Medium and long-chain structured triacylglycerol enhances vitamin D bioavailability in an emulsion-based delivery system: combination of in vitro and in vivo studies.

Vitamin D (VitD) is an essential fat-soluble micronutrient required for maintaining and regulating calcium homeostasis. Although sunlight can provide VitD, epidemiological studies indicate that the occurrence of VitD deficiency and insufficiency is widespread. Lipids are required at all stages of VitD digestion and absorption. In this research two different medium and long-chain triacylglycerol structures, possessing identical fatty acid composition lipids, namely structured triacylglycerol (STG), and physical mixtures of medium/long-chain triacylglycerol (MCT/LCT), were selected. Our results demonstrated that STG had a significant VitD bioavailability compared to MCT/LCT. In terms of the lipid digestion and absorption, the extent of the higher free fatty acid released (69.42%, p < 0.05), extent of lipolysis (89.28%, p < 0.05), lipolysis rate (0.06 s-1, p < 0.05), and the ratio of the long-chain fatty acid to medium-chain fatty acid of STG (4.8, p < 0.05), result in a higher capacity for accommodating VitD when forming mixed micelles (61.31%, p < 0.05). An in vivo animal study also demonstrated that STG significantly increases the delivery ability of VitD (18.75 ng mL-1, p < 0.05). The findings of this work may have unique applications for designing novel interesterified lipids with an effective delivery capacity for fat-soluble nutrients.

The effect of a 6-month ketogenic medium-chain triglyceride supplement on plasma cardiometabolic and inflammatory markers in mild cognitive impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is often accompanied by metabolic abnormalities and inflammation that might play a role in the development of cognitive impairment. The use of ketogenic medium-chain triglycerides (kMCT) to improve cognition in this population has shown promising results but remains controversial because of the potentially detrimental effect of elevated intake of saturated fatty acids on cardiovascular (CV) health and perhaps inflammatory processes. The primary aim of this secondary data analysis report is to describe changes in cardiometabolic markers and peripheral inflammation during a 6-month kMCT intervention in MCI. METHODS: Thirty-nine participants with MCI completed the intervention of 30 g/day of either a kMCT drink or calorie-matched placebo (high-oleic acid) for 6 months. Plasma concentrations of cardiometabolic and inflammatory markers were collected before (fasting state) and after the intervention (2 h following the last drink). RESULTS: A mixed model ANOVA analysis revealed a time by group interaction for ketones (P < 0.001), plasma 8:0 and 10:0 acids (both P < 0.001) and IL-8 (P = 0.002) with follow up comparison revealing a significant increase in the kMCT group (+48%, P = 0.005), (+3,800 and +4,900%, both P < 0.001) and (+147%, P < 0.001) respectively. A main effect of time was observed for insulin (P = 0.004), triglycerides (P = 0.011) and non-esterified fatty acids (P = 0.036). CONCLUSION: Under these study conditions, 30 g/d of kMCT taken for six months and up to 2-hour before post-intervention testing had minimal effect on an extensive profile of circulating cardiometabolic and inflammatory markers as compared to a placebo calorie-matched drink. Our results support the safety kMCT supplementation in individuals with MCI. The clinical significance of the observed increase in circulating IL-8 levels is presently unknown and awaits future studies.

The impact of emulsion droplet size on in vitro lipolysis rate and in vivo plasma uptake kinetics of triglycerides and vitamin D3 in rats.

Emulsions play an important role in the process of triglyceride (TG) digestion (lipolysis). Through emulsification, the oil-water interface is increased by orders of magnitude. This often leads to faster and more efficient lipolysis, which is potentially beneficial for the intestinal uptake of oils and lipophilic compounds. In this paper, we first examined the effect of emulsion droplet size on the in vitro lipolysis rate. Then an in vivo experiment was performed, to examine the plasma uptake kinetics of TGs and vitamin D3 (vitD3) over a 24 hours period after oral administration of the emulsions in rats. Basic corn oil emulsions loaded with vitD3 were prepared using polysorbate 80 as the emulsifier, with three different droplet sizes (D[3,2]): ∼3 µm (large), ∼1 µm (medium) and ∼0.3 µm (small). In vitro lipolysis experiments showed, as expected, that smaller droplets were lipolyzed more rapidly. However, the medium emulsion had by far the highest rate of lipolysis per surface area. This was attributed to bile salt limitation, polysorbate 80 lipolysis inhibition and TG digestion product accumulation. In vivo, the two smallest emulsions showed the highest uptake (Cmax and AUC) of vitD3 and TG, while the largest emulsion and bulk oil control showed lower values. However, only the (incremental) TG plasma values and kinetics displayed some statistically significant differences. These findings may have relevance for the formulation of functional foods/beverages or delivery units containing oils or lipophilic bioactives.

The Pharmacokinetics of Triheptanoin and Its Metabolites in Healthy Subjects and Patients With Long-Chain Fatty Acid Oxidation Disorders.

Long-chain fatty acid oxidation disorders (LC-FAODs) are a group of life-threatening autosomal recessive disorders caused by defects in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids into energy. Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of 3 fatty acids with 7 carbons each on a glycerol backbone developed to treat adult and pediatric patients with LC-FAODs. The pharmacokinetics of triheptanoin and circulating metabolites were explored in healthy subjects and patients with LC-FAODs using noncompartmental analyses. Systemic exposure to triheptanoin following an oral administration was negligible, as triheptanoin is extensively hydrolyzed to glycerol and heptanoate in the gastrointestinal tract. Multiple peaks for triheptanoin metabolites were observed in the plasma following oral administration of triheptanoin, generally coinciding with the time that meals were served. Heptanoate, the pharmacologically active metabolite of triheptanoin supplementing energy sources in patients with LC-FAODs, showed the greatest exposure among the metabolites of triheptanoin in human plasma following oral administration of triheptanoin. The exposure of heptanoate was approximately 10-fold greater than that of beta-hydroxypentoate, a downstream metabolite of heptanoate. Exposure to triheptanoin metabolites appeared to increase following multiple doses as compared with the single dose, and with the increase in triheptanoin dose levels.

Assessing the Impact of Factors that Influence the Ketogenic Response to Varying Doses of Medium Chain Triglyceride (MCT) Oil.

Objectives, Design, Setting: The ketogenic effect of medium chain triglyceride (MCT) oil offers potential for Alzheimer's disease prevention and treatment. Limited literature suggests a linear B-hyroxybutyrate (BHB) response to increasing MCT doses. This pharmacokinetic study evaluates factors affecting BHB response in three subject groups. PARTICIPANTS: Healthy subjects without cognitive deficits <65years, similarly healthy subjects >=65years, and those with Alzheimer's Disease were assessed. INTERVENTION: Different doses (0g,14g, 28g, 42g) of MCT oil (99.3% C8:0) were administered, followed by fasting during the study period. MEASUREMENTS: BHB measured by finger prick sampling hourly for 5 hours after ingestion. Each subject attended four different days for each ascending dose. Data was also collected on body composition, BMI, waist/hip ratio, grip strength, gait speed, nutrient content of pre-study breakfast and side effects. RESULTS: Twenty-five participants: eight healthy; average age of 44yr (25-61), nine healthy; 79yr (65-90) and eight with AD; 78.6yr (57-86) respectively. Compiled data showed the expected linear dose response relationship. No group differences, with baseline corrected area under the blood vs. time curve (r2=0.98) and maximum concentrations (r2=0.97). However, there was notable individual variability in maximum BHB response (42g dose: 0.4 -2.1mM), and time to reach maximum BHB response both, within and between individuals. Variability was unrelated to age, sex, sarcopenic or AD status. Visceral fat, BMI, waist/hip ratio and pretest meal CHO and protein content all affected the BHB response (p<0.001). CONCLUSION: There was a large inter-individual variability, with phenotype effects identified. This highlights challenges in interpreting clinical responses to MCT intake.

Blood clearance kinetics and organ delivery of medium-chain triglyceride and fish oil-containing lipid emulsions: Comparing different animal species.

BACKGROUND & AIMS: Medium-chain triglycerides (TG) (MCT) and fish oil (FO) TG are incorporated as the core TG component into intravenous (IV) lipid emulsions for infusion in parenteral nutrition. Bolus injections of IV emulsions, on the other hand, have emerged as a novel therapeutic approach to treat various acute disorders. However, intravascular metabolism and organ delivery of acute IV injection of emulsions containing both MCT and FO are not fully defined, nor have they been characterized across common experimental animal models. We characterized and compared blood clearance kinetics and organ distribution of bolus injections of MCT/FO emulsions among different animal species. We also examined whether sex differences or feeding status can affect catabolic properties of MCT/FO lipid emulsions. DESIGN: Blood clearance rates of lipid emulsions with specific TG composition were compared in rats IV injected with [3H]cholesteryl hexadecyl ether labeled pure n-6 long-chain (LCT) and n-3 FO TG lipid emulsions, or emulsions containing MCT and FO at different ratios (wt/wt), which include 8:2 (80% MCT: 20% FO), 5:4:1 (50% MCT: 40% LCT: 10% FO) and SMOF (30% LCT: 30% MCT: 25% olive oil: 10% FO). Dose-response effects (0.016 mg-1.6 mg TG/g body weight) of the MCT/FO 8:2 emulsions on blood clearance properties and organ delivery were determined in both mice and rats. Blood clearance kinetics and organ uptake of MCT/FO 8:2 emulsions were compared between male and female rats and between fed and fasted rats. Changes in plasma lipid profiles after acute injections of MCT/FO 8:2 lipid emulsion at different doses (0.043, 0.133, and 0.4 mg TG/g body weight) were characterized in non-human primates (Cynomolgus monkeys). RESULTS: MCT/FO 8:2 emulsion was cleared faster in rats when compared with other emulsions with different TG contents. Mice had faster blood clearance and higher fractional catabolic rates (FCR) when compared with the rats injected with MCT/FO 8:2 emulsions regardless of the injected doses. Mice and rats had similar plasma TG and free fatty acid (FFA) levels after low- or high-dose injections of the MCT/FO emulsion. Tissue distribution of the MCT/FO 8:2 lipid emulsion are comparable between mice and rats, where liver had the highest uptake per recovered dose among all organs (>60%). Feeding status and sex differences did not alter the blood clearance rate of the MCT/FO 8:2 emulsion in rats. In a nonhuman primate model, dose-response increases in plasma TG and FFA were observed after IV injection of MCT/FO 8:2 emulsions within the 1st 10 min. CONCLUSION: A lipid emulsion containing both MCT and FO TG is cleared rapidly in blood and readily available for organ uptake in rodent and primate animal models. Characterization of the blood clearance properties of the MCT/FO 8:2 emulsion administered in various animal models may provide further insight into the safety and efficacy profiles for future therapeutic use of bolus injections of MCT/FO emulsions in humans.

Acute injection of a DHA triglyceride emulsion after hypoxic-ischemic brain injury in mice increases both DHA and EPA levels in blood and brain✰.

We recently reported that acute injection of docosahexaenoic acid (DHA) triglyceride emulsions (tri-DHA) conferred neuroprotection after hypoxic-ischemic (HI) injury in a neonatal mouse stroke model. We showed that exogenous DHA increased concentrations of DHA in brain mitochondria as well as DHA-derived specialized pro-resolving mediator (SPM) levels in the brain. The objective of the present study was to investigate the distribution of emulsion particles and changes in plasma lipid profiles after tri-DHA injection in naïve mice and in animals subjected to HI injury. We also examined whether tri-DHA injection would change DHA- and eicosapentaenoic acid (EPA)-derived SPM levels in the brain. To address this, neonatal (10-day-old) naïve and HI mice were injected with radiolabeled tri-DHA emulsion (0.375 g tri-DHA/kg bw), and blood clearance and tissue distribution were analyzed. Among all the organs assayed, the lowest uptake of emulsion particles was in the brain (<0.4% recovered dose) in both naïve and HI mice, while the liver had the highest uptake. Tri-DHA administration increased DHA concentrations in plasma lysophosphatidylcholine and non-esterified fatty acids. Additionally, treatment with tri-DHA after HI injury significantly elevated the levels of DHA-derived SPMs and monohydroxy-containing DHA-derived products in the brain. Further, tri-DHA administration increased resolvin E2 (RvE2, 5S,18R-dihydroxy-eicosa-6E,8Z,11Z,14Z,16E-pentaenoic acid) and monohydroxy-containing EPA-derived products in the brain. These results suggest that the transfer of DHA through plasma lipid pools plays an important role in DHA brain transport in neonatal mice subjected to HI injury. Furthermore, increases in EPA and EPA-derived SPMs following tri-DHA injection demonstrate interlinked metabolism of these two fatty acids. Hence, changes in both EPA and DHA profile patterns need to be considered when studying the protective effects of DHA after HI brain injury. Our results highlight the need for further investigation to differentiate the effects of DHA from EPA on neuroprotective pathways following HI damage. Such information could contribute to the development of specific DHA-EPA formulations to improve clinical endpoints and modulate potential biomarkers in ischemic brain injury.

Food Structure Modulates the Bioavailability of Triglycerides and Vitamin D, and Partly That of Lutein: A Randomized Trial with a Crossover Design in Adults.

SCOPE: The specific effect of the food matrix structure on fat-soluble micronutrient bioavailability is only partly understood. Evaluating fat-soluble micronutrient bioavailability after consumption of foods displaying similar composition but different structure is aimed at. METHODS AND RESULTS: Twelve healthy subjects are enrolled in a randomized, open label, crossover postprandial trial. Four different model foods are tested: custard, pudding, sponge cake, and biscuit. Vitamin D3 , lutein, and triglyceride chylomicron responses, evaluated as postprandial areas under the curve, are then assayed. Custard triglyceride response is higher than pudding and biscuit responses (up to +122.7%, p < 0.0001). Sponge cake vitamin D3 response is higher than biscuit response (+26.6%, p = 0.047). No difference between the model foods are observed regarding lutein responses. Triglyceride responses peak at 3 h for all conditions, while vitamin D3 and lutein peaks are delayed by 1 h with the biscuit matrix compared to other model foods. CONCLUSION: Food structure can significantly impact on triglyceride and vitamin D3 bioavailability in terms of absorbed amounts and/or maximum absorption time. The data highlight positive correlations between triglyceride, vitamin D, and lutein nutrient responses. These results are of particular interest to develop functional foods for population subgroups such as the elderly.

Ellagic Acid Containing Nanostructured Lipid Carriers for Topical Application: A Preliminary Study.

Ellagic acid (EA) is a potent antioxidant substance of natural origin characterized by poor biopharmaceutical properties and low solubility in water that limit its use. The aim of the present study was to develop lipid-based nanoparticle formulations able to encapsulate EA for dermal delivery. The EA-loaded nanoparticles were prepared using two different lipid compositions, namely tristearin/tricaprylin (NLC-EA1) and tristearin/labrasol (NLC-EA2). The influence of formulations on size, entrapment efficiency, and stability of EA-loaded nanoparticles was investigated. Cryo-TEM and small-angle X-ray scattering (SAXS) analyses showed that no morphological differences are evident among all the types of loaded and unloaded nanostructured lipid carriers (NLCs). The macroscopic aspect of both NLC-EA1 and NLC-EA2 did not change with time. No difference in size was appreciable between empty and drug-containing NLC, thus the nanoparticle diameter was not affected by the presence of EA and in general no variations of the diameters occurred during this time. The entrapment efficiency of both EA-loaded nanoparticles was almost quantitative. In addition, NLC-EA1 maintained EA stability for almost two months, while NLC-EA2 up to 40 days. FRAP (Ferric reducing ability of plasma) assay showed an antioxidant activity around 60% for both the loaded NLC, as compared to the solution. Although both types of NLC are characterized by some toxicity on HaCaT cells, NLC-EA1 are less cytotoxic than NLC-EA2. Taken together these results demonstrated that the inclusion of EA within NLC could improve the water solubility, allowing for a reduction of the dosage. Moreover, both types of NLC-EA maintained a high antioxidant effect and low toxicity.

The modulation of drug-loading stability within lipid membranes via medium chain triglycerides incorporation.

The current research aimed to explore medium chain triglycerides (MCT) incorporation in liposomes to overcome stability challenges when drugs with high molecular weight and payload are loaded within lipid membranes. A model drug clarithromycin was loaded in lipid dispersions with various MCT/phospholipids ratios (RM/P = 0, 0.5, 1.75 and 7.5 w/w). TEM images demonstrated a liposome-to-emulsion structural transformation by MCT incorporation to cause increased particle size (104.3-167.7 nm) but decreased zeta potential (-63.6 to -44.4 mV) of lipid particles. MCT incorporation produced biphasic release in PBS and accelerated released in plasma. The tolerance of liposomes for thermal sterilization, high temperature test and freeze-thaw cycles were significantly improved by MCT incorporation. However, MCT incorporation produced adverse effects on colloidal stability in plasma and pharmacokinetics behavior in vivo to some extent. MCT stabilizing mechanism attributes to the modulation of drug loading area and stability improvement of lipid carriers. MCT incorporated liposomes achieved 2-3 fold cellular uptake level than traditional liposomes without significant cytotoxicity. These results indicated that MCT incorporation could be a promising strategy to apply in liposome production to achieve stable drug loading.

DHA Esterified to Phosphatidylserine or Phosphatidylcholine is More Efficient at Targeting the Brain than DHA Esterified to Triacylglycerol.

SCOPE: Docosahexaenoic acid (DHA, 22:6n-3) is crucial for optimal neuronal development and function, but the brain has a poor capacity to synthesize this fatty acid. When consumed acutely esterified to phosphatidylcholine, DHA is more efficient at targeting the brain than when consumed esterified to triacylglycerol. However, the brain DHA bioavailability of other forms of DHA-containing phospholipids, after oral ingestion, is unknown. The objective of this study is to compare brain uptake of DHA after acute gavage with different DHA carriers. METHODS AND RESULTS: Ten-week-old rats were gavaged with 3 H-labeled DHA esterified to phosphatidylcholine (DHA-PtdCho), phosphatidylethanolamine (DHA-PtdEtn), phosphatidylserine (DHA-PtdSer) or triacylglycerol (DHA-TG). Six hours post-gavage, the animals were euthanized and radioactivity was quantified in the cortex and serum lipid classes. Radioactivity recovered in cortex total phospholipids was similar between the DHA-PtdCho and DHA-PtdSer groups and were 5.8 and 6.7 times higher than in the DHA-TG group, respectively. Serum total lipid radioactivity was higher in the DHA-PtdSer group than in the DHA-PtdCho and DHA-PtdEtn groups, but not compared to the DHA-TG group. CONCLUSION: These results suggest that different mechanisms must be present to explain the serum and brain bioavailability differences between DHA-PtdCho and DHA-PtdSer, but these require further investigation.

Preparation, optimization, and pharmacokinetic study of nanoliposomes loaded with triacylglycerol-bound punicic acid for increased antihepatotoxic activity.

Punicic acid of pomegranate oil (PAP) has gained heightened interest due to several health benefits, such as anticarcinogenic, antidiabetic, and antiatherosclerotic properties. However, these bioactivities have been hampered by chemical instability, poor water solubility, rapid metabolism, and low bioavailability of PAP. Therefore, this study was aimed at optimizing the liposomal formulation of Triacylglycerol-bound punicic acid with its regioisomers (TPAR) for improved oral bioavailability and increased hepatoprotection through antioxidation and anti-inflammation. Herein, the optimized TPAR nanoliposome (TPAR-NL) was developed using thin-film dispersion method and subsequently characterized with appropriate indices. The optimized TPAR-NL produced fairly stable spherical nanoparticles (˂ 200 nm) with encapsulation efficiency (%EE) of 85.77%, as well as enhanced in vitro release and improved oral bioavailability. The TPAR-NL exhibited profound antihepatotoxic effect in mice pretreated with carbon tetrachloride (CCl4 ) via reduction of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels compared with free TPAR. The TPAR-loaded liposome also significantly reduced oxidative stress by increasing superoxide dismutase and glutathione levels while lowering malonaldehyde concentration compared with the free TPAR. The TPAR-LNF further exhibited remarkable anti-inflammatory activity compared with the free drug via inhibition of interleukin-6 and tumor necrosis factor-alpha generation. Thus, the developed nanoliposomes potentiated the antihepatotoxic activity of TPAR via antioxidation and anti-inflammation.

The Soluble Fiber α-Cyclodextrin Does Not Increase the Fecal Losses of Dietary Fat in Adults-A Double-Blind, Randomized, Placebo-Controlled, Crossover Trial.

Background: α-Cyclodextrin (α-CD), a soluble dietary fiber, may improve abnormal plasma lipids and promote weight loss. Preliminary evidence suggests that it may exert these effects by binding dietary fat and reducing absorption; this has not been tested in humans. Objective: The primary objective was to test whether supplemental α-CD increases fecal content of dietary lipid in humans. Methods: This was a randomized, double-blind, placebo-controlled, crossover study completed at the Mayo Clinic. Eight healthy volunteers, 5 premenopausal women and 3 men ages 23-54 y with body mass index (BMI; kg/m2) 18-27, underwent 2 separate study visits with a ≥2-wk washout period. The first morning of each visit volunteers consumed a standardized breakfast (14.5% protein, 27.5% fat, 60% carbohydrate, and 1.5 kcal/mL) containing [14C]tripalmitin and [3H]triolein with 2 g of α-CD or placebo, followed by 2 g of α-CD or placebo per meal for 2 more days. Volunteers consumed 100 g/d of dietary fat. Feces were collected for 72 h after the labeled breakfast to measure radiotracer content and total fecal fat. Radiotracer appearance in plasma TGs was measured at intervals after the labeled meal as a secondary outcome. Results: Virtually no 3H radiotracer, but an average of ∼20% of the 14C radiotracer was recovered in fecal lipids, with no difference between α-CD and placebo. Total fecal fat content and radiotracer appearance in postprandial plasma TGs did not differ between the α-CD and placebo treatments. Plasma appearance of 14C-TG was 37% ± 14% less (P < 0.0001) than 3H-TG. Conclusions: α-CD supplementation did not increase loss of dietary lipid in stool or total fecal fat compared with placebo in healthy adults. Greater stool loss and lesser appearance in plasma TGs of tripalmitin-derived [14C] compared with triolein-derived [3H] TGs imply different metabolic handling of these 2 dietary fat tracers. This trial was registered at www.clinicaltrials.gov as NCT03002168.

Nonclinical safety and pharmacokinetics of Miglyol 812: A medium chain triglyceride in exenatide once weekly suspension.

Exenatide, a glucagon-like peptide-1 receptor agonist was originally developed as either a twice daily or once weekly injectable therapeutic for patients with type 2 diabetes. Exenatide QW suspension was developed for use with an autoinjector device, in which the microspheres are suspended in Miglyol 812, a mixture of medium chain triglycerides (MCTs). MCTs are a class of lipids whose fatty acid chains contain from six to 12 carbon atoms (medium chain fatty acids or MCFAs). While MCTs are edible oils present in many foods, including foodstuffs containing coconut and palm kernel oils, limited information is available regarding the oral and subcutaneous bioavailability of MCTs as well as safety following subcutaneous injection. These studies were designed to investigate the non-clinical pharmacokinetics and safety of MCTs. In a single dose pharmacokinetic study, MCFAs were rapidly detected in the plasma of rats following oral administration of either Miglyol 812 or tricaprylin at doses of 10 or 9.48 g kg-1 , respectively. Following subcutaneous dosing with Miglyol 812, MCFAs were rapidly absorbed with a similar profile to that following oral dosing. Furthermore, the toxicity of Miglyol 812 alone was evaluated in a 3 month repeat dose toxicology studies in cynomolgus monkeys. In this study, weekly subcutaneous doses of 0.15 g kg-1 did not elicit any treatment-related effects in cynomolgus monkeys. In conclusion, these studies alongside the available literature data show that Miglyol 812 is a safe excipient for use in subcutaneously administered therapeutics.

Controlled release of flavor oil nanoemulsions encapsulated in filled soluble hydrogels.

The goal of this project was to create hydrogels, a type of soluble biopolymer delivery system to encapsulate flavored nanoemulsions that are released under artificial saliva conditions. Low methoxyl (LM) pectin and whey protein isolate (WPI) at pH 4.0 were used to form the hydrogels at a ratio of 4:1 (w/w), respectively. Orange oil, medium-chain triglyceride (MCT) oil, and WPI were used to make stable nanoemulsions loaded with flavor oil. The nanoemulsions were encapsulated into hydrogels with a mean diameter of 768 ±â€¯36 nm. The ability of the hydrogels to encapsulate the orange oil and release the flavor in the presence of artificial saliva was determined using size distribution data, confocal microscopy, and the release of limonene as assessed by solid-phase microextraction using gas chromatography mass spectrometry. Results showed that the encapsulation of flavor nanoemulsions in filled hydrogels reduces the release of limonene.

Enhanced oral bioavailability of an antipsychotic drug through nanostructured lipid carriers.

Olanzapine is an atypical antipsychotic, undergoes extensive first pass metabolism, also has poor aqueous solubility and belongs to BCS (Biopharmaceutical Classification System) Class II drug) exhibit low oral bioavailability. To overcome this and to enhance the bioavailability, intestinal lymphatic transport of drugs can be exploited through Nano structured lipid carriers (NLCs). The NLCs were formulated by solvent diffusion method using solid lipid (glyceryl tripalmitate), liquid lipid (castor oil) and surfactants (Pluronic F-68, Soylecithin). The formulated NLCs were characterized for physico-chemical properties, in-vitro release studies and in-vivo oral bioavailability. F6 has shown average particle size of 158.5 nm with PI of 0.115 indicating narrow particle size distribution and follows uni modal distribution. It was found that the batch with stearyl amine has a zeta potential of 28.39 mV which confers stability to the dispersion. Bioavailability studies indicate that there was more than 5½-fold increase in oral bioavailability in case of NLCs (F6) compared to olanzapine suspension which indicates that NLCs provided sustained release of the drugs, and these systems can be the preferred as drug carriers for lipophilic drugs in long term disease conditions such as schizophrenia for enhanced bioavailability.

Butyrate presence in distinct gastrointestinal tract segments modifies differentially digestive processes and amino acid bioavailability in young broiler chickens.

The hypothesis was tested that butyrate presence in the digesta of distinct gastrointestinal tract (GIT) segments of broilers leads to differential effects on digesta retention time, gut morphology, and proteolytic enzymatic activities, ultimately resulting in differences in protein digestibility. A total of 320 male day-old Ross 308 broilers were randomly assigned to 5 dietary treatments: 1) control (no butyrate), 2) unprotected butyrate (main activity in the crop and gastric regions), 3) tributyrin (main activity in the small intestine), 4) fat-coated butyrate (activity in the whole GIT) and 5) unprotected butyrate combined with tributyrin, each replicated 8 times. Rapeseed meal was used in combination with a fine dietary particle size in order to challenge the digestive capacity of young broilers. Birds were dissected at 22, 23, and 24 d of age and samples of digesta at various GIT locations as well as tissues were collected. Butyrate concentration varied significantly across GIT segments depending on treatment, indicating that the dietary contrasts were successful. The apparent ileal digestibility of methionine tended to increase when butyrate and/or propionate was present in colonic and cecal contents, possibly due to modifications of GIT development and digesta transit time. Butyrate presence in the digesta of the crop, proventriculus and gizzard, on the contrary, decreased the apparent ileal digestibility of several amino acids (AA). In addition, butyrate presence beyond the gizzard elicited anorexic effect that might be attributable to changes in intestinal enteroendocrine L-cells secretory activities. The present study demonstrates that, in broilers, effects of butyrate on digestive processes are conditioned by the GIT segment wherein the molecule is present and indicates its influence on digestive function and bioavailability of AA.

Long-chain triglycerides-based self-nanoemulsifying oily formulations (SNEOFs) of darunavir with improved lymphatic targeting potential.

The current studies entail systematic development of SNEOFs containing long-chain triglycerides for improving lymphatic targeting of darunavir for complete inhibition of HIV progression. As per QbD-oriented approach for formulation development, the QTPP was defined and CQAs were earmarked. Preformulation equilibrium solubility and phase diagram studies, and risk assessment through FMEA studies identified Lauroglycol 90, Tween 80 and Transcutol HP as the lipid, emulgent and cosolvent, respectively, for formulating SNEOFs of darunavir. Systematic optimisation of SNEOFs was conducted using IV-optimal mixture design, and the optimised formulation was chosen through numerical desirability function. Characterisation of optimised SNEOFs exhibited globule size of 50 nm, >85% drug release within 15 min and >75% permeation within 45 min. In vivo lymph cannulation and in situ intestinal perfusion studies indicated significant improvement in the drug absorption parameters from SNEOFs via intestinal lymphatic pathways, owing primarily to the presence of long-chain triglycerides. Also, in vivo pharmacokinetic studies in rat corroborated significant improvement in rate and extent of drug absorption into plasma vis-à-vis pure drug. In a nutshell, these studies indicate significant improvement in the biopharmaceutical attributes of a robust and stable SNEOFs formulation of darunavir for holistic management of viral loads in lymph and blood.

Postprandial VLDL-TG metabolism in type 2 diabetes.

BACKGROUND: Type 2 diabetes is associated with excess postprandial lipemia due to accumulation of chylomicrons and VLDL particles. This is a risk factor for development of cardiovascular disease. However, whether the excess lipemia is associated with an impaired suppression of VLDL-TG secretion and/or reduced clearance into adipose tissue is unknown. OBJECTIVE: We measured the postprandial VLDL-TG secretion, clearance and adipose tissue storage to test the hypothesis that impaired postprandial suppression of VLDL-TG secretion, combined with impaired VLDL-TG storage in adipose tissue, is associated with excess postprandial lipemia. DESIGN: We studied 11 men with type 2 diabetes and 10 weight-matched non-diabetic men using ex-vivo labeled VLDL-TG tracers during an oral high-fat mixed-meal tolerance test to measure postprandial VLDL-TG secretion, clearance and storage. In addition, adipose tissue biopsies were analyzed for LPL activity and cellular storage factors. RESULTS: Men with type 2 diabetes had greater postprandial VLDL-TG concentration compared to non-diabetic men. However, postprandial VLDL-TG secretion rate was similar in the two groups with equal suppression of VLDL-TG secretion rate (≈50%) and clearance rate. In addition, postprandial VLDL-TG storage was similar in the two groups in both upper body and lower body subcutaneous adipose tissue. CONCLUSIONS: Despite greater postprandial VLDL-TG concentration, men with type 2 diabetes have similar postprandial suppression of VLDL-TG secretion and a similar ability to store VLDL-TG in adipose tissue compared to non-diabetic men. This may indicate that abnormalities in postprandial VLDL-TG metabolism are a consequence of obesity/insulin resistance more than a result of type 2 diabetes per se.

An in situ-forming phospholipid-based phase transition gel prolongs the duration of local anesthesia for ropivacaine with minimal toxicity.

An injectable, phospholipid-based phase transition gel (PPTG) has been developed for prolonging the release of ropivacaine (RO) for local anesthesia. PPTG was prepared by mixing phospholipids, medium-chain triglyceride and ethanol. Prior to injection, the PPTG is in a sol state with low viscosity. After subcutaneous injection, the PPTG rapidly forms a gel in situ, which acts as a drug release depot as verified by in vitro release profiles and in vivo pharmacokinetics. Administering RO-PPTG to rats led to a significantly smaller initial burst release than administering RO solution or RO base suspension. Nerve blockade in guinea pigs lasted 3-fold longer after injection of RO-PPTG than after injection of RO solution. RO-PPTG showed good biocompatibility and excellent degradability in vivo. These results suggest that this PPTG-based depot system may be useful for sustained release of local anesthetics to prolong analgesia without causing systemic toxicity. STATEMENT OF SIGNIFICANCE: The sustained release of local anesthetics at the surgical site after a single injection is the optimal method to control post-surgical pain. In situ forming implant is an attractive alternative for the sustained release of local anesthetics. However, its practical use is highly limited by certain drawbacks including high viscosity, involved toxic organic solvents and fast drug release. To date, phospholipids-based phase transition gel (PPTG) is emerging for clinical development because of the non-toxicity, biocompatibility and ready availability of phospholipids in body. Thus, we present a novel strategy for sustained release of local anesthetics to control post-surgical pain based on PPTG, which showed a prolonged duration of nerve blockade and excellent biocompatibility.