Novel carriers ensuring enhanced anti-cancer activity of Cornus mas (cornelian cherry) bioactive compounds.

Cornusmas' bioactive compounds are powerful antioxidants. In this study, we evaluated the antioxidant activity of the encapsulated bioactive compounds of Cornus mas extract (CME) and its release in semi digestive condition via enteric coated nanocarriers (NCs). The two forms of CME, encapsulated into enteric coated nanocarriers (CME-NCs) and free CME, were studied to determine the effect of encapsulation on the stability of antioxidants. Then, their effect on cell cycle, cell viability and apoptosis of cancer cells were studied. The characterization analysis reported the mean particle size and zeta potential value of NCs equal to 22.7 ± 6.58 nm and -16 ± 5 mV. The results showed that CME-NCs could improve IC50 value 1.33 and 1.47 times more than the free CME after 24 and 48 h of incubation. These findings confirmed that CME-NCs could stop the cells proliferation in G1 phase, and caused apoptosis in cancer cell line HT-29.

Raft-forming gastro-retentive formulations based on Centella asiatica extract-solid dispersions for gastric ulcer treatment.

Liquid raft-forming formulations comprising solid dispersions of glycoside-rich Centella asiatica extract and Eudragit® EPO (GR-SD) were developed to achieve prolonged delivery of the glycosides, asiaticoside (AS) and madecassoside (MS) in the stomach and thus increase the effectiveness of gastric ulcer treatment. Solid dispersions of GR extract and Eudragit® EPO (GR-SD, weight ratio 1:0.5) resulted in the highest solubility of AS (41.7 mg/mL) and MS (29.3 mg/mL) and completed dissolution of both glycosides occurred in SGF within 10 min. The optimized raft-forming formulation was composed of alginate (2%), HPMC K-100 (0.5%), GR-SD (1.2%), and calcium carbonate (0.5%) as a calcium source and carbon dioxide producer. The formulation provided sufficient raft strength (> 7.0 g), rapid floating behavior in SGF (~30 s), and sustained release of AS (more than 80%) and MS (85%) over 8 h. GR-SD-based formulations administered once daily to rats for two days at a dose of 10 mg AS/kg reduced the severity of gastric ulcer induced by indomethacin with a greater curative efficacy than those of unformulated GR extract and a standard antiulcer agent: lansoprazole (p < 0.05). These findings demonstrate that GR-SD-based raft-forming systems offer significant promise for improving the treatment of gastric ulcers induced by non-steroidal anti-inflammatory drugs.

Silymarin-Loaded Eudragit Nanoparticles: Formulation, Characterization, and Hepatoprotective and Toxicity Evaluation.

The objectives of this study were to formulate, characterize silymarin-loaded Eudragit nanoparticles (SNPs) and evaluate their hepatoprotective and cytotoxic effects after oral administration. SNPs were prepared by nanoprecipitation technique and were evaluated for particle size, entrapment efficiency, TEM, solid-state characterization, and in vitro drug release. The hepatoprotective activity was evaluated after oral administration of selected SNPs in carbon tetrachloride-intoxicated rats. Potential in vivo acute cytotoxicity study was also assessed. The selected SNPs contained 50 mg silymarin and 50 mg Eudragit polymers (1:1 w/w Eudragit RS 100 & Eudragit LS 100). Morphology of the selected SNPs (particle size of 84.70 nm and entrapment efficiency of 83.45% with 100% drug release after 12 h) revealed spherical and uniformly distributed nanoparticles. DSC and FT-IR studies suggested the presence of silymarin in an amorphous state and absence of chemical interaction. The hepatoprotective evaluation of the selected SNPs in CCl4-intoxicated rats revealed significant improvement in the activities of different biochemical parameters (P ≤ 0.01) compared to the marketed product. The histopathological studies suggested that the selected SNPs produced better hepatoprotective effect in CCl4-intoxicated rats compared with the commercially marketed product. Toxicity study revealed no evident toxic effect for blank or silymarin-loaded nanoparticles at the dose level of 50 mg/kg body weight. The obtained results suggested that the selected SNPs were safe and potentially offered enhancement in the pharmacological hepatoprotective properties of silymarin.

Prilling for the development of multi-particulate colon drug delivery systems: pectin vs. pectin-alginate beads.

This paper proposes a multi-particulate drug delivery system produced by prilling technique in combination with an enteric coating. Optimization of process parameters, such as feed viscosity at nozzle, selection of cross-linker, pH of the gelling solution and cross-linking time, allows to obtain beads with strong gelled matrix. Results showed that dextran/piroxicam beads demonstrated high encapsulation efficiency, very narrow dimensional distribution and high sphericity. Coated beads retained shape and narrow size distribution of the uncoated particles. Moreover, the strength of the produced Zn(2+)-pectinate beads allows to reduce Eudragit coating thickness. Piroxicam loaded multi-particulate systems show an interesting prolonged drug release in intestinal fluids. Hence, such platforms could be proposed for the treatment of inflammatory bowel diseases.

Eudragit® S100 coated calcium pectinate microspheres of curcumin for colon targeting.

Currently, colon-specific drug delivery systems have been investigated for drugs that can exert their bioactivities in the colon. In this study, Eudragit® S100 coated calcium pectinate microsphere, a pH-dependent and enzyme-dependent system, as colon-specific delivery carrier for curcumin was investigated. Curcumin-loaded calcium pectinate microspheres were prepared by emulsification-linkage method, and the preparation technology was optimised by uniform experimental design. The morphology of microspheres was observed under scanning electron microscopy. Interactions between drug and polymers were investigated with differential scanning calorimetry (DSC) and X-ray diffraction. In vitro drug release studies were performed in simulated colonic fluid in the presence of Pectinex Ultra SP-L or 1% (w/v) rat caecal content, and the results indicated that the release of curcumin was significantly increased in the presence of 1% (w/v) rat caecal contents. It could be concluded that Eudragit® S100 coated calcium pectinate microsphere was a potential carrier for colon delivery of curcumin.

Design and in vitro performance evaluation of purified microparticles of pravastatin sodium for intestinal delivery.

The purpose of research was to develop a mucoadhesive multiparticulate sustained drug delivery system of pravastatin sodium, a highly water-soluble and poorly bioavailable drug, unstable at gastric pH. Mucoadhesive microparticles were formulated using eudragit S100 and ethyl cellulose as mucoadhesive polymers. End-step modification of w/o/o double emulsion solvent diffusion method was attempted to improve the purity of the product, that can affect the dose calculations of sustained release formulations and hence bioavailability. Microparticles formed were discrete, free flowing, and exhibited good mucoadhesive properties. DSC and DRS showed stable character of drug in microparticles and absence of drug polymer interaction. The drug to polymer ratio and surfactant concentration had significant effect on mean particle size, drug release, and entrapment efficiency. Microparticles made with drug: eudragit S100 ratio of 1:3 (F6) exhibited maximum entrapment efficiency of 72.7% and ex vivo mucoadhesion time of 4.15 h. In vitro permeation studies on goat intestinal mucosa demonstrated a flux rate (1,243 µg/cm(2)/h) that was 169 times higher than the flux of pure drug. The gastric instability problem was overcome by formulating the optimized microparticles as enteric-coated capsules that provided a sustained delivery of the highly water-soluble drug for 12 h beyond the gastric region. The release mechanism was identified as fickian diffusion (n = 0.4137) for the optimized formulation F6. Conclusively, a drug delivery system was successfully developed that showed delayed and sustained release up to 12 h and could be potentially useful to overcome poor bioavailability problems associated with pravastatin sodium.

pH-enzyme di-dependent chronotherapeutic drug delivery system of theophylline for nocturnal asthma.

The purpose of this research work was to develop and evaluate a chronotherapeutic based colon-targeted drug delivery system of theophylline (THEO) exploiting pH-enzyme sensitive property for the prevention of episodic attack of asthma in early morning. Guar gum microspheres of theophylline were prepared by emulsification technique. Coating of microspheres was performed using solvent evaporation method with pH sensitive Eudragit(®) polymers. The particle size and surface morphology, entrapment efficiency and degree of swelling of microspheres were examined. The in vitro drug release studies were performed in pH progression medium and also in the presence of 2% rat caecal content. Theophylline was efficiently microencapsulated in guar gum microspheres at different polymer concentrations (1-4%). Fourier transform infrared (FT-IR)-spectroscopy confirmed the intermolecular interactions between guar gum and glutaraldehyde. Coating of guar gum microspheres by Eudragit led to decelerate the in vitro drug release of THEO. Moreover in vitro drug release studies also performed with 2% rat caecal content showed marked increment in drug release. The controlled release of THEO after a lag time was achieved with developed formulation for chronotherapeutic delivery. The pH dependent solubility behavior of Eudragit and gelling properties of guar gum are found to be responsible for delaying the release.

Agglomerates containing pantoprazole microparticles: modulating the drug release.

Pantoprazole-loaded microparticles were prepared using a blend of Eudragit S100 and Methocel F4M. The accelerated stability was carried out during 6 months at 40 degrees C and 75% relative humidity. In order to improve technological characteristics of the pantoprazole-loaded microparticles, soft agglomerates were prepared viewing an oral delayed release and gastro-resistant solid dosage form. The agglomeration was performed by mixing the pantoprazole microparticles with spray-dried mannitol/lecithin powders. The effects of factors such as the amount of lecithin in the spray-dried mannitol/lecithin powders and the ratio between pantoprazole microparticles and spray-dried mannitol/lecithin powders were evaluated. The pantoprazole-loaded microparticles present no significant degradation in 6 months. The agglomerates presented spherical shape, with smooth surface and very small quantity of non-agglomerated particles. The agglomerates presented different yields (35.5-79.0%), drug loading (58-101%), and mechanical properties (tensile strength varied from 44 to 69 mN mm(-2)), when the spray-dried mannitol/lecithin powders with different lecithin amounts were used. The biopharmaceutical characteristics of pantoprazole microparticles, i.e., their delayed-release properties, were not affected by the agglomeration process. The gastro-resistance of the agglomerates was affected by the amount of spray-dried mannitol/lecithin powders. The ratio of lecithin in the spray-dried mannitol/lecithin powders was the key factor in the agglomerate formation and in the drug release profiles. The agglomerates presenting better mechanical and biopharmaceutical characteristics were prepared with 1:2 (w/w) ratio of pantoprazole-loaded microparticles and mannitol/lecithin (80:20) powder.

In vitro and in vivo evaluation of a novel capsule for colon-specific drug delivery.

The aim of this study was to estimate colon-specific drug delivery of a novel capsule (CS capsule). Theophylline was used as model drug and little was released from the CS capsules in the release medium mimicking physiological environment of stomach to small intestine. However, 66.7 +/- 8.8% theophylline was released from the capsules in the phosphate buffer (pH 6.8) mimicking the physiological environment of colon in the next 4 h, while the addition of galactomannanase (39.3 U/L) accelerated the disintegration of the CS capsule and enhanced the release rate to 92.6 +/- 6.0%. Rats in vivo pharmacokinetics demonstrated that the relative bioavailability of theophylline after intragastric administration of CS capsules was 76.72% with delayed T(max) of 8 h comparing to that of theophylline solution with T(max) of 1.5 h. Radiolabeled with technetium-99m, the CS capsule could keep intact from stomach to small intestine while disintegration of the CS capsule was observed in the proximal colon or the joint between the distal small intestine and right colon. A great quantity of radiolabeled marker was released as well as distributed in the whole colon at 10 h after administration. As a whole, the CS capsule prepared could provide an alternative carrier for the colon-specific drug delivery.

Physicochemical and biological evaluation of cationic polymethacrylates as vectors for gene delivery.

We report here the physicochemical and biological evaluation of a series of polymethacrylates with side groups of different pK(a) values, such as tertiary amines, pyridine groups, acid functions and imidazole groups as synthetic vectors for gene delivery. The ability of the different polymers to condense DNA was studied by ethidium bromide exclusion tests and agarose gel electrophoresis. The results show that all polymers are able to condense DNA. Both the molecular weight and the chemical composition of the polymers have an influence on the DNA condensation process. Furthermore, the biological properties of the polymer-DNA complexes were investigated, including their haemolytic activity, cytotoxicity and in vitro transfection efficiency. Complexes based on polymers containing only tertiary amines, have a transfection efficiency similar to that of poly(ethyleneimine) (PEI). Polymers containing pyridine groups have a reduced transfection efficiency compared to polymers containing tertiary amines. Introduction of imidazole groups or acid functions results in a loss of the transfection efficiency of the corresponding complexes with DNA. In general, the viability of cells incubated with complexes based on the polymethacrylates is higher than with PEI. Polymers with high transfection efficiency induce erythrocyte lysis.

Preclinical evaluation of the cardiotoxicity of PK2: a novel HPMA copolymer-doxorubicin-galactosamine conjugate antitumour agent.

PK2 is a polymeric anticancer conjugate composed of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone and pendant doxorubicin (DOX) linked via a Gly-Phe-Leu-Gly peptide spacer. Additionally galactose residues are present to facilitate liver targeting. To justify clinical evaluation of PK2 it was necessary to determine its late cardiotoxicity compared to that of free DOX. A well standardised Sprague-Dawley rat model was used with either intravenous (i.v.) administration (4, 8 and 12 mg/kg DOX equivalent) or intraperitoneal (i.p.) administration (12, 18, 24 and 36 mg/kg DOX equivalent) of PK2. This variation in the route was due to the limited solubility of PK2 at higher doses. PK2 showed two to three times less acute toxicity (assessed by the maximum reduction in body weight in the first 2 weeks) than free DOX, and both compounds were less toxic when given i.p.. No animals given PK2 i.v. showed clinical signs of cardiotoxicity, the only toxicity seen was abnormal tooth growth (approximately 50% of the animals receiving 12 mg/kg, DOX equivalent). In contrast, several animals receiving free DOX (1-4 mg/kg) i.v. died due to cardiotoxicity in an approximately dose-related manner. All animals receiving free DOX (4 mg/kg) died by 12 weeks. Following i.p. administration of PKZ there were only two late deaths related to cardiotoxicity and these were in the 24 mg/kg DOX equivalent group. All animals receiving PK2 at the highest dose (36 mg/kg DOX equivalent) died within 4 weeks, cardiotoxicity was not the main contributing factor. In this study, PK2 displayed a approximately 5-fold reduction in cardiotoxicity relative to free DOX and this supported the progression of PK2 into early clinical investigation.

The comparative effects on plaque regrowth of phenolic chlorhexidine and anti-adhesive mouthrinses.

The inhibition of bacterial attachment to the tooth surface is one possible approach to plaque control. This study evaluated in vivo the plaque inhibitory action of a novel copolymer reported to have considerable antiadhesive properties in vitro. The study was a single blind, 5-treatment, randomised Latin square crossover design, incorporating balance for carry-over effects. The rinses were the antiadhesive (1%), the antiadhesive with 0.02% chlorhexidine, a 0.2% chlorhexidine rinse product, an essential oil/phenolic rinse product and water. 15 volunteers participated and on day 1 of each study period were rendered plaque-free, ceased toothcleaning and rinsed 2 x daily, under supervision, with the allocated formulation. On day 5, plaque was scored by index and area. Washout periods were 2 1/2 days. Alone or combined with chlorhexidine, the antiadhesive agent showed no effects greater than water. The chlorhexidine rinse was significantly more effective than the essential oil/phenolic rinse which in turn was significantly more effective than the other rinses.

Drinking coffee and carbonated beverages blocks absorption of nicotine from nicotine polacrilex gum.

Patients failing to obtain benefit from nicotine polacrilex gum in their efforts to quit smoking may be inadvertently blocking nicotine absorption. Effective nicotine absorption depends on the mildly alkaline saliva that is produced when buffering agents in the polacrilex are released along with nicotine as the polacrilex is chewed. We found that intermittent mouth rinsing with coffee or cola, but not distilled water, substantially reduced salivary pH and nicotine absorption. Because many commonly consumed substances were also found to be highly acidic, we recommend that patients do not ingest any substance during or immediately before nicotine polacrilex use.