Design and Development of Oral Oil-in-Water Nanoemulsion Formulation Bearing Atorvastatin: In Vitro Assessment

The objective of the present investigation was to design a thermodynamically stable and dilutable nanoemulsion formulation of AT-Ca with minimum surfactant concentration that could improve its solubility as well as its oral bioavailability. The composition of optimized nanoemulsion formulation was Sefsol 218 and oleic acid (1:1) 10% w/w, as an oil phase, Tween-20 (19% w/w) as a surfactant, Carbitol (19% w/w) as a cosurfactant and distilled water (52% w/w) as an aqueous phase, containing 10 mg of AT. The optimized formulation showed higher% drug release (99.34%), lower droplet size (42.8 ± 0.42 nm) with low polydispersity index (0.237 ± 0.012), less viscosity (27.51 ± 1.01 cP) and infinite dilution capability. In vitro drug release from the nanoemulsion formulations was highly significant (p < 0.01) as compared to drug suspension.     

Studies on hydroquinone based maleate bolaamphiphile organogels and their drug formulations

Now a day’s there is an upsurge in topical gel formulations, they can be prepared by varying physico-chemical methods and provide better localized action. A maleate based symmetric bolaamphiphile was synthesized by using cost-effective starting materials under mild reaction condition. The gelation ability of bolaamphiphile in aqueous medium was examined for a series of organic solvents. In hexane, the gelator showed better gelation ability with relatively higher critical strain (54 Pa) values. Further, the microscopic images of the gel revealed flakes like morphology, both the XRD and DFT studies revealed the presence of non covalent interactions. These gels showed a high internal-phase mole ratio of the topical drugs in the order of curcumin < salicylic acid < Ibuprofen. Formation of aqueous and organic gel-phase formulation may facilitate the topical medications for various applications related to ophthalmic and skin infections.     

Paliperidone-Loaded Self-Emulsifying Drug Delivery Systems (SEDDS) for Improved Oral Delivery

The present research is aimed to improve the oral delivery of paliperidone by loading into self-emulsifying drug delivery systems (SEDDS). Oleic acid, Tween 80, and capmul MCM L8 were selected as oil, surfactant, and co-surfactant, respectively and phase diagram was constructed and the region was identified for the formation of SEDDS. The stable formulations were analyzed for globule size, robustness to dilution and in vitro drug release. The globule size of all the formulations was found to be in the range of 205 to 310 nm with good size uniformity and seems to be dependent on the proportion of oil in SEEDS formulation. The optimized formulation (F3) has been adsorbed onto neusilin and characterized. The DSC and XRD spectra unravel the presence of molecular state of paliperidone in solid SEDDS. The in vitro dissolution study indicates improved dissolution characteristics with higher dissolution efficiency for solid SEDDS (SEDDS-N) compared to pure drug. Further ex vivo permeation studies carried out using rat intestine suggest a 2- to 3-fold improvement in permeation for SEDDS compared to pure drug. In conclusion, SEDDS prove to be potential carriers for improved oral delivery of paliperidone.     

Novel Synthesis of CeO2 Nanoparticles Within Formamide/Tri(ethyleneglycol)monododecyl Ether/n-Octane Nonaqueous Microemulsion Systems

The present study evaluates a new method to prepare Cerium oxide (CeO₂) nanoparticles by formamide/tri(ethyleneglycol)monododecyl ether (C₁₂E₃)/n-octane oil-continuous nonaqueous microemulsion. The effect of the polar phase (formamide/water) on the phase behavior, drop size, and conductivity behavior of the reverse microemulsion were investigated. X-ray diffraction (XRD) and transmission electron microscopy (TEM) were used to characterize the phase and morphology of synthesized CeO₂ nanoparticles. It was found that the CeO₂ powders synthesized within nonaqueous microemulsions and aqueous microemulisons had an average particle size of 30–50 nm and 15–40 nm, respectively. The experimental results indicate the formation mechanism of CeO₂ nanoparticles in formamide nonaqueous microemulsion and aqueous microemulsion is similar, and the formamide nonaqueous microemulsion can be used as nanoreactors for preparation of nanoparticles.     

Synergistic Effect of Mixed Cosurfactants on Transdermal Delivery of Indomethacin from O/W Microemulsion

Since large amounts of oils, surfactants and penetration enhancers used in microemulsion systems might lead to seriously skin irritation, the percutaneous absorption and penetration of indomethacin(IMC, model drug) from O/W microemulsion were enhanced by simply changing the composition of cosurfactants. Pseudo-ternary phase diagrams were constructed with mixed cosurfactants at different ratios. Hairless rat skin was used as a barrier for permeation experiments. Four formulations were prepared with fixed oil, surfactant and different cosurfactant content(4%, 20% and 20%, mass fraction), and formulation F4 with menthol added was evaluated to compare the enhancement effect of it with those of mixed cosurfactants. The O/W microemulsion region was the largest when the mass ratio of ethanol/transcutol was 1:1. However, the region changed slightly for the system with incorporated mixed cosurfactants propylene glycol/transcutol. The flux and skin retention of IMC from O/W microemulsion with mixed cosurfactants were much higher than that with single cosurfactant(P<0.01), while incorporation of menthol would only enhance the drug flux through the skin. To conclude, mixed cosufactants could affect the phase behavior and improve the percutaneous absorption and penetration of IMC. Based on this, it provided a promising solution to enhance drug release from microemulsions without raising potential skin damage.     

Simple Rapid Validated RP-LC Method for the Estimation of Flurbiprofen in Rabbit Serum and Aqueous Humor

Abstract

New reversed-phase liquid chromatographic methods, with UV detection, were developed for the quantitative estimation of flurbiprofen in rabbit blood serum and aqueous humor. The mobile phase and other chromatographic conditions were optimized to minimize interference from biological matrix and at the same time provide sufficient sensitivity for the method to be adopted for in vivo studies of ophthalmic formulations of flurbiprofen. Acetonitrile was used to precipitate proteins from serum or aqueous humor during sample preparation. A mobile phase of methanol: acetonitrile: phosphate buffer pH 5.6 (40:20:40) was employed with UV detection at 248 nm for estimation of drug in both the biological matrix. The retention time and asymmetry factor for the proposed method of estimation in serum and aqueous humor was found to be 3.1312±0.0101 min and 1.1310±0.0091 respectively. The linear regression equations obtained by least square regression method, were Area (µV sec) = 52.27 × Conc. (in ng/ml)–1618.70 in serum and Area (µV sec) = 61.79 × Conc. (in ng/ml) ? 783.24 in aqueous humor. The results of analysis were treated statistically, as per ICH guidelines for validation of analytical procedures, USP-2003, and by recovery studies. The results were found to be accurate, reproducible and free from interference. The developed methods were further used for estimation of flurbiprofen in rabbit serum and aqueous humor following single topical administration of in-house aqueous drop and market formulation to rabbit eye.     

Nanomaterial Lipid-Based Carrier for Non-Invasive Capsaicin Delivery; Manufacturing Scale-Up and Human Irritation Assessment

Capsaicin is an active compound in chili peppers (Capsicum chinense) that has been approved for chronic pain treatment. The topical application of high-strength capsaicin has been proven to reduce pain; however, skin irritation is a major drawback. The aim of this study was to investigate an appropriate and scalable technique for preparing nanostructured lipid carriers (NLCs) containing 0.25% capsaicin from capsicum oleoresin (NLC_C) and to evaluate the irritation of human skin by chili-extract-loaded NLCs incorporated in a gel formulation (Gel NLC_C). High-shear homogenization with high intensity (10,000 rpm) was selected to create uniform nanoparticles with a size range from 106 to 156 nm. Both the NLC_C and Gel NLC_C formulations expressed greater physical and chemical stabilities than the free chili formulation. Release and porcine biopsy studies revealed the sustained drug release and significant permeation of the NLCs through the outer skin layer, distributing in the dermis better than the free compounds. Finally, the alleviation of irritation and the decrease in uncomfortable feelings following the application of the Gel NLC_C formulation were compared to the effects from a chili gel and a commercial product in thirty healthy volunteers. The chili-extract-loaded NLCs were shown to be applicable for the transdermal delivery of capsaicin whilst minimizing skin irritation, the major noncompliance cause of patients.     

Preparation of Acrylic Microgels by Modified Microemulsion Polymerization and Phase Inversion

Semi‐transparent reactive microgel in nanosize has been prepared by modified microemulsion polymerization using a common emulsifier, crosslinking agent and functional monomer. The microgels are translucent reactive nanoparticles, with the size of 40–100 nm, consisting of inner‐crosslinked polymer up to 40%. FT‐IR proved the functional groups, such as epoxy and hydroxy, are on the surface of the microgel nanoparticles. Rheological detection demonstrated the apparent pseudoplasticity of the non‐aqueous microgel dispersion prepared by the phase transfering from the O/W microlatexes.     

Evaluation and Optimization of Water-in-Oil Microemulsion Using Ternary Phase Diagram and Central Composite Design

In the present study, water-in-oil (w/o) microemulsions were prepared, evaluated, and optimized using pseudoternary phase diagram and central composite design (CCD). Ternary phase diagrams were designed to determine the microemulsion region whereas face-centered CCD helped in the determination of the effect of variables like oil type and surfactant ratio on globule size and viscosity of w/o microemulsion. The design exhibited that the factors have statistically significant effects (p < 0.0001) on the selected responses. The actual responses showed excellent agreement with the predicted values as suggested by the CCD with lower residual standard error. Similarly, the optimized values were found within the range as predicted by the model. Furthermore, other characteristics of microemulsions like pH, conductivity, refractive index, and transmittance were also analyzed. Overall, the primary objective of the research was to fabricate water-in-oil microemulsions which could facilitate effective delivery of hydrophilic molecules and drugs.     

A Study of the Emulsified Microemulsion by SAXS,Cryo‐TEM,SD‐NMR,and Electrical Conductivity

A water‐in‐oil microemulsion was further dispersed in an aqueous phase containing Pluronic F127 as a steric stabilizer, to form a specific type of double emulsion termed emulsified microemulsion (EME). The inner microemulsion phase was made from glycerol‐monooleate (GMO), R(+)‐limonene, ethanol and glycerol. SAXS (small x‐ray scattering), PGSE‐NMR (pulse gradient spin echo‐NMR), electrical conductivity, and cryo‐TEM (cryogenic‐transmission electron microscopy) imaging techniques were used to confirm the existence of inner W/O nano‐droplets after second emulsification step and upon EME aging. Spherical globules of EME without long‐range internal order were observed by the SAXS measurements and the cryo‐TEM images. The average globule size of about 200–300 nm remained intact for at least 6 months.     

Design of highly porous melamine-based networks through a bicontinuous microemulsion templating strategy

Designing low density polymeric porous materials with defined pore sizes (diameters in the 100 nm range) still remains a real synthesis challenge. Here, for the first time, we present a strategy by which bicontinuous microemulsions are used as templating agents for the in-situ aqueous polycondensation of organic resins (melamine formaldehyde, MF). The behaviour of surfactants with different head-groups in systems including oil and MF-containing aqueous phase is studied. While many surfactants are not compatible with aqueous MF precondensates, here we report a non-ionic surfactant either used solely or along with anionic surfactants which prove to be successful at keeping bicontinuous microemulsion systems homogeneous even during early stages of polymerisation. However, upon acid-catalysis it becomes clear that the pore structure of the organic material is largely controlled by the kinetics of phase separation due to the sol–gel process rather than by the thermodynamic equilibrium of the template (microemulsion). Indeed, despite numerous attempts, stabilising the microemulsion interface with zero curvature (bicontinuous) has remained problematic. Instead, we show a new behaviour for the MF resin whereby non-spherical MF morphologies (i.e. thread-like structures) can be obtained by specific interactions between the aqueous amino resin and the acid counterions.     

Effect of the composition of lecithin/n-propanol/isopropyl myristate/water microemulsions on barrier properties of mice skin for transdermal permeation of tetracaine hydrochloride: in vitro

Effect of composition of lecithin water-in-oil and oil-in-water microemulsion on in vitro transdermal permeation of tetracaine hydrochloride was studied on mice model. The results were compared with an aqueous solution of tetracaine hydrochloride (2.7 mg/ml). In vitro skin flux and permeability coefficients were obtained using the Franz diffusion cell. Differential scanning calorimetry (DSC), transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM) were used to study the mechanism of action of the microemulsion. Micrographs of TEM and CLSM studies were analyzed by using Image Pro Plus image software. Skin flux of tetracaine hydrochloride was found to be dependent on the composition of lecithin/n-propanol/isopropyl myristate/water microemulsions. At lower Km ratio (i.e. 0.5:1 and 0.8:1) of microemulsion, the rate of permeation of tetracaine hydrochloride was higher when compared to the microemulsion of higher Km ratio (1:1 and 1.5:1). Image analysis of TEM micrograph, 6h after application of lecithin microemulsion, showed 3.5+/-0.75-fold (p<0.001) increase in the intercellular space in the epidermis and 3.8+/-0.4-fold (p<0.001) enhancement in upper dermis. CLMS results show that sweat gland and hair follicles also provided path for permeation of the drug through the skin.     

赖氨酸在甘草次酸弹性囊泡形成过程中的作用机制

制备和评价含赖氨酸的甘草次酸弹性囊泡, 并考察赖氨酸在囊泡形成过程中的作用机制. 在水合介质中加入赖氨酸, 利用薄膜-高压均质法制备甘草次酸弹性囊泡. 并合成了甘草次酸赖氨酸盐及其弹性囊泡作为对比制剂. 通过对粒径、zeta电位、包封率、相转变温度、变形性和体外经皮渗透性的测试, 考察赖氨酸在甘草次酸弹性囊泡中的存在形式及作用. 结果显示加入赖氨酸后, 甘草次酸弹性囊泡的粒径略有降低, 膜相转变温度降低, 包封率和囊泡变形性显著提高, 载药量提高近30倍(1.5 mg·mL-1), 并显著高于其赖氨酸盐所形成囊泡的载药量和弹性. 此外, 赖氨酸的加入使弹性囊泡的变形能力增加, 8 h累积透过量和皮肤驻留量分别提高4.3倍和9.2倍. 表明赖氨酸与甘草次酸形成离子缔合物, 促进甘草次酸参与膜的形成, 使膜的流动性增加, 赖氨酸与弹性囊泡对提高囊泡载药量起协同作用.     

In Vitro Skin Permeation Enhancement of KIOM-MA-128 by Monoolein Cubosomes

Monoolein (MO) cubosomes were investigated in terms of in vitro skin permeation enhancer of KIOM-MA-128 (MA-128), a natural product known to be efficacious against atopic dermatitis. First, an aqueous suspension of MA-128 was prepared by homogenizing the powder in Pluronic F-127 (a dispersant) solution in water. The Pluronic F-127 concentration and the pH have no significant effect on the size and the zeta potential of MA-128 particles. The mean diameters and the zeta potentials fell within 1000–1500 nm and ?10 to ?20 mV, respectively. The sedimentation rate of the particles was lower at a higher concentration of the polymeric dispersant, possibly because the polymeric surfactant can act as a spring and push away approaching particles. The size of MO cubosomes was tens to hundreds of nanometers and exhibited black and white stripes. Cumulative amount of MA-128 permeated through hairless mouse skin was obviously higher when the cubosome was included in the MA-128 suspensions. However, the cumulative permeation amount was inversely proportional to the content of cubosomes, when the contents of cubosome in the suspension increased from 0.5% to 2.0% with MA-128 concentrations kept constant (2%).     

Comparison of HPLC and MEEKC for Miconazole Nitrate Determination in Pharmaceutical Formulation

A simple solid phase extraction (SPE) method coupled with high performance liquid chromatography (HPLC) using UV detector and microemulsion electrokinetic chromatography (MEEKC) has been developed and compared for the quantitative determination of miconazole nitrate in pharmaceutical formulation. For HPLC method, two parameters were optimized, namely, the wavelength and the mobile phases. The optimized condition was at the 225 nm wavelength and the mobile phase of ACN:MeOH (90:10 v/v). There are seven MEEKC parameters that were optimized, in this research, which were applied to voltage, temperature, wavelength, sodium dodecyl sulfate (SDS) concentration, buffer pH, buffer concentration and butan-1-ol concentration. The optimum MEEKC condition was obtained using 86.35 % (w/w) 2.5 mM borate buffer pH 9, 0.25 % (w/w) SDS, 0.8 % (w/w) ethyl acetate, 6.6 % w/w butan-1-ol and 6.0 % (w/w) acetonitrile. The combination of SPE using a diol column with HPLC–UV and the MEEKC methods were successfully applied for the determination of miconazole nitrate in a pharmaceutical formulation with the recovery percentage of 98.35 and 92.50 %, respectively.

     

Formulation and evaluation of thermoreversible,mucoadhesive in situ intranasal gel of rizatriptan benzoate

The present study was aimed to formulate and evaluate in situ thermoreversible intranasal gel of an antimigraine drug rizatriptan benzoate. The poloxamer 407 and carbopol 934 were used as thermoreversible and mucoadhesive polymers respectively. The gels were prepared with cold method. The phase transition temperature was determined with visual method. The gels were evaluated for their pH, mucoadhesive strength, in vitro release and ex vivo drug permeation through goat nasal mucosa. The histopathological study of the nasal mucosa was carried out to check for its damage during drug permeation. The 18 % w/v poloxamer solution was found to be showing phase transition at physiologic conditions (34–35 °C). As the percentage of carbopol 934 was increased from 0.1 to 0.5 % w/v the gelling temperature was found to be decreased. All formulations were showing mucoadhesive strength above 4,000 dynes/cm². Drug permeation studies have indicated that the drug permeation rate can be increased by using carbopol 934 above 0.3 % w/v concentration. The histopathological evaluation of nasal mucosa after drug permeation study has not shown any evidence of damage. Thus in situ thermoreversible mucoadhesive gel of rizatriptan benzoate can be a promising approach to treat migraine.     

Preparation and evaluation of topical microemulsion system containing metronidazole for remission in rosacea

The aim of this study was to prepare a topical water-in-oil type microemulsion containing metronidazole and to compare its effectiveness with a commercial gel product in the treatment of rosacea. A pseudo-ternary phase diagram (K(m)=2:1) was constructed using lecithin/butanol/isopropyl myristate/water. The microemulsion was chosen from the microemulsion region in the phase diagram. The formulation was a water-in-oil type microemulsion (droplet size: 11.6 nm, viscosity: 457.3 mPa·s, conductivity: 1.5 μs/cm, turbidity: 6.89 NTU) and the addition of the metronidazole did not alter the properties of the system. The release experiment showed that the release rate of metronidazole from the commercial gel product was higher than that of the microemulsion. Stability experiments showed that the metronidazole microemulsion remained stable for at least 6 months; none of the characteristic properties of the microemulsion had changed, the system retained its clarity and there was no sign that crystallization of metronidazole has occurred. Microemulsion was compared to a gel product in a randomized, double-blind, baseline-controlled, split-face clinical trial for the treatment of patients. After the 6-week treatment period there was a statistically significant difference in reduction of the main symptoms of rosacea. Of the patients treated with the microemulsion, 17% experienced complete relief from inflammatory lesions, and 50% from erythema. The microemulsion resulted in complete relief in 38% of the patients with telangiectasia while the commercial product did not provide any relief of telangiectasia symptoms. In conclusion, the microemulsion containing metronidazole was found to be more effective in reducing the symptoms of rosacea compared to the commercial gel product.     

Comparison of HPLC and MEEKC for Miconazole Nitrate Determination in Pharmaceutical Formulation

A simple solid phase extraction (SPE) method coupled with high performance liquid chromatography (HPLC) using UV detector and microemulsion electrokinetic chromatography (MEEKC) has been developed and compared for the quantitative determination of miconazole nitrate in pharmaceutical formulation. For HPLC method, two parameters were optimized, namely, the wavelength and the mobile phases. The optimized condition was at the 225 nm wavelength and the mobile phase of ACN:MeOH (90:10 v/v). There are seven MEEKC parameters that were optimized, in this research, which were applied to voltage, temperature, wavelength, sodium dodecyl sulfate (SDS) concentration, buffer pH, buffer concentration and butan-1-ol concentration. The optimum MEEKC condition was obtained using 86.35 % (w/w) 2.5 mM borate buffer pH 9, 0.25 % (w/w) SDS, 0.8 % (w/w) ethyl acetate, 6.6 % w/w butan-1-ol and 6.0 % (w/w) acetonitrile. The combination of SPE using a diol column with HPLC–UV and the MEEKC methods were successfully applied for the determination of miconazole nitrate in a pharmaceutical formulation with the recovery percentage of 98.35 and 92.50 %, respectively.     

Enhancing percutaneous delivery of methotrexate using different types of surfactants

Regarding the potential severe toxicity associated with systemic administration of methotrexate (MTX), a topical formulation might be of greater utility for the treatment of psoriasis and other hyperproliferative skin disorders. One of the presumed reasons for the lack of clinical activity of topical methotrexate in psoriasis is insufficient percutaneous penetration necessary to inhibit epidermal DNA synthesis. The present study was undertaken to prepare a formulation to enhance skin penetration of MTX. For this mean, topical gel formulations were prepared and evaluated for MTX percutaneous absorption using rat skin and standard Franz diffusion cells. For enhancing percutaneous absorption, three surfactants (anionic, cationic and nonionic) were incorporated into formulations with different concentrations. Finally salicylic acid as a keratolytic material was added for more enhancement effect. The results showed that SLS (sodium lauryl sulphate) and alkyl benzyl dimethyl chloride did not show significant enhancement effect on the penetration of MTX. Transcutol was able to enhance transdermal absorption of MTX and the higher enhancement ratio was obtained with 2% (w/w) concentration of transcutol. Addition of salicylic acid increased this ratio. Prepared formulation containing transcutol 2% (w/w) and salicylic acid 6% (w/w) showed higher enhancement property and could be used clinically for local treatment of psoriasis.     

Synthesis of VO2 Nanopowders. Part I. Sol–Gel Processing of Vanadium Alkoxide Precursor Within Inverse Micelles

Hydrolysis and condensation of VO(Oi–Pr)₃ within inverse micelles containing aqueous ammonia catalyst is conducted under different reaction conditions as a synthesis strategy for preparing VO₂ nanoparticles having average diameter <100 nm. Sol–gel processing of VO(Oi–Pr)₃ to form V_xO_y gel particles is controlled by varying NH₃(aq) concentration and using oleic acid or acetic acid pre-treatments. Isolated V_xO_y gel nanoparticles are reduced to VO₂ nanoparticles by thermal annealing, although annealing conditions must be optimized for each batch of gel particles. VO₂ nanoparticles of average diameters 24 or 70 nm prepared by this method show an expected hysteretic semiconductor-to-metal phase transition near 68 °C.