Solutol HS Research Articles

Enhancement of Oral Bioavailability of E804 by Self-Nanoemulsifying Drug Delivery System (SNEDDS) in Rats

Indirubin and its derivatives have been shown to interrupt the cell cycle by inhibiting cyclin-dependent kinases, explaining their long-time use in traditional Chinese medicine for the treatment of chronic myelocytic leukemia. A potent derivative of indirubin, indirubin-3'-oxime 2,3-dihydroxypropyl ether (E804), has been shown to block the Src-Stat3 and Src-Stat5 signaling pathway in human cancer cells, inducing apoptosis. The anticancer effects of E804, however, cannot be easily examined in vivo because of its poor water solubility and low absorption. The aim of this study was to develop and evaluate a self-nanoemulsifying drug delivery system (SNEDDS) containing E804 for enhancing its solubility and bioavailability. Solubility of E804 was determined in various vehicles, and pseudoternary phase diagram was used to evaluate the self-emulsifying existence area. The SNEDDS composed of Capmul MCM (oil), Solutol HS 15 (surfactant), and polyethylene glycol 400 (cosurfactant) on the ratio of 20.5:62.5:16 loaded 1.5% of E804. The particle size of droplets was found to be 16.8 and 140 nm, and SNEDDS was stable after freeze-thaw cycles and upon dilution in HCl 0.1 N and pH 7.4 HBSS++. The ability of formulation for absorption enhancement was studied in rats in vivo after oral administration. The results showed that the developed SNEDDS increased the E804 bioavailability 984.23% compared with the aqueous suspension. Our studies for the first time show that the developed SNEDDS can be used as a possible formulation for E804 to improve its solubility and oral bioavailability.

Fatty acid methyl esters and Solutol HS 15 confer neuroprotection after focal and global cerebral ischemia.

We previously showed that palmitic acid methyl ester (PAME) and stearic acid methyl ester (SAME) are simultaneously released from the sympathetic ganglion and PAME possesses potent vasodilatory properties which may be important in cerebral ischemia. Since PAME is a potent vasodilator simultaneously released with SAME, our hypothesis was that PAME/SAME confers neuroprotection in rat models of focal/global cerebral ischemia. We also examined the neuroprotective properties of Solutol HS15, a clinically approved excipient because it possesses similar fatty acid compositions as PAME/SAME. Asphyxial cardiac arrest (ACA, 6 min) was performed 30 min after PAME/SAME treatment (0.02 mg/kg, IV). Solutol HS15 (2 ml/kg, IP) was injected chronically for 14 days (once daily). Histopathology of hippocampal CA1 neurons was assessed 7 days after ACA. For focal ischemia experiments, PAME, SAME, or Solutol HS15 was administered following reperfusion after 2 h of middle cerebral artery occlusion (MCAO). 2,3,5-Triphenyltetrazolium staining of the brain was performed 24 h after MCAO and the infarct volume was quantified. Following ACA, the number of surviving hippocampal neurons was enhanced by PAME-treated (68%), SAME-treated (69%), and Solutol-treated HS15 (68%) rats as compared to ACA only-treated groups. Infarct volume was decreased by PAME (83%), SAME (68%), and Solutol HS15 (78%) as compared to saline (vehicle) in MCAO-treated animals. PAME, SAME, and Solutol HS15 provide robust neuroprotection in both paradigms of ischemia. This may prove therapeutically beneficial since Solutol HS15 is already administered as a solublizing agent to patients. With proper timing and dosage, administration of Solutol HS15 and PAME/SAME can be an effective therapy against cerebral ischemia.

Design, characterization, and in vitro cellular inhibition and uptake of optimized genistein-loaded NLC for the prevention of posterior capsular opacification using response surface methodology

This study was to design an innovative nanostructured lipid carrier (NLC) for drug delivery of genistein applied after cataract surgery for the prevention of posterior capsular opacification. NLC loaded with genistein (GEN-NLC) was produced with Compritol 888 ATO, Gelucire 44/14 and Miglyol 812N, stabilized by Solutol(®) HS15 by melt emulsification method. A 2(4) central composite design of 4 independent variables was performed for optimization. Effects of drug concentration, Gelucire 44/14 concentration in total solid lipid, liquid lipid concentration, and surfactant concentration on the mean particle size, polydispersity index, zeta potential and encapsulation efficiency were investigated. Analysis of variance (ANOVA) statistical test was used to assess the optimization. The optimized GEN-NLC showed a homogeneous particle size of 90.16 nm (with PI=0.33) of negatively charged surface (-25.08 mv) and high encapsulation efficiency (91.14%). Particle morphology assessed by TEM revealed a spherical shape. DSC analyses confirmed that GEN was mostly entrapped in amorphous state. In vitro release experiments indicated a prolonged and controlled genistein release for 72 h. In vitro growth inhibition assay showed an effective growth inhibition of GEN-NLCs on human lens epithelial cells (HLECs). Preliminary cellular uptake test proved a enhanced penetration of genistein into HLECs when delivered in NLC.

In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for the poorly soluble drug fenofibrate

Fenofibrate is indicated in hypercholesterolemia and hypertriglyceridemia alone or combined (types IIa, IIb, III, IV, and V dyslipidemias). However, due to its low solubility in water, it has low bioavailability after oral administration. In order to improve the dissolution rate, fenofibrate was formulated into a self-microemulsifying drug delivery system (SMEDDS). We used pseudoternary phase diagrams to evaluate the area of microemulsification, and an in vitro dissolution test was used to investigate the dissolution rate of fenofibrate. The optimized formulation for in vitro dissolution and bioavailability assessment consisted of propylene glycol laurate (Lauroglycol FCC) (60%), macrogol-15-hydroxystearate (Solutol HS 15) (27%), and diethylene glycol monoethyl ether (Transcutol-P) (13%). The mean droplet size of the oil phase in the microemulsion formed by the SMEDDS was 131.1nm. The dissolution rate of fenofibrate from SMEDDS was significantly higher than that of the reference tablet. In vivo pharmacokinetics study of fenofibrate in beagles administered SMEDDS-A form resulted in a 3.7-fold increase in bioavailability as compared with the reference drug. Our studies suggested that the fenofibrate containing SMEDDS composition can effectively increase the solubility and oral bioavailability of poorly water-soluble drugs.

Pharmacokinetics of a self-microemulsifying drug delivery system of tacrolimus

This study evaluated the pharmacokinetics of tacrolimus (Tac) in a novel self-microemulsifying drug delivery system (SMEDDS) for improved oral administration. SMEDDS Tac consisted of ethyl oleate as the oily phase, Solutol HS 15 as the surfactant and glycofurol as the co-surfactant and contained 0.5mg/mL tacrolimus. Blood and tissue concentrations of tacrolimus from two study groups (oral application of SMEDDS Tac and Prograf®) were determined using ELISA technique following tacrolimus administration in rats. There was no difference between area under the whole blood concentration–time curve in the SEDDM Tac group and the Prograf® group. Maximum concentrations of the drug were three times higher (P<0.05) in the SEDDM Tac group accompanied by a 3-fold earlier peak time. Elimination half-life was significantly lower in the SEDDM Tac group. Application of SMEDDS Tac increased tissue accumulation. Already after 15min, Tac levels of small intestine, liver, kidney, spleen, heart and bone marrow were significantly higher in the SMEDDS Tac group than in the Prograf® group (P<0.05). However, the Tac concentration in the kidney was significantly lower in the SMEDDS Tac group. Formulation of SMEDDS did not affect blood-brain barrier function. The SMEDDS is a potentially useful method for a local delivery of Tac to target organs. The selection of the optimum SMEDDS Tac composition might have advantage as an alternative oral dosage form for Tac.

Preparation and in vitro evaluation of apigenin-loaded polymeric micelles

The objective of this study was to prepare apigenin-loaded polymeric micelles to improve the solubility of apigenin in water. The polymeric micelles composed of Pluronic P123 and Solutol HS 15 were prepared by a thin-film dispersion method and the formulation was optimized with a central composite design (CCD). The obtained micelles were spherical under transmission electron microscope (TEM) with an average diameter of 16.9nm, the entrapment efficiency and drug loading was 96.36% and 1.32%, respectively. The in vitro drug release study showed nearly 84% of apigenin was released from micelles within 36h, showing the sustained release property. Cell toxicity assay indicated that the cytotoxicity of apigenin-loaded polymeric micelles against HepG2 and MCF-7 cancer cell in vitro was remarkably higher than that of the free drug. All the results provided the evidence for the great potential of polymeric micelles as nanocarrier for apigenin as a poorly water soluble drug.

Improved Oral Delivery of Rosuvastatin by Using Self Nanoemulsifying Drug Delivery System

The aim of the present study was to develop a self nanoemulsifying drug delivery system (SNEDDS) for the improved oral delivery of Rosuvastatin, a lipid lowering agent. Captex 810D, based on the higher solubility of Rosuvastatin was selected as an oil phase. Mixture of permeation enhancers such as Solutol HS15 and Acconon MC8 was selected as surfactants for the formulation of SNEDDS. Formulated SNEDDS upon mixing with water, dispersed rapidly into fine droplets size ranging from 95-263nm. Further the SNEDDS was evaluated for self nanoemulsification time, precipitation, cloud point, morphology, in-vitro drug release and ex-vivo permeation. Formulation (F3) showed the globule size of 139nm, quick self nanoemulsifiation time (20 sec) and transparency (97%). Maximum drug release of 99.9% and higher drug permeation of 95% was observed with formulation F3 when compared with conventional tablet. The formulated SNEDDS can be used to improve the oral absorption and bioavailability of Rosuvastatin.

Formulation and characterization of Brucea javanica oil microemulsion for improving safety

Objective: This study engaged in investigation of optimal formulation, characteristics analysis of Brucea javanica oil microemulsion (BJOM) in order to address safety concerns and make recommendations for improvements in BJOM safety during clinical use in vivo.Methods: Pseudo-ternary phase diagram techniques were used to determine the appropriate ratio of surfactant, cosurfactant and oil phases. Subsequent stability testing of BJOM was performed by dilution, centrifugation and accelerated stability testing. The results were expounded through additional assessment utilizing the classical thermostat method to establish the shelf life of the material. These results were utilized to evaluate the safety of BJOM by haemolytic, irritative and allergic testing in vitro. In addition, the cytotoxicity of BJOM was examined using the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), with particular emphasis given to potential uses in cancer treatment.Results: The most suitable method of preparation for BJOM was found to be a one to one ratio (Km 1:1) of Solutol HS15 surfactant matched with sorbitol cosurfactant in the ratio. The microemulsion droplets of BJOM possessed a spherical shape, uniform size and average diameter of 23.8 nm. The expiration date of BJOM was found to be 568 d. The safety study demonstrated no hemolysis activity at the experimental BJOM concentrations; however, mild hemolysis was observed at higher concentrations of Brucea javanica oil emulsion (BJOE), a common commercially available product. Irritation observed upon BJOM treatment can be primarily attributed to Brucea javanica oil (BJO) with little influence of BJOM excipients. In addition, BJOM caused no observed hypersensitivity or other visible allergic reactions in guinea pigs. The anticancer activity curves of BJOM and BJOE demonstrate that both BJOM and BJOE inhibit Hela cells, with BJOM demonstrating significantly more dramatic anticancer activity.Conclusion: An optimal formulation of BJOM superior to commercially available products and safe for medical application such as intravenous injection has been outlined along with its anticancer activity rating.

Identification and Reduction of Matrix Effects Caused by Solutol Hs15 in Bioanalysis Using Liquid Chromatography/Tandem Mass Spectrometry

Ion suppression effect of dosing vehicle excipient Cremophor EL (CrEL) on the accuracy of liquid chromatography/ tandem mass spectrometry (LC-MS/MS) measurements was studied. Ion suppression cause significant errors in accuracy of the measured concentrations of test compounds, thereby invalidating the assessment of pharmacokinetic results. Using CrEL as a probe compound, the concentration-time profile of the excipient in plasma from rats dosed both orally and intravenously was determined. The most abundant molecular ions corresponding to PEG oligomers at m/z 828, 872, 916 and 960 with daughter ion at m/z 89 were selected for multiple reaction monitoring (MRM) in electrospray mode of ionization. Plasma concentrations of CrEL ranging from 0.50-1.0 mg/mL in the initial sampling points caused 2-10 fold ion suppression on most of the analytes studied. This can result in false rejection of compounds in a drug discovery screen. In this paper, various sample preparation methods, enhanced chromatographic selectivity, and alternative ionization methods were investigated as means to avoid or minimize ion suppression effects. The elimination of ion suppression effects was achieved by Liquid-Liquid Extraction (LLE) with hexane, TBME in Electrospray Ionisation (ESI) mode as sample preparation method. In contrast to ESI mode that had severe suppression effects from CrEL, atmospheric pressure chemical ionisation (APCI) mode is totally free of suppression effects. The mechanism of ion suppression caused by CrEL in relation to both liquid and gas phase reactions was discussed.

Neuroprotective effect of resveratrol prophylaxis on experimental retinal ischemic injury

The purpose of the present study was to investigate whether systemically administered resveratrol can protect against acute retinal ischemic reperfusion injury. Two groups of adult male Sprague Dawley rats (n = 6 per group) were used for this study. Resveratrol (30 mg/kg) or an equal volume of vehicle (30% Solutol HS 15 in 0.9% saline) was administered daily for 5 days via intraperitoneal injection. On the third day of treatment, retinal ischemic injury was induced by elevation of intraocular pressure for 45 min. Prior to resveratrol administration and one-week following ischemic insult, retinal function was measured by scotopic electroretinography (ERG). Retinas were harvested and morphologically analyzed one week after ischemic insult. ERG a- and b-wave amplitudes were significantly reduced following ischemic reperfusion injury. Resveratrol treatment attenuated ischemic-induced loss of retinal function. In control vehicle-treated rats, ischemic reperfusion injury elicited marked thinning of inner retinal layers. Resveratrol prophylactic treatment reduced ischemia-mediated thinning of the whole retina and in particular the inner retinal layers. Therefore, resveratrol may have therapeutic value for the management of retinal ischemic disorders.

Development and Evaluation of Tocopherol-Rich Argan Oil-Based Nanoemulsions as Vehicles Possessing Anticancer Activity

In recent years, diverse nanoemulsion vehicles (NEs) have been developed with vast potential for improving therapeutic index of clinically approved and experimental drugs. Using oils rich in omega-3 and omega-6 polyunsaturated fatty acids (PUFA), several promising nanoemulsion formulations have been developed recently for oral and systemic administration. The aim of our present work is to successfully develop and characterize optimized nanoemulsion platform, using the PUFA-rich argan oil that contain several important anti-inflammatory and antimitotic natural components. Using various emulsifying mixtures of polyethoxylated solutol HS-15 and polyethyleneglucol Vitamin E succinyl ester (TPGS), to form different NEs showing extended shelf-life stability. The physicochemical properties of prototype argan NEs were analyzed and utilizing a 32 full factorial design, followed by biocompatibility screen, using normal vascular myocytes and areolar fibroblasts. While 90-180 day stability of NEs correlated with TPGS:solutol surfactant blend ratios, adverse effects on integrity of test cultures were only noted at high TPGS content in the emulsifier system, exceeding 80%. Finally, the anti-proliferative efficacy of selected stable and acceptably biocompatible nanoscale TPGS-emulsified argan oil formulations was investigated using murine breast and colon carcinoma cells. The IC50 values of the combination of argan oil and TPGS (40-80% wt of emulsifiers) were 5-9 folds lower compared to TPGS-free and argan-oil free control NEs. Argan oil NE, stabilized with Vitamin E TPGS and solutol HS mixtures, demonstrated significant pro-apoptotic effect on both test cancer cell lines, indicating built-in anticancer properties for such NE platform, potentially enhancing overall antineoplastic effects of incorporated candidate chemotherapeutic agents.

Formulation and evaluation of microemulsion-based in situ ion-sensitive gelling systems for intranasal administration of curcumin

The purpose of our study was to develop a microemulsion-based in situ ion-sensitive gelling system for intranasal administration of curcumin. A new microemulsion composition for curcumin was optimized with the simple lattice design. And the microemulsion-based in situ ion-sensitive gelling system consisted of Capryol 90 as oil phase, Solutol HS15 as surfactant, Transcutol HP as cosurfactant and 0.3% DGG solution as water phase. The physicochemical properties such as morphology, droplet size distribution, zeta value and the in vitro release were investigated. In addition, the histological section studies on the reaction between the obtained formulation and nasal mucosa showed that the microemulsion-based in situ ion-sensitive gelling system could not produce obvious damage to nasal mucosa. The pharmacokinetics results showed that the absolute bioavailability of curcumin in the microemulsion-based in situ ion-sensitive gelling system was 55.82% by intranasal administration. And the brain targeting index (BTI) was 6.50, and in the tissue distribution experiment, the value of (AUCbrain/AUCblood) following intranasal administration was higher than that following intravenous administration, suggesting that the obvious brain targeting property by nasal delivery be attributed to a direct nose-to-brain drug transport. It can be concluded that the microemulsion-based in situ gelling as an effective and safe vehicle could greatly enhance the in vivo absorption and facilitate the delivery of curcumin to brain by intranasal administration.

Pharmaceutical Excipients Influence the Function of Human Uptake Transporting Proteins

Although pharmaceutical excipients are supposed to be pharmacologically inactive, solubilizing agents like Cremophor EL have been shown to interact with cytochrome P450 (CYP)-dependent drug metabolism as well as efflux transporters such as P-glycoprotein (ABCB1) and multidrug resistance associated protein 2 (ABCC2). However, knowledge about their influence on the function of uptake transporters important in drug disposition is very limited. In this study we investigated the in vitro influence of polyethylene glycol 400 (PEG), hydroxypropyl-β-cyclodextrin (HPCD), Solutol HS 15 (SOL), and Cremophor EL (CrEL) on the organic anion transporting polypeptides (OATP) 1A2, OATP2B1, OATP1B1, and OATP1B3 and the Na(+)/taurocholate cotransporting polypeptide (NTCP). In stably transfected human embryonic kidney cells we analyzed the competition of the excipients with the uptake of bromosulfophthalein in OATP1B1, OATP1B3, OATP2B1, and NTCP, estrone-3-sulfate (E(3)S) in OATP1A2, OATP1B1, and OATP2B1, estradiol-17β-glucuronide in OATP1B3, and taurocholate (TA) in OATP1A2 and NTCP cells. SOL and CrEL were the most potent inhibitors of all transporters with the strongest effect on OATP1A2, OATP1B3, and OATP2B1 (IC(50) < 0.01%). HPCD also strongly inhibited all transport proteins but only for substrates containing a sterane-backbone. Finally, PEG seems to be a selective and potent modulator of OATP1A2 with IC(50) values of 0.05% (TA) and 0.14% (E(3)S). In conclusion, frequently used solubilizing agents were shown to interact substantially with intestinal and hepatic uptake transporters which should be considered in drug development. However, the clinical relevance of these findings needs to be evaluated in further in vivo studies.

CriticalSorb™: enabling systemic delivery of macromolecules via the nasal route.

Systemic delivery of proteins via the nasal route has to date been limited by their poor absorption across the nasal mucosa, and the less than optimal tolerability of known permeation enhancers. We have recently developed a highly effective nasal delivery system (CriticalSorb™) based on Solutol HS15. Extensive toxicology studies have shown CriticalSorb™ to be very well tolerated, non-toxic and non-irritant. Cell culture and ex vivo-isolated tissue studies have shown it to promote transport of molecules mainly via transcellular but also to some extent, via paracellular routes. Pharmacokinetic/pharmacodynamic studies in rats, rabbits, non-human primates and recently in man have demonstrated significantly enhanced systemic delivery of nasally administered proteins including insulin (~6kDa) and human growth hormone (~22kDa), and pharmacodynamics similar to those after subcutaneous injection. CriticalSorb™ therefore opens up the possibility of developing nasal spray formulations for macromolecules such as proteins.

Physicochemical characterization and an injection formulation study of water insoluble ZCVI4-2, a novel NO-donor anticancer compound

ZCVI(4)-2 was a novel nitric oxide-releasing glycosyl derivative of oleanolic acid that displayed strong cytotoxicity selectively against human hepatocellular carcinoma in vitro and in vivo. In this study, ZCVI(4)-2 was characterized by FT-IR spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, Raman spectroscopy, hygroscopicity and stability. A high performance liquid chromatography method was also established for the quantitative determination of solubility and additional stability profile of ZCVI(4)-2. ZCVI(4)-2 was found to be an amorphous and stable solid with low solubility of less than 10 μg/mL. Based on the solubilization tests that included methods of cosolvency and micellization, the solution mixture of 5% Solutol HS-15, 5% 1, 2-propylene glycol and 5% anhydrous ethanol was determined to be the system for the preparation of the ZCVI(4)-2 early injection solution. The effect of pH, temperature, light and injectable isotonic glucose or NaCl solution on ZCVI(4)-2 injection was also investigated. Good stability was observed at all testing conditions. Under the conditions studied, the NO-releasing rate and amount of ZCVI(4)-2 from the early injection solution in rat plasma demonstrated a promising therapeutic efficacy while maintaining a good safety profile.

CriticalSorb™: A novel efficient nasal delivery system for human growth hormone based on Solutol HS15

The absorption enhancing efficiency of CriticalSorb™ for human growth hormone (MW 22kDa) was investigated in the conscious rat model. The principle absorption enhancing component of CriticalSorb™, Solutol® HS15, comprises polyglycol mono- and di-esters of 12-hydroxystearic acid combined with free polyethylene glycol. When administering hGH nasally in rats with increasing concentrations of Solutol® HS15, it was found that for a 10%w/v solution formulation a bioavailability of 49% was obtained in the first 2h after administration. Furthermore it was shown that the most effective ratio of Solutol® HS15 to hGH was 4:1 on a mg to mg basis. Histopathology studies in rats after 5days repeated nasal administration showed that Solutol® HS15 had no toxic effect on the nasal mucosa. These results have been confirmed in a 6month repeat nasal toxicity study in rats. It can be concluded that the principle absorption enhancing component of CriticalSorb™ – Solutol® HS15 – is a potent and non- toxic nasal absorption enhancer that warrants further development.

Self-emulsifying bifendate pellets: preparation, characterization and oral bioavailability in rats

In this study, a self-emulsifying pellet (SEP) was prepared in order to improve the bioavailability of bifendate (DDB). First, a liquid self-emulsifying drug delivery system (SEDDS) was formulated, and then further developed into the SEP by extrusion/spheronization technology using the reconstituted emulsion as the adhesive. The optimized liquid SEDDS consisted of Miglycol® 840, a mixture of Cremorphor® EL and Solutol HS® 15 (1:2, w/w), and Transcutol HP as the oil phase, the surfactant and the co-surfactant at a weight ratio of 40:45:15 (w/w/w), respectively. The SEP were prepared using a mixture of MCC, lactose, and mannitol (45:45:10, w/w/w) as solid adsorbents. The SEP with 40% (w/w) of the liquid SEDDS was round-shaped with a uniform size (800–1000 µm). There was no difference in droplet size between the emulsions obtained from the liquid SEDDS or the SEP (169.8 ± 6.3 nm and 163.7 ± 3.8 nm). Compared with that of DDB pills (less than 20%), in vitro release of DDB from the SEP (over 80% within 60 min) was significantly enhanced in 0.1N HCl, although slower than that of the liquid SEDDS (over 80% within 5 min). AUC of DDB of the SEP after oral administration in rats exhibited 2.36-fold greater than that of DDB pills and no significant difference compared with that of the liquid SEDDS. In conclusion, our studies illustrated that extrusion/spheronization technique could be a useful method to prepare this SEP and it could be a promising way for enhancing oral bioavailability of poorly water-soluble drugs.

In-situ phase transition from microemulsion to liquid crystal with the potential of prolonged parenteral drug delivery

This study is the first to investigate and demonstrate the potential of microemulsions (MEs) for sustained release parenteral drug delivery, due to phase transition behavior in aqueous environments. Phase diagrams were constructed with Miglyol 812N oil and a blend of (co)surfactants Solutol HS 15 and Span 80 with ethanol. Liquid crystal (LC) and coarse emulsion (CE) regions were found adjacent to the ME region in the water-rich corner of the phase diagram. Two formulations were selected, a LC-forming ME and a CE-forming ME and each were investigated with respect to their rheology, particle size, drug release profiles and particularly, the phase transition behavior. The spreadability in an aqueous environment was determined and release profiles from MEs were generated with gamma-scintigraphy. The CE-forming ME dispersed readily in an aqueous environment, whereas the LC-forming ME remained in a contracted region possibly due to the transition of ME to LC at the water/ME interface. Gamma-scintigraphy showed that the LC-forming ME had minimal spreadability and a slow release of 99mTc in the first-order manner, suggesting phase conversion at the interface. In conclusion, owing to the potential of phase transition, LC-forming MEs could be used as extravascular injectable drug delivery vehicles for prolonged drug release.

Effect of formulation compositions on niosomal preparations

This study was aimed to investigate the effects of molar ratio of cholesterol to Span 60 and stabilizers (Solutol HS 15 or dicetyl phosphate (DCP)) on the entrapment of methylene blue, a model hydrophilic drug. The niosomes were prepared by the film hydration method and characterized for drug entrapment efficiency (EE), vesicle size, zeta potential and thermal properties of niosomal membrane. It was found that niosomal vesicles possessed median diameter ranging from 0.35 to 1.85 μm. The niosomes that were formulated with lower molar ratios of cholesterol to Span 60 of 0.33 and 0.50 produced significantly higher EE with both stabilizers when compared to cholesterol to Span 60 molar ratios of 1.0 and above (p < 0.05). The EE of niosomes stabilized with DCP was significantly higher (p < 0.05) than those prepared with Solutol HS 15 except at a molar ratio of cholesterol to Span 60 of 0.33. In conclusion, with low molar ratios of cholesterol to Span 60, more drugs could be entrapped within the niosomes regardless of the type of stabilizers. Furthermore, EE and median diameter of niosomes containing DCP were higher than those stabilized with Solutol HS 15.

Novel aqueous nano-scaled formulations of oleic acid stabilized hydrophobic superparamagnetic iron oxide nanocrystals

Background: Novel aqueous nano-scaled formulations were developed for hydrophobic oleic acid stabilized monodisperse superparamagnetic magnetite nanocrystals.Methods: In the study, single and mixed lipid amphiphiles based on Cremophor RH-40 (Crem-RH-40), Solutol HS-15 (Sol-HS-15), Phospholipon-100H (PL-100H) and sucrose ester M-1695 (SE-M-1695) were employed at varying concentrations. Isotonicity and physiological pH adjustments were achieved by using 5% w/v mannitol in 10 mM pH 7.4 phosphate buffer. Mannitol also served as lyoprotectant for the freeze drying of selected formulation. The developed formulations were characterized by photon correlation spectroscopy (PCS) and asymmetric flow field flow fractionation methods for their size and size distributions and morphologies were examined by transmission electron microscopy (TEM). Moreover, the potential magnetic resonance imaging (MRI) contrast agent application of a selected formulation was investigated by 1H-NMR relaxometric measurements.Results: The results showed that stable formulations of the nanocrystals with hydrodynamic diameters generally below 100 nm were obtained. Among the developed formulations, the one prepared with 0.75% Crem-RH-40, 0.5% PL-100H and 0.25% SE-M-1695 had a mean hydrodynamic diameter of ~64 nm and zeta potential of −20 mV. This formulation exhibited low degree of aggregation, high level of incorporation of magnetite nanocrystals and very good stability profile over a period of 6 months. In addition, it showed transverse and longitudinal relaxivities of 221.8 and 32.1 s−1·mM−1, respectively with r2/r1 ratio of 6.9.Conclusion: This study revealed that mixed lipid-based amphiphiles allow stable aqueous formulations of the normally challenging hydrophobic magnetite nanocrystals with potential in vivo MRI contrast applications.