oxygen species (ROS), sperm succinate dehydrogenase (SDH) activity, sperm mitochondrial membrane potential (MMP), and sperm adenosine triphosphate (ATP) content. The independent t test and one-way repeated measures analysis of variance were used to compare the variables between and within two groups. RESULTS: In the indomethacin group, the percentage of progressive motile sperms, total motility, sperm MMP, and ATP content were increased significantly after 3-month treatment (P < 0.05). In the TAM group, total sperm count, sperm concentration, the percentage of progressive motile sperms, total motility, serum and seminal plasma TAC, sperm MMP, and ATP content were significantly improved or increased (P < 0.05), while spermatozoa intracellular ROS was significantly decreased (P < 0.05). Compared to the indomethacin group, TAM treatment showed better improvement in total sperm count, sperm concentration, serum TAC, seminal plasma TAC, spermatozoa intracellular ROS, and sperm SDH activity. CONCLUSIONS: TAM treatment can significantly improve sperm quality, which is achieved through alleviating oxidative stress, improving sperm mitochondrial functionality, and subsequently increasing sperm motility.

Evaluation of matrix type mucoadhesive tablets containing indomethacin for buccal application.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered for pain relief from oral mucositis. However, the systemic administration of NSAIDs is limited due to systemic side effects. To avoid these side effects and treat local lesions effectively, a matrix type mucoadhesive tablet was developed. A mixture of hard fat, ethylcellulose (EC) and polyethylene glycol (PEG) was used as a matrix base, and indomethacin (IMC) was used as the principal agent. In tablets consisting of hard fat, EC and IMC, the drug release was sustained. In tablets consisting of hard fat, EC, considerable amounts of PEG and IMC, the drug release was relatively increased and IMC existed as the molecular phase or in an amorphous state. The in vitro adhesive force of the tablets consisting of hard fat, EC, considerable amounts of PEG and IMC was significantly increased as compared with the tablets consisting of hard fat and IMC. A significantly high tissue concentration and significantly low plasma concentration were observed after buccal administration of this matrix type mucoadhesive tablet as compared with that after oral administration of IMC. Thus, the matrix type mucoadhesive tablet has good potential as a preparation for the treatment of pain due to oral aphtha.