Solid Lipid Nanoparticles Bearing Flurbiprofen for Transdermal Delivery

Topical application of the drugs at the pathological sites offer potential advantages of delivering the drug directly to the site of action and thus producing high tissue concentrations of the drug. The solid lipid nanoparticles (SLN) bearing flurbiprofen were prepared by microemulsion method by dispersing o/w microemulsion in a cold aqueous surfactant medium under mechanical stirring. The SLN gel was prepared by adding SLN dispersion to polyacrylamide gel prepared by using polyacrylamide (0.5%), glycerol (10%), and water (69.5%). Shape and surface morphology was determined by scanning electron microscopy that revealed fairly spherical shape of the formulation. Percent drug entrapment was higher in SLN dispersion in comparison to SLN gel formulations. In vitro drug release, determined using cellophane membrane, showed that SLN dispersion exhibited higher drug release compared with SLN gel formulations. Both the SLN dispersion and SLN-gel formulation possessed a sustained drug release over a 24-hr period, but this sustained effect was more pronounced with SLN-gel formulations. The percent inhibition of edema after 8 hr was 55.51 ± 0.26% in case of SLN-T4-gel, whereas flurbiprofen and SLN-T4 dispersion exhibited 28.81 ± 0.46 and 31.89 ± 0.82 inhibition of edema. The SLN-T4-gel not only decreased the inflammation to larger magnitude, but also sustained its effect.     

Formulation and evaluation of flurbiprofen microemulsion

The purpose of the present study was to investigate the microemulsion formulations for topical delivery of Flurbiprofen (FP) in order to by pass its gastrointestinal adverse effects. The pseudoternary phase diagrams were developed and various microemulsion formulations were prepared using Isopropyl Myristate (IPM), Ethyl Oleate (EO) as oils, Aerosol OT as surfactant and Sorbitan Monooleate as cosurfactant. The transdermal permeability of flurbiprofen from microemulsions containing IPM and EO as two different oil phases was analyzed using Keshary-Chien diffusion cell through excised rat skin. Flurbiprofen showed higher in vitro permeation from IPM as compared to that of from EO microemulsion. Thus microemulsion containing IPM as oil phase were selected for optimization. The optimization was carried out using 2(3) factorial design. The optimized formula was then subjected to in vivo anti-inflammatory study and the performance of flurbiprofen from optimized formulation was compared with that of gel cream. Flurbiprofen from optimized microemulsion formulation was found to be more effective as compared to gel cream in inhibiting the carrageenan induced rat paw edema at all time intervals. Histopathological investigation of rat skin revealed the safety of microemulsion formulation for topical use. Thus the present study indicates that, microemulsion can be a promising vehicle for the topical delivery of flurbiprofen.     

Solid lipid nanoparticle and microemulsion for topical delivery of triptolide.

Triptolide (TP) has been shown to have anti-inflammatory, immunosuppressive, anti-fertility and anti-neoplastic activities. However, its clinical use is restricted to some content due to its poor water solubility and some toxic effects. In order to find innovative ways for administering TP and alleviating its disadvantages, the controlled release delivery systems such as solid lipid nanoparticle (SLN) and microemulsion have been developed. In the present paper we describe the preparation and some characterization of specialized delivery systems for TP. The transdermal delivery capacity and anti-inflammatory activity were also evaluated. The results indicated that these SLN dispersions and microemulsions could serve as efficient promoters for the TP penetrating into skin. Furthermore, different formulations were optimized in this study. The best formulation of SLN dispersion consisted of 5% tristearin glyceride, 1.20% soybean lecithin and 3.60% polyethylene glycol (400) monosterate, while the best formulation of microemulsion consisted of 40% isopropyl myristate, 50% Tween-80: 1,2-propylene glycol (5:1, v/v) and water. The steady-state flux (Js) and permeability coefficient (Kp) of triptolide for the SLN dispersion of the first 6 h were 3.1+/-0.4 microg/cm2 per h and 0.0124+/-0.001 cm/h or 6.4+/-0.7 microg/cm2 per h and 0.0256+/-0.002 cm/h for the microemulsion, which was 3.45 and 7.02 times higher than those of triptolide solution, respectively. The anti-inflammatory activity of SLN dispersion was stronger than that of microemulsion in carrageenan induced rat paw edema. However, the results were the reverse in complete Frenud's adjuvant induced paw edema. Further investigations should be carried out on the toxicity of different formulations of triptolide to tissues.     

Modulation of drug release from nanocarriers loaded with a poorly water soluble drug (flurbiprofen) comprising natural waxes

In this study, flurbiprofen (FLB) Solid Lipid Nanoparticles (SLN) composed from a mixture of beeswax and carnauba wax, Tween 80 and egg lecithin as emulsifiers have been prepared. FLB was incorporated as model lipophilic drug to assess the influence of matrix composition in the drug release profile. SLN were produced by microemulsion technique. In vitro studies were performed in Phosphate Buffered Saline (PBS). The FLB loaded SLN showed a mean particle size of 75 +/- 4 nm, a polydispersity index approximately 0.2 +/- 0.02 and an entrapment efficiency (EE) of more than 95%. Suspensions were stable, with zeta potential values in the range of -15 to -17 mV. DSC thermograms and UV analysis indicated the stability of nanoparticles with negligible drug leakage. Nanoparticles with higher beeswax content in their core exhibited faster drug release than those containing more carnauba wax.     

Pluronic lecithin organogel as a topical drug delivery system

The objective of this study was to formulate and evaluate the pluronic lecithin organogel containing flurbiprofen for topical application. Different formulations of pluronic lecithin organogels were prepared by using pluronic F127, lecithin, flurbiprofen, isopropyl palmitate, water, sorbic acid, and potassium sorbate. To study the in vitro potential of these formulations, permeation studies were performed with Keshary-Chien diffusion cells. The results of the in vitro permeation studies found that release of flurbiprofen from dialysis membrane-70 was more than excised dorsal rat skin. Gelation temperature study was carried out to determine the temperature where sol-gel transformation takes place. The viscosities of different formulations were determined by using Brookfield Viscometer at 25°C, the viscosity of formulations increases as the lecithin concentration increases. Also the formulations were tested for appearance and feel psychorheologically, pH, and drug content. Interactions between the components of the gel have been investigated by differential scanning calorimetry and X-ray powder diffractometry. The optimized formulation subjected to differential scanning calorimetry shows no drug–polymer interaction. To investigate the in vivo performance of the formulations, a carrageenan-induced rat paw edema model and skin irritation study was used. The stability studies and freeze–thaw thermal cyclic test were carried out, showing no phase separation of gel, and representing gel stability. Statistical analysis of the data of animal study (anti-inflammatory activity) was done by using one way analysis of variance (ANOVA) followed by Dunnett’s test. The formulation shows a statistically significant anti-inflammatory activity and is non-irritant to skin.     

Pluronic lecithin organogel as a topical drug delivery system

The objective of this study was to formulate and evaluate the pluronic lecithin organogel containing flurbiprofen for topical application. Different formulations of pluronic lecithin organogels were prepared by using pluronic F127, lecithin, flurbiprofen, isopropyl palmitate, water, sorbic acid, and potassium sorbate. To study the in vitro potential of these formulations, permeation studies were performed with Keshary-Chien diffusion cells. The results of the in vitro permeation studies found that release of flurbiprofen from dialysis membrane-70 was more than excised dorsal rat skin. Gelation temperature study was carried out to determine the temperature where sol-gel transformation takes place. The viscosities of different formulations were determined by using Brookfield Viscometer at 25°C, the viscosity of formulations increases as the lecithin concentration increases. Also the formulations were tested for appearance and feel psychorheologically, pH, and drug content. Interactions between the components of the gel have been investigated by differential scanning calorimetry and X-ray powder diffractometry. The optimized formulation subjected to differential scanning calorimetry shows no drug-polymer interaction. To investigate the in vivo performance of the formulations, a carrageenan-induced rat paw edema model and skin irritation study was used. The stability studies and freeze-thaw thermal cyclic test were carried out, showing no phase separation of gel, and representing gel stability. Statistical analysis of the data of animal study (anti-inflammatory activity) was done by using one way analysis of variance (ANOVA) followed by Dunnett's test. The formulation shows a statistically significant anti-inflammatory activity and is non-irritant to skin.     

Formulation and ex vivo evaluation of rofecoxib gel for topical application

The potential gastrointestinal disorders associated with oral administration of rofecoxib can be avoided by delivering the drug to the inflammation site at a sustained, concentrated level over an extended period of time. Hydroxypropylmethylcellulose (HPMC), sodium alginate and Carbopol 940 were used in an attempt to develop topical gel formulations of rofecoxib. The effects of polymer composition on the rate of drug release from the gel formulations were examined through cellulose membrane mounting on a Keshary-Chien diffusion cell. The effects of initial drug concentration and viscosity on the permeation rate of rofecoxib from the gel formulations were evaluated using rat epidermis at 37 +/- 0.5 degrees C. The anti-inflammatory activity of the rofecoxib gel formulation was evaluated using the rat hind paw edema model. The gel formulation consisting of 4% w/w sodium alginate-Carbopol 940 at 3:1 ratio was found to be suitable for topical application based on in vitro evaluation and ex vivo permeation studies. The drug permeation rate increased with an increase of the initial drug concentration in gels up to 25% w/w. An inverse relationship was observed between the in vitro drug release rate/ex vivo permeation rate and viscosity of the gel formulations. The anti-inflammatory activity of 4% w/w sodium alginate-Carbopol 940 gel containing 25% w/w rofecoxib in the rat hind paw edema model reveals that the drug was delivered to the inflammation site at a controlled level over a period of 6 h. These results suggest the feasibility of the topical gel formulation of rofecoxib.     

SLN and NLC for topical delivery of ketoconazole

The clinical use of ketoconazole has been related to some adverse effects in healthy adults, specially local reactions, such as severe irritation, pruritus and stinging. The purpose of the present work is the assessment of ketoconazole stability in aqueous SLN and NLC dispersions, as well as the physicochemical stability of these lipid nanoparticles, which might be useful for targeting this drug into topical route, minimizing the adverse side effects and providing a controlled release. Lipid particles were prepared using Compritol 888 ATO as solid lipid. The natural antioxidant alpha-tocopherol was selected as liquid lipid compound for the preparation of NLC. Ketoconazole loading capacity was identical for both SLN and NLC systems (5% of particle mass). SLN were physically stable as suspensions during 3 months of storage, but the SLN matrix was not able to protect the chemically labile ketoconazole against degradation under light exposure. In contrast, the NLC were able to stabilize the drug, but the aqueous NLC dispersion showed size increase during storage. Potential topical formulations are light-protected packaged SLN or NLC physically stabilized in a gel formulation.     

Multivesicular liposomes bearing celecoxib-beta-cyclodextrin complex for transdermal delivery

In our work depot delivery systems of celecoxib were developed using multivesicular liposomes. Moreover, the solubility of celecoxib was enhanced by complexing drug with cyclodextrin to overcome the limitation of conventional therapy. The multivesicular liposomes (MVLs) bearing celecoxib-β -cyclodextrin inclusion complex were prepared by reverse phase evaporation method, and multilamellar vesicles (MLVs)-bearing drug complex was prepared by the cast film method. The formulations were characterized for vesicle size, encapsulation efficiency, and in vitro drug release. In vivo performance of multivesicular liposomes bearing celecoxib-β -cyclodextrin inclusion complex was evaluated by assessing anti-inflammatory activity using carrageenan-induced rat paw edema volume method. The results were compared with that of celecoxib-cyclodextrin complex and MLVs containing celecoxib-β -cyclodextrin inclusion complex in equal amounts. Phase solubility studies for the celecoxib-β -cyclodextrin inclusion complex clearly indicated an increase in aqueous solubility of celecoxib with an increase in β -CD concentration. The in vitro release studies reveal that MLVs release more than 80% drug within 48 hr whereas MVL formulations release nearly the same amount of drug in 120 hr. In vivo data reveal that reduction in paw volume with MVL formulation was not rapid and fast, but the effect was maintained for prolonged periods, and even after 24 hr there was 40.7 ± 3.40% reduction in paw volume. MVL formulation showed more sustained and prolonged anti-inflammatory effect compared with plain drug and MLVs. We concluded that multivesicular liposome can be successfully utilized for the sustained delivery of celecoxib.     

Design,development, physicochemical,and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt

In this study, matrix-type transdermal patches containing diclofenac diethylamine were prepared using different ratios of polyvinylpyrrolidone (PVP) and ethylcellulose (EC) by solvent evaporation technique. The drug matrix film of PVP and EC was casted on a polyvinylalcohol backing membrane. All the prepared formulations were subjected to physical studies (moisture content, moisture uptake, and flatness), in vitro release studies and in vitro skin permeation studies. In vitro permeation studies were performed across cadaver skin using a modified diffusion cell. Variations in drug release profiles among the formulations studied were observed. Based on a physicochemical and in vitro skin permeation study, formulation PA4 (PVP/EC, 1:2) and PA5 (PVP/EC, 1:5) were chosen for further in vivo experiments. The antiinflammatory effect and a sustaining action of diclofenac diethylamine from the two transdermal patches selected were studied by inducing paw edema in rats with 1% w/v carrageenan solution. When the patches were applied half an hour before the subplantar injection of carrageenan in the hind paw of male Wistar rats, it was observed that formulation PA4 produced 100% inhibition of paw edema in rats 12 h after carrageenan insult, whereas in the case of formulation PA5, 4% mean paw edema was obtained half an hour after the carrageenan injection and the value became 19.23% 12 h after the carrageenan insult. The efficacy of transdermal patches was also compared with the marketed Voveran gel and it was found that PA4 transdermal patches produced a better result as compared with the Voveran gel. Hence, it can be reasonably concluded that diclofenac diethylamine can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition (PVP/EC, 1:2) was found to be the best choice for manufacturing transdermal patches of diclofenac diethylamine among the formulations studied.     

SLN and NLC for topical delivery of ketoconazole

The clinical use of ketoconazole has been related to some adverse effects in healthy adults, specially local reactions, such as severe irritation, pruritus and stinging. The purpose of the present work is the assessment of ketoconazole stability in aqueous SLN and NLC dispersions, as well as the physicochemical stability of these lipid nanoparticles, which might be useful for targeting this drug into topical route, minimizing the adverse side effects and providing a controlled release. Lipid particles were prepared using Compritol®888 ATO as solid lipid. The natural antioxidant α-tocopherol was selected as liquid lipid compound for the preparation of NLC. Ketoconazole loading capacity was identical for both SLN and NLC systems (5% of particle mass). SLN were physically stable as suspensions during 3 months of storage, but the SLN matrix was not able to protect the chemically labile ketoconazole against degradation under light exposure. In contrast, the NLC were able to stabilize the drug, but the aqueous NLC dispersion showed size increase during storage. Potential topical formulations are light-protected packaged SLN or NLC physically stabilized in a gel formulation.     

盐霉素钠纳米脂质体的制备及表征

目的制备并表征盐霉素钠纳米脂质体(SLN)。方法采用薄膜分散法制备盐霉素钠纳米脂质体,通过调节脂质体中胆固醇比例,以盐霉素钠包封率为评价指标,筛选盐霉素钠纳米脂质体的优化处方。结果透射电镜显示盐霉素钠纳米脂质体形态圆整,分散性良好,激光粒度仪显示盐霉素钠纳米脂质体平均粒径为99.0nm,Zeta电位为-33.5mV,包封率为85.7%,载药量为6.7%。通过脂质体包裹,盐霉素钠在水中的最高浓度可提高15倍,并证明其具有一定缓释效果。结论笔者得到了粒径大小在100nm左右,形态均一,包封率和载药量较高的盐霉素钠纳米脂质体,为进一步测定其杀伤肿瘤活性奠定了坚实的制剂学基础。     

Preparation and evaluation of flurbiprofen-loaded microemulsion for parenteral delivery.

The purpose of this study was to improve the solubility of flurbiprofen, a poorly water-soluble drug, in an oil-in-water (o/w) microemulsion that is suitable for parenteral administration. Microemulsions with varying ratios of oil to surfactant were prepared with ethyl oleate, Tween 20 and isotonic solution. The effect of formulation variables on the particle size of microemulsion and solubility of flurbiprofen in microemulsion system was investigated. The pharmacokinetic parameters of flurbiprofen after intravenous administration of flurbiprofen-loaded microemulsion were compared with those of a solution of the drug. The mean droplet diameter of microemulsion containing less than 1% (w/w) of flurbiprofen was below 100 nm. The maximum solubility of flurbiprofen in the microemulsion system was found to be 10 mg/ml. However, the mean droplet diameters of flurbiprofen-loaded o/w microemulsions tend to be increased at room temperature. The pharmacokinetic parameters of flurbiprofen after intravenous administration of flurbiprofen-loaded microemulsion to rats were not significantly different from those of flurbiprofen in phosphate-buffered saline solution. It can be concluded that microemulsions of flurbiprofen prepared with ethyl oleate and Tween 20 can be used as a parenteral drug carrier for this and other poorly water-soluble drugs, provided that physical stability can be properly addressed. Copyright     

Rheological and in vitro release behaviour of clotrimazole-containing aqueous SLN dispersions and commercial creams

Clotrimazole is a wide spectrum local imidazolic antifungal agent used in several dermatological creams, having e.g. 1% (m/m) such as Canesten and Fungizid-ratiopharm cream. In the present work, a new system based on solid lipid nanoparticles (SLN) containing the identical concentration of drug has been developed. A comparative study between the rheological properties of the referred creams and the developed aqueous SLN dispersions was carried out. The influence of incorporation of SLN in a standard hydrophilic cream on its flow curves was also assessed. In addition, the release of clotrimazole from the two commercial creams, as well as from aqueous SLN dispersions was studied. Concerning the rheological investigations, all tested commercial creams revealed very low shear rates and no yield points. Lipid nanoparticles having a mean diameter of approx. 200 nm have been incorporated into a hydrophilic cream, in a concentration of 20%, 30% or 40% (m/m). The hydrophilic cream containing 20% of SLN showed a dilatant-like character; however, increasing the percentage of incorporated lipid nanoparticles to 30% and 40% the formulation changed to a more pseudoplastic character, showing yield values of 28 Pa and 39 Pa, respectively. For in vitro release studies, Franz diffusion cells with a cellulose acetate membrane were used to measure the release of clotrimazole from two different commercial formulations in comparison to the aqueous SLN dispersion. After 6 h the amount of drug released was higher than 48% when delivered from both investigated commercial formulations and not higher than 25% when delivered from the aqueous SLN dispersion. The percentage of drug released determined after 24 h was more than 50% for Canesten cream and Fungizid-ratiopharm cream and not higher than 30% for the developed SLN formulation showing its prolonged release character.     

Long-term stability, biocompatibility and oral delivery potential of risperidone-loaded solid lipid nanoparticles

A solid lipid nanoparticles (SLN) formulation to improve the oral delivery of risperidone (RISP), a poorly water-soluble drug, was designed and tested. Initially, lipid-RISP solubility was screened to select the best lipid for SLN preparation. Compritol(?)-based formulations were chosen and their long-term stability was assessed over two years of storage (at 25°C and 4°C) by means of particle size, polydispersity index (PI), zeta potential (ZP) and encapsulation efficiency (EE) measurements. SLN shape was observed by transmission electron microscopy (TEM) at the beginning and end of the study. The oxidative potential (OP) of the SLN was measured and their biocompatibility with Caco-2 cells was evaluated using the (4,5-dimethylthiazol-2-yl)2,5-dyphenyl-tetrazolium bromide (MTT) assay. In vitro drug release and transport studies were performed to predict the in vivo release profile and to evaluate the drug delivery potential of the SLN formulations, respectively. The RISP-loaded SLN systems were stable and had high EE and similar shape to the placebo formulations before and after storage. Classical Fickian diffusion was identified as the release mechanism for RISP from the SLN formulation. Biocompatibility and dose-dependent RISP transport across Caco-2 cells were observed for the prepared SLN formulations. The viability of SLN as formulations for oral delivery of poorly water-soluble drugs such as RISP was illustrated.     

Enhance transdermal delivery of flurbiprofen via microemulsions: Effects of different types of surfactants and cosurfactants

Background and the purpose of the study

Microemulsions are thermodynamically stable, clear dispersions of water, oil, surfactant, and cosurfactant. This study was aimed to develop flurbiprofen microemulsion for enhanced transdermal delivery and investigate the effects of different surfactants and cosurfactants on its delivery and phase behavior.

Method

Various surfactant-cosurfactant mixtures in ratio of 2:1 (Smix) along with oleic acid (oil) were selected and phase diagrams were constructed. Six microemulsions each containing 5% drug, 5% oil, 56% Smix and 34% water, were prepared and compared for their permeation and phase behaviors to determine the effects of the type of Smix.

Results

In vitro transdermal permeation through rabbit skin of all microemulsions was high than saturated aqueous drug solution. Tween 20 and ethanol as Smix produced the highest flux amongst all the Smix, and were used to prepare formulations with different values of oil and Smix. While the type of surfactant did not affect the droplet size, propylene glycol as cosurfactant produced the largest droplets and highest viscosity. Decrease in oil or Smix concentration resulted in decrease of the droplet size and increase in permeation flux while decrease in viscosity also increased the permeation flux of microemulsions. Finally the selected microemulsion formulation comprising 5% flurbiprofen, 5% oleic acid, 46% Tween 20:ethanol (2:1) and 44% water, showed the highest transdermal flux and caused no skin irritation.

Conclusion

Type of surfactant and cosurfactant affect both the phase behavior and transdermal drug delivery of microemulsion; and results of this study showed that they are promising vehicles for improved transdermal delivery and sustained action of flurbiprofen.     

Preparation and characterization of solid lipid nanoparticles containing cloricromene

This article describes the development of solid lipid nanoparticles (SLN) as colloidal carriers for cloricromene. Nanoparticles were prepared by the microemulsion or precipitation technique. In vitro drug release profile from SLN was studied under various experimental conditions mimicking some body fluids. The drug release rate of drug at pH 7.4 and human plasma is high. In plasma, after 15 min, about 70% of drug was released. The cloricromene that was not released within 4 hr was found in the SLN. This result suggests that this colloidal system could be useful for targeted drug delivery to the central nervous system after intravenous administration.     

Influence of Dosage Form on the Gastroenteropathy of Flurbiprofen in the Rat: Evidence of Shift in the Toxicity Site

Purpose. Gastroduodenal and intestinal permeability were compared after single doses of sustained release and regular release flurbiprofen in the rat to assess possible site-specific formulation-dependent toxicity. Methods. Pharmacokinetics was assessed and gastrointestinal permeability was evaluated using sucrose and ⁵¹Cr-EDTA as gastroduodenal and intestinal permeability probes, respectively. Results. The two formulations demonstrated equal areas under the flurbiprofen concentration-time curve. The sustained release formulation peaked 2–3 h slower with 57–74% lower concentrations than regular release formulation. In comparison, the regular release powder induced greater gastroduodenal permeability while sustained release granules induced greater intestinal permeability. When S-flurbiprofen concentrations were plotted versus intestinal permeability, a linear relationship and an anti-clockwise hysteresis were obtained for regular and sustained release formulations, respectively. Conclusions. Sustained release formulations of flurbiprofen demonstrate reduced gastroduodenal permeability but shift the site of this side-effect to the more distal intestine.     

Preparation, in vitro and in vivo evaluation of algino-pectinate bioadhesive microspheres: An investigation of the effects of polymers using multiple comparison analysis

Ionotropic gelation was used to entrap aceclofenac into algino-pectinate bioadhesive microspheres as a potential drug carrier for the oral delivery of this anti-inflammatory drug. Microspheres were investigated in vitro for possible sustained drug release and their use in vivo as a gastroprotective system for aceclofenac. Polymer concentration and polymer/drug ratio were analyzed for their influence on microsphere properties. The microspheres exhibited good bioadhesive property and showed high drug entrapment efficiency. Drug release profiles exhibited faster release of aceclofenac from alginate microspheres whereas algino-pectinate microspheres showed prolonged release. Dunnet's multiple comparison analysis suggested a significant difference in percent inhibition of paw edema when the optimized formulation was compared to pure drug. It was concluded that the algino-pectinate bioadhesive formulations exhibit promising properties of a sustained release form for aceclofenac and that they provide distinct tissue protection in the stomach.