Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.

Involvement of Estrogen Receptor-α in the Activation of Nrf2-Antioxidative Signaling Pathways by Silibinin in Pancreatic β-Cells

Silibinin exhibits antidiabetic potential by preserving the mass and function of pancreatic β-cells through up-regulation of estrogen receptor-α (ERα) expression. However, the underlying protective mechanism of silibinin in pancreatic β-cells is still unclear. In the current study, we sought to determine whether ERα acts as the target of silibinin for the modulation of antioxidative response in pancreatic β-cells under high glucose and high fat conditions. Our in vivo study revealed that a 4-week oral administration of silibinin (100 mg/kg/day) decreased fasting blood glucose with a concurrent increase in levels of serum insulin in high-fat diet/streptozotocin-induced type 2 diabetic rats. Moreover, expression of ERα, NF-E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in pancreatic β-cells in pancreatic islets was increased by silibinin treatment. Accordingly, silibinin (10 μM) elevated viability, insulin biosynthesis, and insulin secretion of high glucose/palmitate-treated INS-1 cells accompanied by increased expression of ERα, Nrf2, and HO-1 as well as decreased reactive oxygen species production in vitro. Treatment using an ERα antagonist (MPP) in INS-1 cells or silencing ERα expression in INS-1 and NIT-1 cells with siRNA abolished the protective effects of silibinin. Our study suggests that silibinin activates the Nrf2-antioxidative pathways in pancreatic β-cells through regulation of ERα expression.

Cholesterol-tuned liposomal membrane rigidity directs tumor penetration and anti-tumor effect

Recently, liposomes have been widely used in cancer therapeutics, but their anti-tumor effects are suboptimal due to limited tumor penetration. To solve this problem, researchers have made significant efforts to optimize liposomal diameters and potentials, but little attention has been paid to liposomal membrane rigidity. Herein, we sought to demonstrate the effects of cholesterol-tuned liposomal membrane rigidity on tumor penetration and anti-tumor effects. In this study, liposomes composed of hydrogenated soybean phospholipids (HSPC), 1,2-distearoyl--glycero-3-phosphoethanolamine--[methoxy(polyethylene glycol)-2000] (DSPE-PEG) and different concentrations of cholesterol were prepared. It was revealed that liposomal membrane rigidity decreased with the addition of cholesterol. Moderate cholesterol content conferred excellent diffusivity to liposomes in simulated diffusion medium, while excessive cholesterol limited the diffusion process. We concluded that the differences of the diffusion rates likely stemmed from the alterations in liposomal membrane rigidity, with moderate rigidity leading to improved diffusion. Next, the tumor penetration and the anti-tumor effects were analyzed. The results showed that liposomes with moderate rigidity gained excellent tumor penetration and enhanced anti-tumor effects. These findings illustrate a feasible and effective way to improve tumor penetration and therapeutic efficacy of liposomes by changing the cholesterol content, and highlight the importance of liposomal membrane rigidity.

Preparation of Lyophilized Epirubicin Long Circulation Liposome Powder / 医药导报

Objective To improve the stability of epirubicin long circulation liposomes via lyophilizing technology and preliminarily evaluate their quality. Methods The effect of the various cryoprotectant,different pre-freezing and total drying time on the preparation was analyzed. The stability of the lyophilized powder was tested at (25±2) ℃ and (60±10)% relative humidity for 3 months. Results The protective agent trehalose to liposomes was 31. The freeze-drying was conducted with pre-freezing temperature at -70 ℃,precooling for 8 h and total drying for 24 h. There were no significant differences in particle size,encapsulation efficiency and drug content of lyophilized long-circulating liposomes compared with those un-lyophilized. After 3 months under the accelerated condition,it had good redispersibility, entrapment rate (>94%) and drug content (>99%) . Conclusion Lyophilizing the long-circulation epirubicin liposomes can effectively improve the stability of the preparation.

Effect of stretch on muscarinic receptor- and 5-hydroxytryptamine receptor-mediated contractile responses in isolated gastric smooth muscle of rats / 中国药理学与毒理学杂志

OBJECTlVE To investigate the effect of stretch on muscarinic receptor- and 5-hydroxytryptamine( 5-HT)receptor-mediated contractiIe responses in isoIated circuIar muscIe strips taken from the rat stomach. METHODS The contractiIe responses to carbachoI(CCh)0.001-30 μmoI·L-1 or 5-HT 0.0001 -30 μmoI·L-1 administered cumuIativeIy were recorded in isoIated circuIar muscIe strips taken from the gastric fundus,body,cardia and pyIorus of rats under different preIoads of 1.0,1.5,2.0, 2.5 and 3. 0 g,but a singIe concentration of CCh 0. 3 μmoI·L-1 was administered to the antrum. RESULTS The -Log EC50 vaIue for CCh in the isoIated circuIar muscIe strips of the gastric fundus, body and pyIorus under 1.0 g preIoad was the Iargest,but decreased significantIy with higher preIoads (P﹤0.05,P﹤0.01). A simiIar resuIt was obtained in the isoIated circuIar muscIe strips of the gastric body when 5-HT was used as an agonist. The Emax vaIue of contractiIe responses to CCh and 5-HT in the cir-cuIar muscIe strips of the gastric cardia under 3.0 g preIoad was increased by 117.4% and 75.7% com-pared to that under 1.0 g preIoad. The Emax vaIue of contractiIe responses to 5-HT in the circuIar muscIe strips of the gastric body under 3.0 g preIoad was aIso increased by 115.9% when compared to 1.0 g preIoad. The Emax( g) vaIue of contractiIe responses to CCh in four types of muscIe strips was 10.453±2.956(cardia under 3.0 g preIoad),13.878±2.618(fundus under 2.5 g preIoad),10.244±1.843 (gastric body under 2.5 g preIoad)and 2.585±1.098(pyIorus under 2.5 g preIoad),respectiveIy. The Emax(g)vaIue of contractiIe responses to 5-HT in three types of muscIe strips was 4.363±1.705(cardia under 3.0 g preIoad),3.931±0.615(fundus under 3.0 g preIoad)and 3.161±0.680(gastric body under 3.0 g preIoad),respectiveIy. CONCLUSlON 0.5 g or 1.0 g preIoad is inadequate for accurate determi-nation of contractiIe responses mediated by muscarinic receptors and 5-HT receptors in isoIated circuIar muscIe strips taken from the rat gastric cardia,fundus,body and pyIorus,but 2.0 g preIoad is optimaI for investigating muscarine receptor- or 5-HT receptor-mediated contractiIe responses of isoIated gastric strips of rats.

Anti-tumor activity of folate receptor targeting docetaxel-loaded membrane-modified liposomes / 药学学报

The anti-tumor activity of folate receptor targeting docetaxel-loaded membrane-modified liposomes (FA-PDCT-L) was investigated in vitro and in vivo. FA-PDCT-L was prepared by organic solvent injection method. Transmission electron microscope, dynamic light scattering and electrophoretic light scattering were employed to study the physicochemical parameters of FA-PDCT-L. The inhibitory effects of docetaxel injection (DCT-I), non-modified DCT liposomes (DCT-L) and FA-PDCT-L on the growth of MCF-7 and A-549 cells at different incubation times were detected by CCK-8 assay; and the hemolytic test was employed in vitro. Tumor mice were randomized into 4 groups: DCT-I, DCT-L, FA-PDCT-L and control group (normal saline), and given drugs at 10 mg x kg(-1) x d(-1) through tail vein. The tumor volume, mice weight, inhibition rate of tumor and life span were measured at the end of experiments. The IC50 of the FA-PDCT-L for MCF-7 and A549 cell lines were significantly lower than that of DCT-I and DCT-L, without hemolysis reaction observed. Compared with control group, the weights of tumor in DCT-I, DCT-L and FA-PDCT-L were decreased, especially for FA-PDCT-L, with inhibitory rates at 79.03 % (P < 0.05). The life span and median survival time of FA-PDCT-L treated mice were significantly higher than that of DCT-I and DCT-L. In conclusion, FA-PDCT-L shows a good anti-tumor activity, indicating that it is potential carriers for DCT in the treatment of tumor.

Preparation and characterization of oxaliplatin-loaded nanostructured lipid carriers / 药学学报

Oxaliplatin-loaded nanostuctured lipid carriers (OP-NLC) were prepared by ultrasonic emulsification method. And its optimal prescription was selected by orthogonal design. The laser light scattering technique, zeta potential analyzer, TEM, DSC, XRD and HPLC were employed to study the physicochemical parameters of OP-NLC, which displayed in terms of particle size, zeta potential, crystalline, drug loading and encapsulation efficiency. The results showed that OP-NLC had an average diameter of (111 +/- 20) nm, zeta potential of (-27.4 +/- 13.1) mV, encapsulation efficiency of (77.4 +/- 2.5) % and drug content of (0.8 +/- 1.5) mg mL(-1). TEM, DSC and XRD indicated that OP-NLC was spherical and the drug was dispersed as nanoparticles by means of non-crystalline. The in vitro release test showed that the drug could be sustained-released from NLC in buffer solution (pH 4.5) after a burst release in initial phase.

Study on Preparation and Pharmaceutical Character of Capreomycin Sulfate Liposomes by Three Kinds of Methods / 中国药房

OBJECTIVE:To prepare and characterize capreomycin sulfate liposomes(CSL).METHODS:Capreomycin sulfate was entrapped into liposomes using active loading that pH gradient methods,ammonium sulfate gradient methods and sodium acetate gradient methods respectively followed by lyophilization technique.The liposome was characterized by entrapment efficiency,particle size,? potential and the stability.RESULTS:The entrapment efficiency of CSL pre-and post-lyophilization prepared by three methods were 65.7% and 65.2 %,20.1% and 18.6%,34.6% and 32.4%,with particle size of 136 and 145 nm,144 and 153 nm,142 and 159 nm,? potential of —20.2 and —19.5 mV,—24.4 and —22.9 mV,—18.7 and —17.8 mV respectively.No obvious changes were found in all the indexes in the stability test.CONCLUSIONS:The pH gradient technique is suitable for preparing CSL in 3 kinds of methods.

Determination of Dolasetron Mesylate by HPLC / 中国药房

OBJECTIVE:To establish a HPLC method for the determination of dolastron mesylate.METHODS:The sample was separated on Diamonsil C18 column.The mobile phase consisted of acetonitrile-water-1mol? L-1 ammonium formate(450∶ 440∶ 110)(pH=8.0 adjusted with trithylamine)with a flow rate of 1.0mL? min-1.The UV detection wavelength was set at 285nm and the sample size was 20? L.RESULTS:The linear range of dolasetron mesylate was 24～ 56? g? min-1(r=0.999 6),with average recovery at 99.7%(RSD=0.74%).CONCLUSION:The established is simple,sensitive and reproducible,and suitable for the quality control of dolasetron mesylate.

Preparation and Physico-chemical Property of Coenzyme Q_(10) Submicroemulsion / 中国药房

OBJECTIVE:To prepare coenzyme Q10 submicroemulsion and investigate its stability and physico-chemical properties.METHODS:Orthogonal experiment was designed to optimize the formulation and preparation procedure of coenzyme Q10 submicroemulsion.The content and entrapment efficiency of the preparation were determined by HPLC,and its properties such as particle size,? potential,pH value and stability were studied.RESULTS:The optimal formulation and preparation procedure of coenzyme Q10 submicroemulsion were as follows:the ratio of soybean oil to medium-chain triglyceride was 1∶2;the ratio of soybean phospholipids to poloxamer 188 was 3∶1;the high speed shearing emulsification time was 10min and the preparation temperature was 60℃.The mean entrapment efficiency of 3 batches of coenzyme Q10 submicroemulsions was 98.07%,with a ? potential of —28.4mV and a mean particle size of 168 nm.Illumination and freeze thawing should be avoided for the preparation in storing,which showed a satisfactory stability at 4℃.CONCLUSION:The prepared coenzyme Q10 submicroemulsion was up to the standards of intravenous injection preparations.

Preparation of Levofloxacin Thermosensitive Ocular Gel and Study on Drug Release in Vitro / 中国药房

OBJECTIVE:To prepare the levofloxacin(LEF)thermosensitive gel for ophthalmic drug delivery,and to study the drug release in vitro.METHODS:Poloxamer407was used as themosensitive material for the LEF eye drop,the best con?centration of poloxamer in prescription was selected according to the temperature of gel,a novel membraneless model was used to study the drug release.RESUTS:The detected concentration of LEF was in the linear range of3～11?g/ml(r=0.9991,n=6),the recovery was99.62%;The best concentration of poloxamer in prescription was18%;Drug release followed zero-order kinetics,and the quantity of drug release was controlled by that of gel dissolution.CONCLUSION:The preparation is simple in method and easy to control in dosage,therefore it shows a promising future in development.

Content Determination of Pamidronate Disodium by RP-HPLC / 中国药房

OBJECTIVE: To establish a RP-HPLC method for the determination of pamidronate disodium. METHODS: The determination was performed on C18 column with acetonitrile-0.4% sodium hydroxide solution of EDTA-Na2 (14∶86) as mobile phase at a flow rate of 0.6mL?min-1,the sample size was 10?L and the detection was performed by fluorescence detector with excitation wavelength at 395nm and emission wavelength at 480nm. RESULTS: The linear range of pamidronate disodium was 7.2～16.8?g?mL-1(r=0.999 8,n=9),the recovery rate was 100.11%(RSD=0.7%, n=9). CONCLUSIONS: The established method is simple and accurate.