Long-term Survival, Tolerability, and Safety of First-Line Bevacizumab and FOLFIRI in Combination With Ginsenoside-Modified Nanostructured Lipid Carrier Containing Curcumin in Patients With Unresectable Metastatic Colorectal Cancer.

BACKGROUND: Colorectal cancer is the third most common malignant disease and the second leading cause of death worldwide. Previous studies showed improved bioavailability and cytotoxicity of ginsenoside-modified nanostructured lipid carrier containing curcumin (G-NLC) in human colon cancer cell lines. This study aimed to evaluate the safety and tolerability with long-term survival rates in patients with colorectal cancer with unresectable metastases after treatment with first-line bevacizumab/FOLFIRI (folinic acid, bolus/continuous fluorouracil, and irinotecan) in combination with a dietary supplement of G-NLC. METHODS: This study was a prospective, observational, single-group analysis. The enrolled patients had colorectal cancer with unresectable metastases and were administered bevacizumab and FOLFIRI in combination with daily oral G-NLC as first-line treatment. Overall survival, progression-free survival, tumor response, and adverse events were evaluated. RESULTS: A total of 44 patients were enrolled between 2015 and 2019. The median age was 65 (range 45-81) years and the sex ratio was 31:13 (male:female). The primary tumor locations were the colon (31 patients) and rectum (13 patients). The metastatic sites included, liver only (n = 20), lung only (n = 6), both liver and lung (n = 12), and others (n = 6). The median duration of curcumin supply was 7.9 (range 0.9-16.6) months. The most common grade 3 or higher adverse events were neutropenia (n = 15, 34.1%), followed by nausea (n = 4, 9.1%) and vomiting (n = 4, 9.1%). Within the median follow-up period of 22.8 months, the median overall survival was 30.7 months, and the median progression-free survival was 12.8 months. None of the patients achieved complete response (CR); however, 9 patients showed partial response (PR), and 3 patients underwent conversion surgery. CONCLUSIONS: Bevacizumab/FOLFIRI with G-NLC as first-line chemotherapy in patients with colorectal cancer with unresectable metastases presented comparable long-term survival outcomes with acceptable toxicity outcomes. Additional randomized controlled studies are needed to establish definitive conclusions regarding this new regimen for metastatic colorectal cancer.

Curcumin-Loaded Nanostructured Lipid Carrier Modified with Partially Hydrolyzed Ginsenoside.

The objective of the present study was to investigate the effect of partially hydrolyzed ginsenoside on the physicochemical properties and in vitro release of curcumin from phospholipid-based nanostructured lipid carrier (NLC). NLC formulas modified with partially hydrolyzed ginsenoside (NLC-PG) were prepared with different amounts of ginsenoside using the conventional hot-melt method. The average particle size of curcumin-loaded NLC-PG ranged from 150 to 200 nm, and polydispersity index was in the range of 0.101-0.177, indicating monodispersed particle size distribution. Optical microscopy showed no sedimentation or recrystallization of curcumin even at 10,000 µg/ml concentration as NLC-PG in distilled water, indicating significantly enhanced solubility. TEM image showed that the nanoparticles were monodispersed with a multilayered core/shell structure. X-ray diffraction and FTIR spectroscopy showed that curcumin was amorphous in the NLC-PG, and there was no interaction between curcumin and the excipients. In vitro release study using simulated gastric/intestinal fluid media revealed that the release rate (Jss) of curcumin from the NLC-PG increased as a function of the ginsenoside content in the lipid carrier. Moreover, the Jss of curcumin kept gradually increasing in the presence of lipase, whereas in the presence of viscozyme, it sharply increased until the ginsenoside content reached 9.09% and subsequently plateaued. Partially hydrolyzed ginsenoside increased the Jss of curcumin from curcumin-loaded NLC-PG and therefore may be useful for improving the bioavailability of curcumin.

In Vitro Cytotoxicity and Bioavailability of Ginsenoside-Modified Nanostructured Lipid Carrier Containing Curcumin.

Our aim was to investigate the cellular uptake, in vitro cytotoxicity and bioavailability of ginsenoside-modified nanostructured lipid carrier loaded with curcumin (G-NLC). The formulation was prepared by melt emulsification technique, in which water was added to the melted lipids and homogenized to give a uniform suspension of NLC (without ginsenoside) and G-NLC. Cellular uptake of curcumin in two colon cancer cell lines (HCT116 and HT29) was increased when administered using both NLC and G-NLC compared to control (curcumin dissolved into DMSO) as measured by fluorescence microscopy. Ginsenoside modification resulted in 2.0-fold and 1.4-fold increases in fluorescence intensity in HCT116 and HT29 cell lines, respectively, compared to plain NLC. In vitro cytotoxicity (assessed by MTT assay) had a dose-dependent relationship with curcumin concentration for both NLC and G-NLC. Although G-NLC was taken up more readily in HCT116 cells, ginsenoside modification did not produce a significant increase in cytotoxic effect; a significant increase was observed in HT29 cells. Oral administration of G-NLC in ten colon cancer patients produced an appreciable plasma level of unbound curcumin (2.9 ng/mL). In conclusion, introduction of ginsenoside into NLC enhanced the cellular uptake and cytotoxicity of curcumin as well as its oral bioavailability, and this strategy can be used to improve clinical outcomes in the treatment of colon cancer with similar genotype to HT29.

Ginsenoside improves physicochemical properties and bioavailability of curcumin-loaded nanostructured lipid carrier.

The aim of this study was to develop a ginsenoside-modified nanostructured lipid carrier (G-NLC) dispersion containing curcumin. The NLC was prepared by melt emulsification with slight modification process. Different G-NLC dispersion systems were prepared using lipid carrier matrix composed of ginsenoside, phosphatidylcholine, lysophosphatidylcholine, and hydrogenated bean oil. TEM image of the nanoparticles in the NLC dispersion showed core/shell structure, and there was corona-like layer surrounding the particles in the G-NLC. The mean particle size of G-NLC dispersion was in the range of about 300-500 nm and stayed submicron size up to 12 months. The in vitro release of curcumin was faster in pH 1.2 compared to pH 6.8 and it showed linear release pattern after lag time of 1 h. When the G-NLC dispersion was orally administered to rats, Cmax of the free curcumin was 15.2 and 32.3 ng/mL at doses of 50 and 100 mg/kg, respectively, while it was below quantification limit when curcumin was administered as of dispersion in distilled water. Based on these results, it is certain that ginsenoside modulated the NLC dispersion, leading to enduring shelf-life of the dispersion system and enhanced bioavailability. These results strongly suggest that ginsenoside holds a promising potential as a pharmaceutical excipient in the pharmaceutical industries to increase the utility of various bioactives.

Quercetin-Loaded Solid Lipid Nanoparticle Dispersion with Improved Physicochemical Properties and Cellular Uptake.

The objective of this study was to formulate and characterize properties of solid lipid nanoparticle (SLN) dispersion containing quercetin. SLN was prepared by ultrasonication method using tripalmitin and lecithin as lipid core and then the surface was coated with chitosan. Entrapment efficiency was greater than 99%, and mean particle size of SLN was 110.7 ± 1.97 nm with significant increase in the coated SLN (c-SLN). Zeta potential was proportionally increased and reached plateau at 5% of chitosan coating with respect to tripalmitin. Differential scanning calorimetry showed disappearance of endothermic peak of quercetin in SLNs, indicating conversion of crystalline state to amorphous state. FTIR study of SLNs showed no change in the spectrum of quercetin, which indicates that the lipid and chitosan were not incompatible with quercetin. When coating amount was greater than 2.5% of tripalmitin, particle size and zeta potential were very stable even at 40°C up to 90 days. All SLN dispersions showed significantly faster release profile compared to pure quercetin powder. At pH 7.0, the release rate was increased in proportion to the coating amount. Interestingly, at pH 3.0, chitosan coating of 5.0% or greater decreased the rate. Cellular uptake of quercetin was performed using Caco-2 cells and showed that all SLN dispersions were significantly better than quercetin dispersed in distilled water. However, cellular uptake of quercetin from c-SLN was significantly lower than that from uncoated SLN.

Skin permeation and retention of topical bead formulation containing tranexamic acid.

The objective of this study is to develop a topical bead formulation of tranexamic acid (TA) which can be used concomitantly with laser treatment. The bead formulation of TA (TAB) was successfully prepared by fluidized bed drying method. Physicochemical properties of the TAB were evaluated in terms of chemical stability of TA and differential scanning calorimetry. TA in the bead was stable up to six months at 25°C and existed as amorphous state. In vitro skin permeation and in vivo skin retention of TA in the beads were significantly higher compared to a commercial product. When the bead was dissolved into distilled water and applied concomitantly with laser treatment, the amount of TA retained in the skin in the in vivo study was inversely proportional to the energy levels of laser treatment, indicating absorption into subcutaneous tissue and drainage to systemic circulation. Therefore, when laser treatment is used concomitantly with TAB, energy level should be very carefully monitored to avoid possible adverse events associated with systemic side effects of TA.

Meta-analysis of the Efficacy and Safety of Secukinumab for the Treatment of Plaque Psoriasis.

BACKGROUND: In January 2015, US FDA approved secukinumab, a human interleukin-17A (IL-17A) antagonist, for the treatment of plaque psoriasis. OBJECTIVE: To provide unbiased drug information about the efficacy and safety of secukinumab for the treatment of moderate to severe plaque psoriasis by performing meta-analysis. METHODS: PubMed and EMBASE database searches were conducted. Among the literatures retrieved, relevant Phase III clinical trials were analyzed. Statistical analysis of the data was performed by RevMan. RESULTS: Four pivotal and three non-pivotal Phase III clinical trials were retrieved. All the trials evaluated the efficacy and safety of secukinumab for the treatment of moderate to severe plaque psoriasis with two co-primary endpoints: proportions of Psoriasis Area and Severity Index (PASI) responders and Investigator's Global Assessment (IGA) responders. The overall odd ratios for proportions of PASI responders and IGA responders in secukinumab-containing arm were 65.6 and 62.5 compared to the placebo arm, respectively. Secukinumab was superior to etanercept resulting in both of the odd ratios being 3.7 compared to the etanercept. Secukinumab was generally well tolerated during the one year trial. However, as with other monoclonal antibody medications, vulnerability of respiratory infection (especially nasopharyngitis) was reported as most common adverse event. CONCLUSIONS: Meta-analysis of the seven Phase III clinical trials resulted in superiority of secukinumab over etanercept in terms of the efficacy and safety. However, long-term safety data is lacking at this time so post-marketing surveillance should be performed for any adverse events associated with the use of this new biological medication.

Meta-analysis of the efficacy and safety of sofosbuvir for the treatment of hepatitis C virus infection.

BACKGROUND: Hepatitis C virus infection is a worldwide health problem and one of the leading causes of cirrhosis and hepatocellular carcinoma. Recently, sofosbuvir was introduced to the therapeutic arsenal against this virus, thereby paving the way for all-oral regimen. Aims of the review This study aimed to systematically analyze the efficacy and safety of sofosbuvir for the treatment of hepatitis C virus infection. METHOD: PubMed and EMBASE database searches were conducted using "sofosbuvir" as the search term. Phase III clinical studies retrieved from the two databases and resources posted on the Drug@FDA and ClinicalTrials.gov websites were evaluated with regard to outcomes of the efficacy and safety analyses of the drug. RESULTS: Eight Phase III clinical studies compared the efficacy and safety of sofosbuvir. When sofosbuvir replaced peginterferon which was used in the previous standard regimen, a superior sustained virologic response, as defined by a viral RNA load less than the lower limit of quantification 12 weeks after cessation of therapy, was obtained (74.3 vs. 66.7%, p < 0.05). The response improved even more (90.8 vs. 66.7%, p < 0.0001) when sofosbuvir was used as an add-on therapy to the standard regimen. The overall odds ratio to achieve the response in the sofosbuvir-containing arm of the eight clinical studies was 3.66 times greater (95% CI 3.00-4.46) than that of the standard regimen arm. During the eight clinical studies, adverse events were observed in 83.61 and 87.22% of the patients in the sofosbuvir and non-sofosbuvir arms, respectively, with the most frequent events being mild central nervous system symptoms such as fatigue, headache, and asthenia. CONCLUSIONS: Sofosbuvir was safe and effective in the treatment of hepatitis C virus genotype 1, 2, 3, or 4 infections. However, the lack of persistence of the sustained virologic response beyond the study duration and long-term safety concerns need to be addressed in future studies.

Enhanced skin permeation of 5α-reductase inhibitors entrapped into surface-modified liquid crystalline nanoparticles.

The objective of this study is to enhance skin permeation of finasteride and dutasteride for the treatment of androgenetic alopecia using surface-modified liquid crystalline nanoparticle (sm-LCN) dispersion. LCN entrapped with the drugs was prepared by using monoolein as a liquid crystal former, and surface modification was performed by treatment of the LCN dispersion with same volume of 1 % v/v acetic acid solution containing chitosan. Physicochemical properties of the LCN's were studied with regard to particle size, polydispersity index, zeta potential, and release of the drugs. Skin permeation of drugs entrapped into the LCN and sm-LCN was investigated with porcine abdominal skin using Franz diffusion cell. Cytotoxicity of the LCN's was also studied using human skin keratinocytes. The particle size and zeta potential of the LCN were 197.9 ± 2.5 nm and -20.2 ± 1.9 mV, respectively, and sm-LCN showed slightly bigger size and positive zeta potential due to the presence of thin coating on the surface of the nanoparticles. Compared to LCN, sm-LCN resulted in significantly enhanced skin permeation of the drugs whereas in vitro release was significantly reduced. Cell viability as a measure of cytotoxicity was above 80 % up to 20 µg/ml concentration of both LCN and sm-LCN. In conclusion, sm-LCN may provide a strategy to maximize therapeutic efficacy minimizing unwanted systemic side effects associated with the use of the drugs for the treatment of androgenetic alopecia.

Entrapment of curcumin into monoolein-based liquid crystalline nanoparticle dispersion for enhancement of stability and anticancer activity.

Despite the promising anticancer potential of curcumin, its therapeutic application has been limited, owing to its poor solubility, bioavailability, and chemical fragility. Therefore, various formulation approaches have been attempted to address these problems. In this study, we entrapped curcumin into monoolein (MO)-based liquid crystalline nanoparticles (LCNs) and evaluated the physicochemical properties and anticancer activity of the LCN dispersion. The results revealed that particles in the curcumin-loaded LCN dispersion were discrete and monodispersed, and that the entrapment efficiency was almost 100%. The stability of curcumin in the dispersion was surprisingly enhanced (about 75% of the curcumin survived after 45 days of storage at 40°C), and the in vitro release of curcumin was sustained (10% or less over 15 days). Fluorescence-activated cell sorting (FACS) analysis using a human colon cancer cell line (HCT116) exhibited 99.1% fluorescence gating for 5 µM curcumin-loaded LCN dispersion compared to 1.36% for the same concentration of the drug in dimethyl sulfoxide (DMSO), indicating markedly enhanced cellular uptake. Consistent with the enhanced cellular uptake of curcumin-loaded LCNs, anticancer activity and cell cycle studies demonstrated apoptosis induction when the cells were treated with the LCN dispersion; however, there was neither noticeable cell death nor significant changes in the cell cycle for the same concentration of the drug in DMSO. In conclusion, entrapping curcumin into MO-based LCNs may provide, in the future, a strategy for overcoming the hurdles associated with both the stability and cellular uptake issues of the drug in the treatment of various cancers.

Enhanced topical delivery of finasteride using glyceryl monooleate-based liquid crystalline nanoparticles stabilized by cremophor surfactants.

The aim of this study was to investigate the capability of two surfactants, Cremophor RH 40 (RH) and Cremophor EL (EL), to prepare liquid crystalline nanoparticles (LCN) and to study its influence on the topical delivery of finasteride (FNS). FNS-loaded LCN was formulated with the two surfactants and characterized for size distribution, morphology, entrapment efficiency, in vitro drug release, and skin permeation/retention. Influence of FNS-loaded LCN on the conformational changes on porcine skin was also studied using attenuated total reflectance Fourier-transform infrared spectroscopy. Transmission electron microscopical image confirmed the formation of LCN. The average particle size of formulations was in the range of 165.1-208.6 and 153.7-243.0 nm, respectively. The formulations prepared with higher surfactant concentrations showed faster release and significantly increased skin permeation. Specifically, LCN prepared with RH 2.5% presented higher permeation flux (0.100 ± 0.005 µgcm(-2)h(-1)) compared with lower concentration (0.029 ± 0.007 µgcm(-2)h(-1)). Typical spectral bands of lipid matrix of porcine skin were shifted to higher wavenumber, indicating increased degree of disorder of the lipid acyl chains which might cause fluidity increase of stratum corneum. Taken together, Cremophor surfactants exhibited a promising potential to stabilize the LCN and significantly augmented the skin permeation of FNS.

Evaluation of the effect of tacrolimus-loaded liquid crystalline nanoparticles on psoriasis-like skin inflammation.

Psoriasis is a chronic relapsing inflammatory skin disorder affecting 2-3% of world population. In present context, a novel topical formulation that could effectively deliver tacrolimus for psoriasis treatment would be of great interest. Liquid crystalline nanoparticle (LCN) is one of the potential drug delivery systems for topical drug delivery. Herein, the effects of tacrolimus-loaded LCNs on in vitro skin permeation and retention as well as on in vivo psoriasis-like skin inflammation are studied. Characterization of nanoparticles included particle size and entrapment efficiency analysis that presented nanoparticles of 149.1 nm for monoolein-based and 204.3 nm for oleic acid added monoolein-based nanoparticles with entrapment efficiency of tacrolimus above 99%. Skin permeation and retention study has revealed a significant increase in the amount of tacrolimus permeated and retained by the use of LCNs. Tacrolimus-loaded LCNs are more effective in the treatment of psoriasis-like skin inflammation as compared to tacrolimus dissolved in propylene glycol. Hence, this study provides a basis for possible applicability of tacrolimus-loaded LCNs in the treatment of psoriasis.

Self-nanoemulsifying drug delivery system of lutein: physicochemical properties and effect on bioavailability of warfarin.

Objective of present study was to prepare and characterize self-nanoemulsifying drug delivery system (SNEDDS) of lutein and to evaluate its effect on bioavailability of warfarin. The SNEDDS was prepared using an oil, a surfactant, and co-surfactants with optimal composition based on pseudo-ternary phase diagram. Effect of the SNEDDS on the bioavailability of warfarin was performed using Sprague Dawley rats. Lutein was successfully formulated as SNEDDS for immediate self-emulsification and dissolution by using combination of Peceol as oil, Labrasol as surfactant, and Transcutol-HP or Lutrol-E400 as co-surfactant. Almost complete dissolution was achieved after 15 min while lutein was not detectable from the lutein powder or intra-capsule content of a commercial formulation. SNEDDS formulation of lutein affected bioavailability of warfarin, showing about 10% increase in Cmax and AUC of the drug in rats while lutein as non-SNEDDS did not alter these parameters. Although exact mechanism is not yet elucidated, it appears that surfactant and co-surfactant used for SNEDDS formulation caused disturbance in the anatomy of small intestinal microvilli, leading to permeability change of the mucosal membrane. Based on this finding, it is suggested that drugs with narrow therapeutic range such as warfarin be administered with caution to avoid undesirable drug interaction due to large amount of surfactants contained in SNEDDS.

Optimization of self-microemulsifying drug delivery system for telmisartan using Box-Behnken design and desirability function.

OBJECTIVES: To develop and optimize the novel self-microemulsifying drug delivery system (SMEDDS) formulation for enhanced water solubility and bioavailability of telmisartan (TMS) using the Box-Behnken design (BBD) and desirability function. METHOD: TMS-SMEDDS formulation consisted of the mixture of oil (Peceol), surfactant (Labrasol), co-surfactant (Transcutol), TMS and triethanolamine. A three-level BBD was applied to explore the main effect, interaction effect and quadratic effect of three independent variables, including the amount of Peceol (X1 ), Labrasol (X2 ) and Transcutol (X3 ). Determined conditions were 20 < X1 < 40, 50 < X2 < 80 and 5 < X3 < 30. The response variables were droplet size (Y1 ), polydispersity index (Y2 ) and dissolution percentage of TMS after 15 min (Y3 ). KEY FINDINGS: The optimized conditions were 28.93, 80 and 28.08 (mg) for X1 , X2 and X3 , respectively, and the response variables were predicted to be 159.8 nm, 0.241 and 85.8% for Y1 , Y2 and Y3 , respectively. The actual values from the optimized formulation showed good agreement with predicted values. The optimized TMS-SMEDDS formulation showed faster drug dissolution rate and higher bioavailability than TMS powder. CONCLUSIONS: Our results suggest that response surface methodology using BBD and desirability function is a promising approach to understand the effect of SMEDDS variables and to optimize the formulation.

Design and in vitro evaluation of finasteride-loaded liquid crystalline nanoparticles for topical delivery.

In this study, liquid crystalline nanoparticles (LCN) have been proposed as new carrier for topical delivery of finasteride (FNS) in the treatment of androgenetic alopecia. To evaluate the potential of this nanocarrier, FNS-loaded LCN was prepared by ultrasonication method and characterized for size, shape, in vitro release, and skin permeation-retention properties. The particle size ranged from 153.8 to 170.2 nm with a cubical shape and exhibited controlled release profile with less than 20% of the drug released in the first 24 h. The release profile was significantly altered with addition of different additives. Formulation with lower monoolein exhibited higher skin permeation with a flux rate of 0.061±0.005 µg cm(-2) h(-1) in 24 h. The permeation however, significantly increased with glycerol, propylene glycol, and polyethylene glycol 400, while it declined for the addition of oleic acid. A similar trend was observed with skin retention study. In conclusion, FNS-loaded LCN could be advocated as a viable alternative for oral administration of the drug.

The efficacy and safety of liraglutide.

AIM OF THE REVIEW: To systematically analyze the efficacy and safety of liraglutide for the treatment of diabetes mellitus in comparison to other mono- and combination therapies. METHOD: PubMed (any date) and EMBASE (all years) search was conducted with liraglutide as a search term. Phase III clinical trials retrieved by the two databases and resources posted in Drug@FDA website were evaluated with regard to outcomes of efficacy and safety. RESULTS: Eight Phase III clinical studies compared the efficacy and safety of liraglutide to other monotherapies or combinations. Liraglutide as monotherapy in doses of 0.9 mg or above showed a significantly superior reduction in HbA1C compared to monotherapies with glimepiride or glyburide. When liraglutide was used as add-on therapy to glimepiride in doses of 1.2 mg or above, the reduction of HbA1C was greater than that in the combination therapy of glimepiride and rosiglitazone. However, liraglutide as add-on therapy to metformin failed to show benefit over combination of metformin and glimepiride. Triple therapy of using liraglutide in addition to metformin plus either glimepiride or rosiglitazone resulted in additional benefit in HbA1C reduction. Most common adverse events were gastrointestinal disturbance such as nausea, vomit, diarrhea, and constipation. During the eight clinical studies, six cases of pancreatitis and five cases of cancer were reported in liraglutide arm, whereas there was one case of each of pancreatitis in exenatide and glimepiride arms, respectively, and one case of cancer in metformin plus sitagliptin arm. CONCLUSION: Liraglutide is a new therapeutic option to improve glycemic control in patients with type 2 diabetes. However, the present lack of evidence of durability of efficacy and long-term safety appear to limit its utility in the general treatment of type 2 diabetes at this time.

Enhanced oral bioavailability of curcumin via a solid lipid-based self-emulsifying drug delivery system using a spray-drying technique.

In this study, a novel liquid self-emulsifying drug delivery system (SEDDS) containing curcumin was formulated and further developed into a solid form by a spray drying method using Aerosil 200 as the solid carrier. The optimum liquid SEDDS consisted of Lauroglycol Fcc, Labrasol and Transcutol HP as the oil phase, the surfactant and the co-surfactant at a weight ratio of 15.0 : 70.8 : 14.2 (w/w/w), respectively. There was no difference in droplet size between the emulsions obtained from the liquid and solid forms of SEDDS. Solid state characterization of the solid SEDDS was performed by scanning electron micrograph (SEM), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The drug formulated in the solid SEDDS was quickly and completely dissolved within 5 min, both in 0.1 N HCl and phosphate buffer pH 6.8 dissolution media, whereas crude curcumin powder was significantly less dissoluble. The solid SEDDS formulation was stable for at least 3 months at 40°C with 75% relative humidity. After oral administration to rats, curcumin in the solid SEDDS resulted in significant improvement in in vivo absorption compared with that of curcumin powder. As the dose of curcumin formulated in solid SEDDS increased from 25 to 100 mg/kg, the C(max) and area under the drug concentration time curve (AUC) of curcumin were increased by 4.6 and 7.6 times, respectively. However, the over-proportional increase in the AUC in the higher dose group might be due to underestimation of AUC in the lower dose group. In conclusion, this solid SEDDS is a promising solid dosage form for poorly water-soluble curcumin.

Solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein.

The objectives of this study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine (PC), an endogenous phospholipid with excellent in vivo solubilization capacity, as oil phase for the delivery of bioactive carotenoid lutein, by spray drying the SNEDDS (liquid system) containing PC using colloidal silica (Aerosil® 200 VV Pharma) as the inert solid carrier, and to evaluate the enhanced bioavailability (BA) of lutein from S-SNEDDS. The droplet size analyses revealed droplet size of less than 100 nm. The solid state characterization of S-SNEDDS by SEM, DSC, and XRPD revealed the absence of crystalline lutein in the S-SNEDDS. The bioavailability study performed in rabbits resulted in enhanced values of C(max) and AUC for S-SNEDDS. The enhancement of C(max) for S-SNEDDS was about 21-folds and 8-folds compared with lutein powder (LP) and commercial product (CP), respectively. The relative BA of S-SNEDDS compared with CP or LP was 2.74-folds or 11.79-folds, respectively. These results demonstrated excellent ability of S-SNEDDS containing PC as oil phase to enhance the BA of lutein in rabbits. Thus, S-SNEDDS containing PC as oil phase could be a useful lipid drug delivery system for enhancing the BA of lutein in vivo.

Novel self-nanoemulsifying drug delivery system for enhanced solubility and dissolution of lutein.

Self-nanoemulsifying drug delivery system (SNEDDS) containing oil (Phosal 53 MCT), surfactant (Labrasol), and cosurfactant (Transcutol-HP or Lutrol-E400) was prepared to enhance solubility and dissolution of lutein. Ternary phase diagram of the SNEDDS was constructed to identify the self-emulsifying regions following which the percentage of oil, surfactant, and cosurfactant in the SNEDDS were optimized in terms of emulsification time and mean emulsion droplet size. The optimized SNEDDS consists of 25% oil, 60% surfactant, and 15% cosurfactant. When measured using USP XXIII dissolution apparatus II, the emulsification time of the SNEDDS prepared with Transcutol-HP as cosurfactant was less than 20 sec, and it was 20-30 sec in the SNEDDS prepared with Lutrol-E400. Mean emulsion droplet size was slightly smaller when Transcutol-HP was used as cosurfactant (80 +/- 6 nm), compared to when Lutrol- E400 was used (93 +/- 6 nm). Dissolution of lutein from the solid SNEDDS (physical mixture of the optimized SNEDDS and Aerosil 200) took place immediately (less than 5 min) in distilled water, and, once dissolved, no precipitation or aggregation of the drug were observed. In contrast, no drug was released from lutein powder or from the commercial product (Eyelac(R)) until 3 h of the study duration.

Plerixafor for stem cell mobilization in patients with non-Hodgkin's lymphoma and multiple myeloma.

OBJECTIVE: To evaluate the literature characterizing the mechanism of action, pharmacokinetics, pharmacodynamics, and therapeutic efficacy of plerixafor for hematopoietic stem cell (HSC) mobilization for autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) or multiple myeloma. DATA SOURCES: A PubMed search (1966-September 2009) was conducted using the key words plerixafor and AMD3100. Manufacturer's prescribing information was also used. STUDY SELECTION AND DATA EXTRACTION: English-language articles were selected and data were extracted with a focus on clinical studies of HSC mobilization in patients with NHL or multiple myeloma. DATA SYNTHESIS: Plerixafor exerts its effect by reversibly blocking the ability of HSC to bind to the bone marrow matrix. When used with granulocyte colony-stimulating factor (G-CSF), plerixafor helps increase the number of HSCs in the peripheral blood, where they can be collected for use in autologous transplantation. In clinical studies, plerixafor was rapidly absorbed after subcutaneous injection, reaching a maximum plasma concentration at approximately 0.5 hours. Plerixafor is renally excreted as the parent drug, with an elimination half-life ranging from 3 to 5 hours. Plerixafor increases circulating CD34+ cells in the peripheral blood, with a peak effect about 6-9 hours after subcutaneous administration. An approximate 2- to 3-fold increase in the CD34+ cell count is seen by the first dose of plerixafor after 4 consecutive days of G-CSF treatment. In 2 Phase 3 studies in patients with NHL or multiple myeloma, addition of plerixafor to G-CSF resulted in a higher CD34+ cell collection with fewer apheresis days, but failed to show better graft durability or overall patient survival for up to 12 months of follow-up. CONCLUSIONS: Clinical trials have demonstrated that the addition of plerixafor to G-CSF was beneficial for HSC mobilization to peripheral blood for collection and subsequent transplantation in patients with NHL or multiple myeloma. Further studies should assess the benefit of the additive use of plerixafor on clinical outcomes.