Preparation of Ethanol Extract of Propolis Loaded Niosome Formulation and Evaluation of Effects on Different Cancer Cell Lines.

Propolis is a candidate for cancer treatment with its activity against different tumor cells and, has a wide spectrum of biological and pharmacological activities due to the diversity of its components. In this study, antitumorigenic activities of ethanol extract of propolis (EEP) and ethanol extract of propolis loaded niosome (PLN) were compared using 2D and 3D cell culture. Niosome formulations were prepared by thin film hydration technique. Cell viability of EEP and PLN was analyzed on MCF7, A549, MDA-MB-231, SK-MEL, SK-BR-3, DU145 and L-929 cell lines using MTT assay. L929, MCF7 and A549 cells were cultured using the 3D petri dish technique and their spherical forms were obtained after 142 h. After 24 h, PLN and EEP application, cell viability analysis was performed on 3D cultures with WST assay. As a result, niosome formulations containing EEP showed higher activity than ethanol extract of propolis in cancer cells. While a slow decrease was observed in cell viability in EEP treated cancer cells, it was observed that the percentage viability rates decreased in a shorter time in PLN treated cancer cells. Also, PLN can be used as an anticancer activity drug such as Doxorubicin, but this is not the case for EEP.

Design and development of a self-microemulsifying drug delivery system of olmesartan medoxomil for enhanced bioavailability.

Olmesartan medoxomil (OM) is a hydrophobic antihypertensive drug with low bioavailability (26%) and is known to have adverse effects such as celiac disease and enteropathy. The purpose of this study was to develop SMEDDS to increase bioavailability and decrease potential side effects of OM. Hydrophilic lipophilic balance was calculated by testing solubility of OM in different oils, surfactants, and cosurfactants to obtain the most suitable combination of SMEDDS. Pseudoternary phase diagram was used to select the better oil/water formulation of SMEDDS. After a test for 3-month stability, dissolution tests and parallel artificial membrane permeability assay (PAMPA) were conducted to investigate drug solubility and permeability. Biodistribution of fluorescent marked SMEDDS was observed by using in vivo imaging system. The pharmacodynamics of the drug were determined by measuring blood pressure from tails of rats. At the end of the experiment, intestines were examined for adverse effects of OM. Compared with tablet formulation according to the dissolution study, SMEDDS formulation showed 1.67 times improvement in solubility of OM. PAMPA studies suggested a much faster permeability rate for OM SMEDDS compared to the suspension form. Labeled SMEDDS gave 3.96 times stronger fluorescent emission than control dye administered mice in in vivo imaging system (IVIS®) studies, indicating an increased bioavailability. Treating effect of SMEDDS was 3.1 times more efficient compared to suspension in hypertensive rats. It caused neither celiac-like enteropathy nor diarrhea, during 21-day noninvasive blood pressure system (NIBP) assay. Our results suggest that SMEEDS formulation improves dissolution and oral bioavailability of OM while reducing its adverse effects.

Novel application of Eudragit RL and cholesteryl oleyl carbonate to thermo-sensitive drug delivery system.

The Eudragit RL 100 and propylene glycol (PG) membranes with and without cholesteryl oleyl carbonate (COC) were prepared by the solvent casting method to pioneer a novel application of a thermo-sensitive drug delivery system. After that, the properties of these membranes were investigated by thermal, scanning, and porosity studies. Drug permeation studies through all membranes were carried out using salbuthamol sulphate (SBS) at constant temperatures (25°C and 37°C), respectively. The permeability of SBS through the membranes with COC has been shown to be a discontinuous function of temperature, that is, their permeability increased steeply above the phase transition temperature (37°C) of the COC. The thermo-sensitive permeation mechanism for the membranes might be based on the structure change of the membranes caused by the phase transition, so that the membranes could absorb more water. Considering the high biological safety of Eudragit RL 100 and PG membranes with and without COC might be used to develop a novel thermo-sensitive drug delivery system.

Novel microparticle drug delivery systems based on chitosan and Eudragit® RSPM to enhance diltiazem hydrochloride release property.

The aim of this study was to enhance the release properties of diltiazem hydrochloride (diltiazem HCl) by using microparticle system. For this reason, microparticle drug delivery systems based on chitosan and Eudragit(®)RSPM were developed. The microparticles were prepared by using double-emulsion solvent extraction method and the mean sizes of microparticles were less than 120 µm. The in vitro drug release from microparticles was studied in simulated gastric (pH 1.2) and intestinal media (pH 7.4) than the results were evaluated by kinetically. In vitro diltiazem HCl release from microparticles showed good zero order kinetic. For the microparticles with chitosan, the release of diltiazem HCl at pH 1.2 could be effectively sustained, while the release of diltiazem HCl increased at pH 7.4 when compared to Eudragit(®)RSPM microparticles. The highest release percent obtained was 1:1 ratio of drug: polymer at pH 1.2 and 7.4. All results clearly suggest that the release properties of diltiazem HCl were improved by using microparticle systems especially which contain chitosan.

Clinical findings and gingival crevicular fluid prostaglandin E2 and interleukin-1-beta levels following initial periodontal treatment and short-term meloxicam administration.

OBJECTIVE: To evaluate the effects of adjunctive meloxicam administration on clinical periodontal measurements and gingival crevicular fluid (GCF) prostaglandin E(2) (PGE(2)) and interleukin-1-beta (IL-1beta) levels in chronic periodontitis. METHODS: Forty chronic periodontitis patients were randomized to receive either meloxicam 7.5 mg or placebo tablets for 10 days with scaling and root planing (SRP). GCF levels of PGE(2) and IL-1beta at baseline, day 10 of drug intake and 4 weeks after SRP were determined by enzyme-linked immunosorbent assay. Demographic, clinical periodontal data were analyzed using a repeated measures ANOVA and Bonferroni analysis. GCF PGE(2) and IL-1beta levels were compared between different evaluation times using the Friedman test. The Mann-Whitney test was used to compare biochemical data between the study groups. Pearson correlation analysis was used to relate clinical and biochemical data. RESULTS: Study groups showed significant reductions in all clinical periodontal measurements and GCF volume (p < 0.05). In both groups, IL-1beta was reduced significantly on day 10 and at week 4 compared with baseline (p < 0.01) without significant changes in PGE(2) levels (p > 0.05). No significant differences were found between study groups in GCF IL-1beta or PGE(2) levels (p > 0.05). CONCLUSION: Adjunctive meloxicam does not seem to provide additional improvement in clinical parameters or GCF PGE(2) and IL-1beta levels. Larger-scale studies may better clarify potential usage of anti-inflammatory agents in periodontal therapy.

The effect of bee propolis on oral pathogens and human gingival fibroblasts.

Propolis is one of the few natural remedies that have maintained its popularity over a long period of time. The aim of this study is to investigate the antimicrobial properties of six propolis solutions and evaluate their cytotoxicity on gingival fibroblasts at different dilutions. Two different solutions of powder propolis (Sigma) and Turkish propolis were prepared and propylene glycol (PG) and alcohol were used as solvents for each propolis sample. In addition to the four propolis solutions, two other propolis samples of far geographic regions (USA and Australia) were included in the study. The antibacterial effects of six solutions on oral pathogen microorganisms were tested and their cytotoxic effects on human gingival fibroblasts were evaluated by MTT assay. The effective dilutions of the six propolis samples on periodontopathogen microorganisms were found to be cytotoxic to gingival fibroblasts. All solutions had strong antifungal activity and the effective dilutions were safe for gingival fibroblasts. Propolis could have a promising role in the future medicine, if appropriate solutions can be prepared being strongly antibacterial and non-cytotoxic as well.

In vitro studies of a degradable device for controlled-release of meloxicam.

BACKGROUND: Plaque biofilm and associated host responses are the primary factors in the pathogenesis of periodontitis. Delivery of medications directly into the periodontal pockets to suppress or eradicate the pathogenic microbiota or modulate the inflammatory response has attracted significant interest to limit periodontal tissue destruction. The aim of the present study was twofold: (1) to describe the development of a biodegradable controlled-release device containing meloxicam as the therapeutic agent and (2) to evaluate the in vitro release of meloxicam from this device into different release media. METHODS: Films of cross-linked gelatin matrix containing meloxicam were prepared, hardened for various time periods and cut in a form to fit to the periodontal pocket anatomy. The release of active agents was studied separately in 10 ml distilled water, artificial saliva and pH 7.4 phosphate buffer at 37 degrees C. Apparatus Vibrax was used at 120 r.p.m. Determinations were carried out spectrophotometrically, and the release profiles were plotted as a function of time. The results were evaluated by the similarity test. RESULTS: The release rates of meloxicam from the hardened (1 h, 4 h, 8 h) formulations were slower than the unhardened formulation in all the three release media. Increasing the hardening time decreased the release rates. The overall release rates were similar in artificial saliva and pH 7.4 phosphate buffer, while it was lower in distilled water. CONCLUSIONS: As a conclusion, cross-linked gelatin matrix films may be considered as a suitable inert material for obtaining a prolonged local release of meloxicam as an adjunct to the mechanical periodontal treatment. As required, further in vitro and in vivo studies will be performed before starting clinical applications of this controlled-release formulation of the anti-inflammatory agent.

In vitro studies on controlled-release cellulose acetate films for local delivery of chlorhexidine, indomethacin, and meloxicam.

BACKGROUND: Delivery of medications into periodontal pockets to suppress or eradicate the pathogenic microbiota or modulate the inflammatory response, thereby limiting periodontal tissue destruction, has attracted significant interest with the purpose of effective periodontal treatment. However, no study has previously attempted to develop a controlled-release formulation of anti-inflammatory agents to be used in the field of periodontology. The aim of the present study was to examine the in vitro release profile of chlorhexidine gluconate, indomethacin, and meloxicam from cellulose acetate films. METHODS: Cellulose acetate films containing chlorhexidine gluconate, indomethacin, and meloxicam were prepared and cut in a form to fit to the periodontal pocket anatomy. The release of active agents was studied in 10 ml artificial saliva at 37 degrees C. Apparatus Vibrax was used at 150 r.p.m. Determinations were carried out spectrophotometrically and the release profiles were plotted as a function of time. RESULTS: The formulations showed two different release patterns for a total observation period of approximately 120 h. When the formulations of the three active agents were compared, the release patterns of meloxicam and chlorhexidine gluconate were found to be similar, while the indomethacin-containing formulation exhibited the fastest release rate. CONCLUSIONS: As a conclusion, cellulose acetate may be a suitable inert material for obtaining a prolonged local release of various anti-inflammatory agents like meloxicam. Further in vitro and in vivo studies are required before starting clinical applications of these controlled-release formulations of anti-inflammatory agents.

The effect of adjunctive low-dose doxycycline therapy on clinical parameters and gingival crevicular fluid matrix metalloproteinase-8 levels in chronic periodontitis.

BACKGROUND: Low-dose doxycycline (LDD) is recognized to have non-antimicrobial properties that can therapeutically modulate the host response. The aim of the present randomized, double-blind, placebo-controlled, parallel-arm study was to examine the effectiveness of LDD in combination with non-surgical periodontal therapy, compared to non-surgical periodontal therapy alone, on gingival crevicular fluid (GCF) matrix metalloproteinase-8 (MMP-8) levels and clinical parameters over a 12-month period in patients with chronic periodontitis. METHODS: GCF samples were collected, and clinical parameters including probing depth (PD), clinical attachment level, gingival index (GI), and plaque index were recorded. Thirty chronic periodontitis patients were randomized either to a low-dose doxycycline (LDD) or placebo group. The LDD group received low-dose doxycycline (20 mg) b.i.d. for 3 months plus scaling and root planing (SRP), while the placebo group was given placebo capsules b.i.d. for 3 months plus SRP. The patients were evaluated every 3 months during the 12-month study period. At each visit, all clinical measurements and GCF sampling were repeated. GCF MMP-8 levels were determined by a time-resolved immunofluorescence assay. Intragroup comparisons were tested by the Friedman test followed by Wilcoxon signed-rank test to analyze significance of changes over time. The Mann-Whitney test was used to determine differences between the LDD and placebo groups. RESULTS: Significant improvements were observed in all clinical parameters in both groups over the 12-month period (P < 0.0125). The LDD group showed a significantly greater reduction in mean PD scores at 9 and 12 months and in mean GI scores at all time points than the placebo group (P < 0.05). From baseline to 12 months, GCF MMP-8 levels were significantly reduced in both groups (P < 0.0125). The GCF MMP-8 level in the LDD group was significantly lower than that of the placebo group at 6 months (P < 0.05). CONCLUSIONS: The present results indicate that low-dose doxycycline therapy in combination with scaling and root planing can reduce GCF MMP-8 levels and improve clinical periodontal parameters in patients with chronic periodontitis. These results provide additional information about the usefulness of low-dose doxycycline therapy as an adjunct to non-surgical periodontal therapy in the long-term management of periodontal disease. The effectiveness and course of low-dose doxycycline therapy can be monitored conveniently by assessing GCF MMP-8 levels.

Extended release lipophilic indomethacin microspheres: formulation factors and mathematical equations fitted drug release rates.

Extended release liphophilic microspheres of indomethacin were prepared using cetostearyl alcohol (CsA), stearyl alcohol (SA) and cetyl alcohol (CA) in the various drug-lipid ratios. The release of indometacin was studied on the basis of USP criteria and the effects of drug-lipid ratio, the size of microspheres and carboxymethylcellulose sodium (CMC-Na) added as a hydrophilic polymer on the drug release were investigated. In vitro dissolution studies were performed using USP XXIII apparatus I at pH 6.2. Release profiles were evaluated according to first order, Higuchi square root of time and Hixson-Crowell cube root models. The best fit was found with the square root of time model (r2=0.991) for the microspheres (125-250 microm) prepared in 1:4:1 drug-lipid-copolymer ratio using stearyl alcohol. With a further regression analysis, an excellent equation (Release%=-10.721+42.549*square root of (t)-4.027*t) was developed for empirical drug estimation (r2=0.998).