Eutexia for enhanced dissolution rate and anti-inflammatory activity of nonsteroidal anti-inflammatory agents: Caffeine as a melting point modulator.

Fast dissolution of nonsteroidal anti-inflammatory drugs (NSAIDs) is a prerequisite from patient perspective. However, most NSAIDs are slowly dissolving acidic compounds. Caffeine, a commonly used analgesic adjuvant with NSAIDs showed high potential as eutectic co-former for acidic compounds. The study investigated eutectic forming potential of caffeine with meloxicam, aceclofenac and flurbiprofen. Each drug was co-ground with caffeine in various ratios and the products were characterized by thermal analysis to determine the optimum eutectic composition from phase diagram and Tamman's triangle. The optimum systems were subjected to X-ray powder diffraction (XRPD), Fourier-transform infrared (FTIR) and dissolution studies. Co-ground systems at dose ratio were also assessed for drug dissolution and anti-inflammatory effect using carrageenan induced rat paw edema method. Eutexia was confirmed by thermal analysis with the optimum composition being 1:1, 1:1 and 1:2 (NSAID: caffeine) for aceclofenac, flurbiprofen and meloxicam, respectively. Eutexia did not alter FTIR spectra with minor changes being recorded in XRPD patterns. The eutectic systems underwent fast liberation of drugs with fast dissolution being retained even at dose ratios. Dissolution enhancement was associated with enhanced anti-inflammatory response. The study introduced caffeine as eutectic forming analgesic for fixed dose combination with NSAIDs to enhance drug dissolution and anti-inflammatory effect.

Clove oil based co-surfactant free microemulsion of flurbiprofen: Improved solubility with ameliorated drug-induced gastritis.

Flurbiprofen, an NSAID, is a water insoluble drug that is also notorious for gastric irritation and inflammation. This study was aimed at using a natural gastrprotective oil as the internal phase to develop flurbiprofen micro emulsion (ME) to improve it solubility and ameliorate its gastric side effects. Upon screening of ME components for drug solubility, clove oil, tween 80 and transcutol were identified as the oil, surfactant and co surfactant, respectively, with higher flurbiprofen solubility. Pseudo-ternary phase diagrams revealed that the ME made with surfactant only and without co-surfactant displayed the similar ME region as made with the mixture of surfactant and co-surfactant. Furthermore, drug loaded oil was also used to draw pseudo-ternary phase diagram and a very little decrease in the ME region was observed. Therefore, co-surfactant free flurbiprofen loaded ME was developed to avoid side effects associated with the use of excessive surfactant quantities. ME were found to possess size in the range of 11-41 nm with PDI <0.5 and a slightly negative charge. Conductivity, pH and refractive indices of the selected MEs were well in the range. Drug release studies indicated maximum drug release from MEs within 5 min. Analysis of the gastric mucosa of rats after oral administration of drug solution and drug loaded ME confirmed that clove oil based ME provided significant protection against the NSAIDs induced gastric damage.

Prediction of Skin Permeation of Flurbiprofen from Neat Ester Oils and Their O/W Emulsions.

Although many in silico models were reported to predict the skin permeation of drugs from aqueous solutions, few studies were founded on the in silico estimation models for the skin permeation of drugs from neat oil formulations and o/w emulsions. In the present study, the cumulative amount of a model lipophilic drug, flurbiprofen (FP), that permeated through skin was determined from 12 different kinds of ester oils (Qoil) and an in silico model was developed for predicting the skin permeation of FP from these ester oils. Thus, the obtained Qoil values were well predicted with the FP solubility in the oils (Soil), the amount of FP uptake into the stratum corneum (SCoil) and molecular descriptors of dipolarity/polarizability (π2H) and molecular density. This model suggests that the thermodynamic activities of FP both in the formulations and skin are the key factors for predicting the skin permeation of FP from the ester oils. In addition, a high linear relationship was observed in the double-logarithm plots between the Qoil and the cumulative amount of FP permeated through skin from 20% ester oil in water emulsion (Qemul20%). Furthermore, the skin permeations of FP from 5 and 10% ester oil in water emulsions, Qemul5% and Qemul10%, respectively, were also predicted by the horizontal translation of the y-axis intercept of the liner equation for the relation between the Qoil and Qemul20%. These prediction methods must be helpful for designing topical oily and/or o/w emulsion formulations having suitable and high skin permeation rate of lipophilic drugs.

Kondogogu gum-Zn+2-pectinate emulgel matrices reinforced with mesoporous silica for intragastric furbiprofen delivery.

Flurbiprofen (FLU), a non-steroidal anti-inflammatory drug, exhibits limited clinical response due to its poor physicochemical properties. This study aimed at developing reliable drug carriers for intrgastric FLU delivery with a view to improve biopharmaceutical characteristics of drug and modulate its release in a controlled manner. In this context, FLU-loaded kondogogu gum (KG)-Zn+2-low methoxyl (LM) pectinate emulgel matrices reinforced with calcium silicate (CS) were accomplished by ionotropic gelation technique employing zinc acetate as cross-linker and characterized for their in vitro performances. All the formulations demonstrated excellent drug encapsulation efficiency (DEE, 46-87%) and sustained drug release behavior (Q7h, 70-91%). These quality attributes were remarkably influenced by polymer-blend (LM pectin:KG) ratios, low-density oil types and CS inclusion. The drug release profile of the FLU-loaded optimized matrices (F-7) was best fitted in Korsmeyer-Peppas model with Fickian diffusion driven mechanism. It also conferred excellent in vitro gastroretention capabilities. Moreover, the drug-excipient compatibility, alteration of crystallinity and thermal behavior of drug and surface morphology of matrices were evidenced with the results of FTIR, XRD, DSC and SEM analyses, respectively. Thus, the newly developed matrices are appropriate for sustained intragastric FLU delivery and simultaneous zinc supplementation for effective inflammation and arthritis management.

Effect of olive oil on transdermal penetration of flurbiprofen from topical gel as enhancer.

The present study was conducted to formulate and evaluate flurbiprofen transdermal gel. A standard calibration curve was constructed to obtain a regression line equation to be used for finding out the concentration of drug in samples. Olive oil was used as penetration enhancer and was added in different concentrations to some selected formulations to see its enhancement effect on in vitro drug release profiles. The prepared gels were evaluated for several physico-chemical parameters to justify their suitability for topical use. The in vitro drug release studies were carried out by using Franz cell diffusion apparatus across both synthetic membrane and excised albino rabbit skin. In order to investigate the drug release mechanism a kinetic approach was made by employing Korsmeyer kinetic model to the in vitro drug release profiles of flurbiprofen. The flurbiprofen topical gels were successfully prepared and could be beneficial for topical use.

Design and ocular tolerance of flurbiprofen loaded ultrasound-engineered NLC.

Packaging small drug molecules, such as non-steroidal anti-inflammatory drugs (NSAIDs) into nanoparticulate systems has been reported as a promising approach to improve the drug's bioavailability, biocompatibility and safety profiles. In the last 20 years, lipid nanoparticles (lipid dispersions) entered the nanoparticulate library as novel carrier systems due to their great potential as an alternative to other systems such as polymeric nanoparticles and liposomes for several administration routes. For ocular instillation nanoparticulate carriers are required to have a low mean particle size, with the lowest polydispersity as possible. The purpose of this work was to study the combined influence of 2-level, 4-factor variables on the formulation of flurbiprofen (FB), a lipophilic NSAID, in lipid carriers currently named as nanostructured lipid carriers (NLC). NLC were produced with stearic acid (SA) and castor oil (CO) stabilized by Tween® 80 (non-ionic surfactant) in aqueous dispersion. A 2(4) full factorial design based on 4 independent variables was used to plan the experiments, namely, the percentage of SA with regard to the total lipid, the FB concentration, the stabilizer concentration, and the storage conditions (i.e., storage temperature). The effects of these parameters on the mean particle size, polydispersity index (PI) and zeta potential (ZP) were investigated as dependent variables. The optimization process was achieved and the best formulation corresponded to the NLC formulation composed of 0.05 (wt%) FB, 1.6 (wt%) Tween® 80 and a 50:50 ratio of SA to CO, with an average diameter of 288 nm, PI 0.245 of and ZP of -29 mV. This factorial design study has proven to be a useful tool in optimizing FB-loaded NLC formulations. Stability of the optimized NLC was predicted using a TurbiScanLab® and the ocular tolerance was assessed in vitro and in vivo by the Eytex® and Draize test, respectively. The developed systems were shown physico-chemically stable with high tolerance for eye instillation.

Transglycosylated stevia and hesperidin as pharmaceutical excipients: dramatic improvement in drug dissolution and bioavailability.

The capability of transglycosylated materials, α-glycosyltransferase-treated stevia (Stevia-G) and α-glycosyl hesperidin (Hsp-G), to enhance the bioavailability of poorly water-soluble drugs was investigated. Spray-dried particles (SDPs) of drug/transglycosylated material, such as, flurbiprofen (FP)/Stevia-G, probucol (PRO)/Stevia-G, FP/Hsp-G, and PRO/Hsp-G were prepared. All SDPs showed pronounced improvement in both dissolution rate and apparent drug solubility. The amount of dissolved PRO was significantly improved to that of untreated PRO crystals when prepared as SDPs of PRO/Stevia-G or PRO/Hsp-G. There was no cytotoxicity to Caco-2 cells at levels of 10% Stevia-G or Hsp-G solution. Values for the area under the plasma concentration-time curve (AUC) of untreated PRO, SDPs of PRO/Hsp-G and PRO/Stevia-G after oral administration to rats were 4.94±2.06, 26.08±4.52 and 48.79±9.97µgh/mL, respectively. Interestingly, AUC values in cases of the FP system were in the order of untreated FP

In vitro evaluation of proniosomes as a drug carrier for flurbiprofen.

The purpose of the present investigation is to formulate and evaluate proniosomal transdermal carrier systems for flurbiprofen. Proniosomes were prepared using various non-ionic surfactants, namely span 20 (Sp 20), span 40 (Sp 40), span 60 (Sp 60) and span 80 (Sp 80) without and with cholesterol at percentages ranging from 0% to 50%. The effect of surfactant type and cholesterol content on drug release was investigated. Drug release was tested by diffusion through cellophane membrane and rabbit skin. Drug release from the prepared systems was compared to that from flurbiprofen suspensions in distilled water and HPMC (hydroxypropylmethylcellulose) gels. In case of Sp 20 and Sp 80, the added amount of cholesterol affected the preparation type to be either proniosomal alcoholic solutions or liquid crystalline gel systems. On the other hand, both Sp 40 and Sp 60 produced gel systems in presence or absence of cholesterol. Microscopic observations showed that either proniosomal solutions or gel formulations immediately converted to niosomal dispersions upon hydration. Due to the skin permeation barrier, rabbit skin showed lower drug diffusion rates compared to cellophane membrane. The proniosomal composition controlled drug diffusion rates to be either faster or slower than the prepared flurbiprofen suspensions in HPMC gels or distilled water, respectively. In conclusion, this study demonstrated the possibility of using proniosomal formulations for transdermal drug delivery.

Formulation studies and in vivo evaluation of a flurbiprofen-hydroxypropyl beta-cyclodextrin system.

The purpose of this study was 1) to investigate in vivo advantages of a flurbiprofen (FPN)-hydroxypropyl beta-cyclodextrin (HPbetaCD) solid dispersion (SD) in rats, 2) to study factors affecting the drug release from SD formulations, and 3) to evaluate the pharmacokinetic profile of the drug when administered as SD, in humans. The solubility of FPN in water and dissolution media was evaluated as a function of HPbetaCD concentration. The SD was prepared by coevaporation from dilute aqueous NH3 and evaluated in rats. The release of the drug from tablet formulations and capsules of SD was studied in simulated gastric fluid and phosphate buffer, pH 7.2. The bioavailability of drug when administered as SD was evaluated in humans. HPbetaCD enhanced the solubility of the drug, and SD improved bioavailability and reduced ulcerogenicity of the drug in rats. The type of excipient used affected drug release from tablets. Presence of microcrystalline cellulose, a hydrophilic polymeric excipient, resulted in uptake of water and stabilization of the resulting gels-like structure of HPbetaCD-containing tablets. This adversely affected drug release. The release from capsules filled with SD was comparable to that obtained from plain SD powder. The drug-HPbetaCD association constant in water was much lower than the values reported in literature. The bioavailability (which could suffer in case of higher association constant) was enhanced on administration of SD-filled capsules to humans.

Evaluation of the bioavailability of flurbiprofen and its beta-cyclodextrin inclusion complex in four different doses upon oral administration to rats.

The dissolution profiles of flurbiprofen (Flu) and its beta-cyclodextrin inclusion complex (Flu/beta-CD) in buffer solutions at various pH values were examined. The percent dissolved at 15 min for Flu and Flu/beta-CD was almost 100% at pH 6.8 and 8.0 but the dissolution rate of Flu was extremely reduced at pH 1.2 and 4.0. In these lower pH conditions, Flu/beta-CD improved the dissolution rate of Flu. The percent dissolved at 1 h for Flu/beta-CD at pH 1.2 and 4.0 were 33.4 and 41.3%, respectively, and about 10 times larger than those for Flu. The oral bioavailability of Flu from Flu or Flu/beta-CD at doses of 1, 3, 10, and 30 mg/kg (as Flu) was examined in rats. An apparent linear relationship between doses and C(max) and AUC was observed after administration of Flu and Flu/beta-CD. The Flu C(max) and AUC values at 30 mg/kg, however, were much lower than would have been predicted from doses of 1-10 mg/kg. Those of Flu/beta-CD were also lower than the predicted values, but the gap was quite small. The results suggest that the absorption of Flu in rats was saturated at 10 mg/kg, and that the enhanced dissolution rate of Flu/beta-CD increased the saturation dose to 30 mg/kg.

Effects of pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on eicosanoid release from various rat organs ex vivo.

The effects of oral treatment of rats with pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on ex vivo release of eicosanoids from gastric mucosa, jejunum, lung, brain and clotting whole blood were investigated. With the S(+) enantiomer and the racemate dose-dependent inhibition of release of cyclooxygenase products of arachidonate metabolism in all tissues tested was observed, while release of leukotriene (LT) C4 was inhibited in gastric mucosa, but not in jejunum and lung. On the other hand, the R(-) enantiomer inhibited cyclooxygenase in the various tissues less potently and to a variable degree with no significant effect in the jejunum. The R(-) enantiomer had no effect on LTC4 release from any of the tissues investigated. Furthermore, the effect of a high dose of 25 mg/kg of the S(+) enantiomer on release of cyclooxygenase products from the various tissues was much longer lasting than that of an identical dose of the R(-) enantiomer. Stereoselective pharmacokinetics of the flurbiprofen enantiomers and/or organ specific cyclooxygenase activities could underly these results. The more potent cyclooxygenase inhibition by the S(+) enantiomer correlates with its higher anti-inflammatory activity and gastrointestinal toxicity. On the other hand, both enantiomers have been shown previously to be almost equally effective analgesics. Inhibition of brain cyclooxygenase might contribute to this effect.