Antinociceptive and anti-inflammatory activity of DW-1021, the ionic complex of pelubiprofen and tramadol, in rodents.

Although drugs such as acetaminophen, opioids, and nonsteroidal anti-inflammatory drugs (NSAIDs), are commonly used for pain management, the side effects of these drugs such as hepatotoxicity, nephrotoxicity, nausea, and vomiting, can not be neglected. Therefore, combinations of analgesics with different mechanisms raise the possibility of developing novel analgesics. Therefore, the aim of the present study was to evaluate whether DW-1021, the ionic complex of pelubiprofen (NSAID) and tramadol (opioid), has synergic antinociceptive and anti-inflammatory effects in nociceptive as well as inflammation-induced nociceptive models compared to pelubiprofen- or tramadol-only administration. Strong synergistic antinociceptive efficacy of DW-1021 was observed in the mouse writhing test and von Frey paw withdrawal threshold test in the carrageenan-induced rats. The hot plate test in mice and the Randall-Selitto mechanical paw pressure test in carrageenan-induced rats revealed that DW-1021 had a preferable effect on relieving pain to pelubiprofen, but not as much as tramadol. In the carrageenan-induced rats, DW-1021 had a more potent effect on reducing paw inflammation (paw volume, width, and thickness) via the suppression of PGE2 production than tramadol, but less than that of pelubiprofen. Taken together, our results suggest that the administration of DW-1021, a combination of pelubiprofen and tramadol, exerted a potent effect and can be used as a potential therapeutic agent for relieving pain and inflammation.

High-Resolution and Large-Area Patterning of Highly Conductive Silver Nanowire Electrodes by Reverse Offset Printing and Intense Pulsed Light Irradiation.

Conventional printing technologies such as inkjet, screen, and gravure printing have been used to fabricate patterns of silver nanowire (AgNW) transparent conducting electrodes (TCEs) for a variety of electronic devices. However, they have critical limitations in achieving micrometer-scale fine line width, uniform thickness, sharp line edge, and pattering of various shapes. Moreover, the optical and electrical properties of printed AgNW patterns do not satisfy the performance required by flexible integrated electronic devices. Here, we report a high-resolution and large-area patterning of highly conductive AgNW TCEs by reverse offset printing and intense pulsed light (IPL) irradiation for flexible integrated electronic devices. A conductive AgNW ink for reverse offset printing is prepared by carefully adjusting the composition of AgNW content, solvents, surface energy modifiers, and organic binders for the first time. High-quality and high-resolution AgNW micropatterns with various shapes and line widths are successfully achieved on a large-area plastic substrate (120 × 100 mm2) by optimizing the process parameters of reverse offset printing. The reverse offset printed AgNW micropatterns exhibit superior fine line widths (up to 6 µm) and excellent pattern quality such as sharp line edge, fine line spacing, effective wire junction connection, and smooth film roughness. They are post-processed with IPL irradiation, thereby realizing excellent optical, electrical, and mechanical properties. Furthermore, flexible OLEDs and heaters based on reverse offset printed AgNW micropatterns are successfully fabricated and characterized, demonstrating the potential use of the reverse offset printing for the conductive AgNW ink.

Improved Dissolution and Oral Bioavailability of Valsartan Using a Solidified Supersaturable Self-Microemulsifying Drug Delivery System Containing Gelucire® 44/14.

To improve the dissolution and oral bioavailability of valsartan (VST), we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMED) composed of Capmul® MCM (oil), Tween® 80 (surfactant), Transcutol® P (cosurfactant), and Poloxamer 407 (precipitation inhibitor) but encountered a stability problem (Transcutol® P-induced weight loss in storage) after solidification. In the present study, replacing Transcutol® P with Gelucire® 44/14 resulted in a novel SuSMED formulation, wherein the total amount of surfactant/cosurfactant was less than that of the previous formulation. Solidified SuSMED (S-SuSMED) granules were prepared by blending VST-containing SuSMED with selective solid carriers, L-HPC and Florite® PS-10, wherein VST existed in an amorphous state. S-SuSMED tablets fabricated by direct compression with additional excipients were sufficiently stable in terms of drug content and impurity changes after 6 months of storage at accelerated conditions (40 ± 2 °C and 75 ± 5% relative humidity). Consequently, enhanced dissolution was obtained (pH 1.2, 2 h): 6-fold for S-SuSMED granules against raw VST; 2.3-fold for S-SuSMED tablets against Diovan® (reference tablet). S-SuSMED tablets increased oral bioavailability in rats (10 mg/kg VST dose): approximately 177⁻198% versus raw VST and Diovan®. Therefore, VST-loaded S-SuSMED formulations might be good candidates for practical development in the pharmaceutical industry.

Empirical design of slot-die having shallow reservoir for thin-film printed electronics.

Slot-die coating plays an important role in printed electronics, which are fabricated by stacking thin films and patterns. As electronic devices are being required to have higher performance, the importance of coating uniformity cannot be overestimated in the slot-die coating. The coating uniformity consists of two directions: nozzle direction, which is affected by the interior design of the head, and machine direction, which is majorly related to exterior operating conditions. In this research, the empirical design procedure of a slot-die head is proposed. The internal resistance values of the slot-die were calculated using the experimental parameter obtained through a coating experiment, and the acquired resistances were reflected in the modeling of the interior design of the slot-die head. The hanger type reservoir was adapted to minimize the consumption of ink. After fabricating the slot-die head, coating experiments were carried out using PEDOT:PSS ink. The resulting deviation of the coating thickness was within ±1.7%, thus proving that the proposed design predicted the uniformity of the actual thickness of the coating correctly. The significance of the slot-die design method presented in this paper is that it is based on the experimental equation that can be readily applied to the printed electronics industry.

Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability.

In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul® MCM (13.2 mg), Tween® 80 (59.2 mg), Transcutol® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite® PS-10 (119.1 mg) and Vivapur® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility.

Enhanced oral bioavailability of valsartan using a polymer-based supersaturable self-microemulsifying drug delivery system.

A novel, supersaturable self-microemulsifying drug delivery system (S-SMEDDS) was successfully formulated to enhance the dissolution and oral absorption of valsartan (VST), a poorly water-soluble drug, while reducing the total quantity for administration. Poloxamer 407 is a selectable, supersaturating agent for VST-containing SMEDDS composed of 10% Capmul® MCM, 45% Tween® 20, and 45% Transcutol® P. The amounts of SMEDDS and Poloxamer 407 were chosen as formulation variables for a 3-level factorial design. Further optimization was established by weighting different levels of importance on response variables for dissolution and total quantity, resulting in an optimal S-SMEDDS in large quantity (S-SMEDDS_LQ; 352 mg in total) and S-SMEDDS in reduced quantity (S-SMEDDS_RQ; 144.6 mg in total). Good agreement was observed between predicted and experimental values for response variables. Consequently, compared with VST powder or suspension and SMEDDS, both S-SMEDDS_LQ and S-SMEDDS_RQ showed excellent in vitro dissolution and in vivo oral bioavailability in rats. The magnitude of dissolution and absorption-enhancing capacities using quantity-based comparisons was in the order S-SMEDDS_RQ > S-SMEDDS_LQ > SMEDDS > VST powder or suspension. Thus, we concluded that, in terms of developing an effective SMEDDS preparation with minimal total quantity, S-SMEDDS_RQ is a promising candidate.

Strategic approaches for enhancement of in vivo transbuccal peptide drug delivery in rabbits using iontophoresis and chemical enhancers.

PURPOSE: To evaluate the feasibility of iontophoresis and the combination effects with chemical enhancers on in vivo hypocalcemic effect of transbuccally delivered salmon calcitonin (sCT). METHODS: N-acetyl-L-cysteine (NAC), sodium deoxyglycocholate (SDGC), and ethanol were used as chemical enhancers; and 0.5 mA/cm(2) fixed electric current was employed as a physical enhancer. sCT hydrogel was applied to rabbit buccal mucosa, and blood samples were obtained via the central auricular artery. Blood calcium level was measured by calcium kit and the conformational changes of buccal mucosa were investigated with FT-IR spectroscopy. Hematoxylin/eosin staining was used for the histological evaluation of buccal mucosa. RESULTS: Iontophoresis groups except iontophoresis-NAC group showed significant hypocalcemic effect compared to negative control, in particular iontophoresis-SDGC combination group showed fast onset of action as well as sustained hypocalcemic effect (p < 0.05). FT-IR result demonstrated the reduction of buccal barrier function, and the histological study showed a decrease in buccal thickness as well as minor damage to the dermal-epidermal junctions in the enhancing method groups; however, the damaged tissues virtually recovered within 24 h after the removal of electrodes. CONCLUSIONS: Iontophoresis and combination with SDGC were found to be safe and potential strategies for transbuccal peptide delivery in vivo.

A two-dimensional laser scanning mirror using motion-decoupling electromagnetic actuators.

This work proposes a two-dimensional (2-D) laser scanning mirror with a novel actuating structure composed of one magnet and two coils. The mirror-actuating device generates decoupled scanning motions about two orthogonal axes by combining two electromagnetic actuators of the conventional moving-coil and the moving-magnet types. We implement a finite element analysis to calculate magnetic flux in the electromagnetic system and experiments using a prototype with the overall size of 22 mm (W) × 20 mm (D) × 15 mm (H) for the mirror size of 8 mm × 8 mm. The upper moving-coil type actuator to rotate only the mirror part has the optical reflection angle of 15.7° at 10 Hz, 90° at the resonance frequency of 60 Hz at ±3 V (±70 mA) and the bandwidth of 91 Hz. The lower moving-magnet type actuator has the optical reflection angle of 16.20° at 10 Hz and 50° at the resonance frequency of 60 Hz at ±5 V (±34 mA) and the bandwidth of 88 Hz. The proposed compact and simple 2-D scanning mirror has advantages of large 2-D angular deflections, wide frequency bandwidth and low manufacturing cost.

Enhanced percutaneous delivery of recombinant human epidermal growth factor employing nano-liposome system.

We encapsulated recombinant human epidermal growth factor (rhEGF) into nano-liposomes (NLs) system for topical delivery. The rhEGF-loaded NLs were prepared using a high pressure homogenization method. Morphology and overall particle distribution of NLs were investigated using transmission electron microscopy (TEM) and high resolution microscope (CytoViva™). Particle size, zeta (ζ) potential and encapsulation efficiency were measured and the percutaneous delivery of NLs was evaluated using Franz diffusion cells and immunofluorescence confocal laser scanning microscopy (CLSM). The mean particle size, zeta potential and encapsulation efficiency of the NLs were 155.57 ± 2.59 nm, -57.92 ± 4.35 mV and 9.00 ± 0.39%, respectively. TEM and microscopic analysis showed spherical, very even-sized vesicles approximately 150 nm. The skin permeation and localization of rhEGF were enhanced by NLs. CLSM image analysis provided that the NLs enhanced the permeation and localization of rhEGF in rat skin by facilitating entry through pores of skin.

Enhanced transbuccal salmon calcitonin (sCT) delivery: effect of chemical enhancers and electrical assistance on in vitro sCT buccal permeation.

This study investigates the combined effect of absorption enhancers and electrical assistance on transbuccal salmon calcitonin (sCT) delivery, using fresh swine buccal tissue. We placed 200 IU (40 µg/mL) of each sCT formulation--containing various concentrations of ethanol, N-acetyl-L-cysteine (NAC), and sodium deoxyglycocholate (SDGC)--onto the donor part of a Franz diffusion cell. Then, 0.5 mA/cm(2) of fixed anodal current was applied alone or combined with chemical enhancers. The amount of permeated sCT was analyzed using an ELISA kit, and biophysical changes of the buccal mucosa were investigated using FT-IR spectroscopy, and hematoxylin-eosin staining methods were used to evaluate histological alteration of the buccal tissues. The flux (J(s)) of sCT increased with the addition of absorption enhancer groups, but it was significantly enhanced by the application of anodal iontophoresis (ITP). FT-IR study revealed that all groups caused an increase in lipid fluidity but only the groups containing SDGC showed statistically significant difference. Although the histological data of SDGC groups showed a possibility for tissue damage, the present enhancing methods appear to be safe. In conclusion, the combination of absorption enhancers and electrical assistance is a potential strategy for the enhancement of transbuccal sCT delivery.

Characteristic electron microscopic findings in the skin of patients with fibromyalgia--preliminary study.

This blinded study was done to determine if there are any abnormal electron microscopic (EM) findings in the skin of fibromyalgia syndrome (FMS) patients, which might contribute to or be due to the increased pain sensitivity seen in this condition. Skin biopsy samples were obtained from 13FMS patients and 5 control subjects. All tissues were prepared for EM examination by immediate prefixation in 2.5% glutaraldehyde for 2 h and postfixation in 1% osmium acid for 24 h. Ultrathin sections on grids were stained by uranylacetate and lead citrate. Biopsies were read by an individual without knowledge of participant status. Five skin biopsies from healthy controls showed relatively even distribution of variegated sized unmyelinated axons sheathed well by complicatedly folded Schwann cell membranes. In tissues from 9/13 FMS patients, unmyelinated Schwann cells were noted to be ballooned, whereas this finding was not noted in any controls (p=0.029). Axons in most patients trended towards being localized in the periphery of the unmyelinated Schwann cell sheaths (p=0.002). Particularly, peripheral localization of axon in the unmyelinated Schwann cell sheath had a strong relationship with ballooning of Schwann cell (p=0.042), simplified folding of Schwann cell sheath (p=0.039) and smaller axon (p=0.034). Myelinated nerve fibers were unremarkable. The EM findings seen in the skin of FMS patients show unusual patterns of unmyelinated nerve fibers as well as associated Schwann cells. If these findings are replicated in a larger study, these abnormalities may contribute to, or be due to, the lower pain threshold seen in FMS patients.

Characteristic electron microscopic findings in the skin of patients with fibromyalgia: preliminary study.

This blinded study was done to determine if there are any abnormal electron microscopic (EM) findings in the skin of fibromyalgia syndrome (FMS) patients, which might contribute to or be due to the increased pain sensitivity seen in this condition. Skin biopsy samples were obtained from 13 FMS patients and 5 control subjects. All tissues were prepared for EM examination by immediate prefixation in 2.5% glutaraldehyde for 2 h and postfixation in 1% osmium acid for 24 h. Ultrathin sections on grids were stained by uranyl acetate and lead citrate. Biopsies were read by an individual without knowledge of participant status. Five skin biopsies from healthy controls showed relatively even distribution of variegated sized unmyelinated axons sheathed well by complicatedly folded Schwann cell membranes. In tissues from 9/13 FMS patients, unmyelinated Schwann cells were noted to be ballooned, whereas this finding was not noted in any controls (p = 0.029). Axons in most patients trended towards being localized in the periphery of the unmyelinated Schwann cell sheaths (p = 0.002). Particularly, peripheral localization of axon in the unmyelinated Schwann cell sheath had a strong relationship with ballooning of Schwann cell (p = 0.042), simplified folding of Schwann cell sheath (p = 0.039) and smaller axon (p = 0.034). Myelinated nerve fibers were unremarkable. The EM findings seen in the skin of FMS patients show unusual patterns of unmyelinated nerve fibers as well as associated Schwann cells. If these findings are replicated in a larger study, these abnormalities may contribute to, or be due to, the lower pain threshold seen in FMS patients.