Structured triglyceride vehicles for oral delivery of halofantrine: examination of intestinal lymphatic transport and bioavailability in conscious rats

Purpose. To compare the influence of triglyceride vehicle intramolecular structure on the intestinal lymphatic transport and systemic absorption of halofantrine in conscious rats. Methods. Conscious, lymph cannulated and nonlymph cannulated rats were dosed orally with three structurally different triglycerides; sunflower oil, and two structured triglycerides containing different proportion and position of medium-(M) and long-chain (L) fatty acids on the glycerol backbone. The two structured triglycerides were abbreviated MLM and LML to reflect the structural position on the glycerol. The concentration of halofantrine in blood and lymph samples was analyzed by HPLC. Results. Both the lymphatic transport and the total absorption of halofantrine were enhanced by the use the MLM triglyceride. The estimated total absorption of halofantrine in the lymph cannulated animals was higher than in the nonlymph cannulated animals, and this was most pronounced for the animals dosed with the structured triglycerides. Conclusions. Using MLM as vehicle increases the portal absorption of halofantrine and results in similar lymphatic transport levels when compared to sunflower oil. Total absorption when assessed as absorption in the blood plus lymphatic transport for halofantrine after administration in the MLM triglyceride was higher than after administration in sunflower oil.     

In Vivo ESR Studies on Pharmacokinetics and Metabolism of Parenteral Lipid Emulsion in Living Mice

Purpose. We applied non-invasive and real-time method with in vivo ESR spectroscopy to determining pharmacokinetics and metabolism of lipid emulsion as a drug carrier in living mice. Methods. A spin-labeled triglyceride (SL-TG) was newly synthesized and lipid emulsion containing SL-TG was prepared. In vivo ESR spectra in mice were observed after intravenous administration of the lipid emulsion. Results. In vivo ESR spectra consisted of three components, coinciding with the in vitro spectra of SL-TG particles, free and immobilized fatty acids. The amount of the components depended on both the observing domain and the period after administration. In the chest, all three components were observed, while SL-TG particle was lacking in the abdomen. The half-life of the lipid particles in the chest was 2 hr. Conclusions. Non-invasive and real-time analysis of drug carriers in living animal is successfully accomplished using an in vivo ESR method.     

Self-microemulsifying drug delivery system (SMEDDS) – challenges and road ahead

Abstract

Self-microemulsifying drug delivery system (SMEDDS) has emerged as a vital strategy to formulate poor water soluble compounds for bioavailability enhancement. However, certain limitations are associated with SMEDDS formulations which include in vivo drug precipitation, formulation handling issues, limited lymphatic uptake, lack of predictive in vitro tests and oxidation of unsaturated fatty acids. These limitations restrict their potential usage. Inclusion of polymers or precipitation inhibitors within lipid based formulations helps to maintain drug supersaturation after dispersion. This, thereby, improves the bioavailability and reduces the variability on exposure. Also, formulating solid SMEDDS helps to overcome liquid handling and stability problems. Usage of medium chain triglycerides (MCT) and suitable antioxidants to minimize oxidation of unsaturated fatty acids are few of the steps to overcome the limitations associated with SMEDDS. The review discussed here, in detail, the limitations of SMEDDS and suitable measures that can be taken to overcome them.     

Long-Circulating Emulsions (Oil-in-Water) as Carriers for Lipophilic Drugs

Purpose. Rapid clearance of parenterally administered oil-in-water emulsions from blood by the reticuloendothelial system (RES), mainly macrophages of the liver and spleen, has been one of the major obstacles for delivering lipophilic drugs to cells other than those in the RES. The purpose of this study therefore is to overcome this problem and develop emulsions that will have prolonged blood circulation time. Methods. A series of amphipathic polyethylene-glycol (PEG) derivatives have been included as co-emulsifier into emulsions composed of Castor oil and phosphatidylcholine. The effect of amphipathic PEG on reducing the RES uptake and prolonging the blood circulation of the emulsion particles has been tested in vivo using mice as an animal model. Results. Inclusion of PEG derivatives such as Tween-80 or dioleoyl N-(monomethoxy-polyethyleneglycol succinyl)phosphotidylethanolamine (PEG-PE) into emulsions composed of Castor oil and phosphatidylcholine decreases the RES uptake and increases blood residence time of the emulsions. The activity of PEG derivatives in prolonging the circulation time of emulsions depends on the PEG chain length (PEG2000PEG5000>PEG1000, Tween-80) and the PEG density on emulsion surface. Conclusions. Inclusion of amphipathic PEG as emulsifier into oil-in-water emulsions is a very effective method to prolong the blood half life of the emulsions. Emulsions with long circulating half life in blood should be very useful as a delivery vehicle for lipophilic drugs.     

新生儿使用中/长链脂肪乳与多种油脂肪乳安全性队列研究

目的 分析新生儿使用中/长链脂肪乳与多种油脂肪乳发生药物不良反应的差异,并探索潜在的危险因素。方法 采用回顾性队列研究方法,针对2020年1月—2023年6月使用中/长链脂肪乳或多种油脂肪乳的新生儿患者的数据,利用中国医院药物警戒系统(China Hospital Pharmacovigilance System,CHPS),检索不良反应信息并做评价,纳入中/长链脂肪乳组新生儿患者499例,多种油脂肪乳组新生儿患者1 940例。利用Logistic回归及分层分析探索组间安全性差异及影响不良反应发生的危险因素。结果 中/长链脂肪乳组总不良反应发生率为19.24%,其中常见不良反应包括发热(5.81%),血红蛋白减少(3.01%),血压升高(2.40%),低血糖(2.40%)等;多种油脂肪乳组总不良反应发生率为36.44%,其中十分常见的不良反应为发热(10.57%);常见的不良反应为血红蛋白减少(8.97%),血压降低(3.20%),血压升高(3.09%)等;罕见的不良反应为肝功能异常(0.05%),脾肿大(0.05%),发绀(0.05%)。单因素分析中,多种油脂肪乳组发生发热,血红蛋白减少和血糖升高的风险均高于中/长链脂肪乳组(P<0.05),但此关联在总体多因素分析中的差异无统计学意义,进一步以胎龄为分层因素进行多因素分析,发现极早产儿中多种油脂肪乳组发生发热和血红蛋白减少的风险显著高于中/长链脂肪乳组,相应的OR(95%CI)分别为6.437(1.327,31.227)和5.066(1.089,23.570),其余胎龄分层中未见明显差异。结论 新生儿患者使用中/长链脂肪乳与多种油脂肪乳的风险相近,但在极早产儿中多种油脂肪乳发生发热、血红蛋白减少的风险高于中/长链脂肪乳,建议对体温、血红蛋白、血压等指标进行定期监测,做好药物警戒工作。     

Health effects of oleic acid and long chain omega-3 fatty acids (EPA and DHA) enriched milks. A review of intervention studies

Substitution of dietary saturated fat by oleic acid and/or polyunsaturated fatty acids (PUFA) has been described to reduce the cardiovascular risk by reducing blood lipids, mainly cholesterol. Additional benefits have been described for long chain omega-3 PUFA (eicosapentaenoic acid—EPA and docosahexaenoic acid—DHA) from fish oils. In recent years, food technology has been used to produce dairy drinks with a reduced content of saturated fat in favour of those fatty acids, most of them claiming cardiovascular benefits. This review summarises all the scientific evidence regarding the effects of milks enriched with long chain omega-3 PUFA (EPA + DHA) and/or oleic acid on cardiovascular health. Nine controlled intervention studies with enriched milks have reported effects on healthy volunteers, subjects with increased risk factors and cardiovascular patients. The main effects observed were reductions of blood lipids, mainly cholesterol, LDL-cholesterol and triglycerides.     

In Vitro Human Skin Barrier Modulation by Fatty Acids: Skin Permeation and Thermal Analysis Studies

Purpose. This study aims to elucidate the skin permeation enhancement and the skin perturbation effects of a number of fatty acids, i.e. straight-chain saturated (SFA), monounsaturated (MUFA) and polyunsaturated acids (PUFA). Methods. The skin permeation enhancement effects were studied using human stratum corneum (SC) and p-aminobenzoic acid (PABA) as a model permeant. The fatty acids in propylene glycol (FA/PG) were applied according to a pre-treatment/co-treatment protocol. The perturbation effects were studied using differential thermal analysis (DTA) on SC after pretreatment with FA/PG. Results. SFA with 6 to 12 carbons exhibit a parabolic correlation between enhancement effect and chain-length, with a maximum at nonanoic-decanoic acids (with 9 and 10 carbons). Nonanoic and decanoic acids exert barely noticeable effects on the thermal behaviour of SC, suggesting that they easily mix with the skin lipids. All cis-6-, 9-, 11- or 13-octadecenoic acids (MUFA) enhance the permeation of PABA to the same extent. DTA revealed that the cis-9- and 13-isomers form a separate domain containing mostly the pure fatty acids within the SC lipids and suppress the lipid transitions at 70°/80°C. PUFA—linoleic (LA), -linolenic (ALA) and arachidonic acids—enhance PABA permeation stronger than MUFA but additional double bonds do not further increase the degree of enhancement. LA and ALA form separate domains but do not completely suppress the SC lipid transitions at 70°/ 80°C. Increase in the enthalpy changes of 70°/80° transitions linearly correlates to the decrease in the permeability coefficients, suggesting that an increased perturbation of the skin lipids not necessarily has to yield an increased PABA permeation. Conclusions. The enhancement effects of fatty acids on the PABA penetration through SC are structure-dependent, associated with the existence of a balance between the permeability of pure fatty acids across SC and the interaction of the acids to skin lipids.     

Lipophilization of Somatostatin Analog RC-160 Improves Its Bioactivity and Stability

Purpose. Acromegaly is a symptomatically disabling condition, resulting from a growth hormone (GH) secreting pituitary tumor. The somatostatin analog RC-160 is known to potently inhibit hypersecretion of GH, from pituitary adenomas. However, the therapeutic potential of RC-160, is limited by its short serum half life. To overcome this limitation, fatty acids with carbon chain lengths ranging from 4 to 18 were conjugated to RC-160. Methods. The GH-inhibitory activity of these lipopeptides, as well as their binding profile to somatostatin receptors, on the rat pituitary adenoma cell line GH3 was studied in vitro. The relative stability of lipophilized RC-160 towards degradation by crude papaya protease was also determined. Results. The long chain lipopeptides, like myristoyl-RC-160 (carbon chain length = 14) were found to exhibit greater receptor affinity and GH-inhibitory activity, as compared to their counterparts of lower chain lengths. However, the receptor affinity and GH-inhibitory activity of stearoyl-RC-160 (carbon chain length = 18), was found to lower than RC-160 and its lipophilized derivatives. Unlike RC-160, the myristoylated derivative was found to have significantly greater resistance to protease and serum degradation (p < 0.01). Conclusions. Lipophilization of RC-160 with long chain fatty acids improves its stability and GH-inhibitory activity. The activity of lipophilized RC-160 seems to increase with increasing hydrophobicity of the lipopeptide, and reaches a maxima at myristoyl-RC-160 for GH3. Hence, optimizing the hydrophobicity should be an important consideration governing the design and synthesis of bioactive lipopeptides.     

Water-in-Oil Microemulsions Containing Medium-chain Fatty Acids/Salts: Formulation and Intestinal Absorption Enhancement Evaluation

Purpose. Water-in-oil (w/o) microemulsions have been developed which, in addition to non-ionic medium-chain glycerides, incorporate ionic lipids, primarily medium-chain fatty acids, such as caprylic (C₈) capric (C₁₀) and lauric (C₁₂) acids and their corresponding sodium salts. The absorption enhancing activity of w/o microemulsions incorporating these lipids was evaluated in the rat using Calcein (MW = 623) a water-soluble and poorly absorbed marker molecule. Methods. Phase diagrams were constructed where C₈/C₁₀ or C₁₂ fatty acids were treated as lipophilic surfactants and their sodium salts as hydrophilic ones. The anesthetised rat model was employed to evaluate Calcein absorption upon a single intraduodenal administration from a solution and the various w/o microemulsions. Results. A wide range of clear and transparent w/o microemulsions were obtained at ambient temperature either in liquid or solid form when a fixed blend of medium chain fatty acid/salt was titrated by a fixed ratio of the oil containing the oil-soluble mono- and diglycerides and deionized water or physiological saline. Upon intraduodenal administration in the anesthetised rat, the absorption of Calcein was improved from about 2% in aqueous solution up to about 37% in w/o microemulsions. Solid and liquid formulations were equally effective in improving bioavailability. The absorption enhancement activity of the fatty acids/salts followed the order C₈ C₁₀ > C₁₂. Absorption enhancement of Calcein was significantly reduced in the absence or presence of low levels of C₈/C₁₀ mono-/diglycerides. Conclusions. These results further support the use of medium-chain glycerides and fatty acids/salts in microemulsion formulations to improve intestinal absorption of water-soluble compounds.     

In Vivo Evaluation of Acyclovir Prodrug Penetration and Metabolism Through Rat Skin Using a Diffusion/Bioconversion Model

Purpose. In order to evaluate the in vivo penetration of prodrugs which undergo metabolism in skin, we analyzed thein vivo penetration profiles of acyclovir prodrugs based on a two-layer skin diffusion model in consideration of metabolic process. Methods. Acyclovir prodrugs (e.g., valerate, isovalerate and pivarate) were used as model prodrugs and the amounts excreted in urine were measured after percutaneous application. In vivo penetration profiles were then estimated by employing a deconvolution method and the penetration of acyclovir prodrugs was analyzed using a diffusion model. Subsequently, diffusion, partitioning and metabolic parameters were compared under in vitro and in vivo conditions. Results. Although total penetration amounts at the end of the experiment were similar for the three prodrugs, the ratio of intact prodrug to total penetration amount differed significantly. Moreover, the excretion and absorption profiles were also very different for each prodrug. Enzymatic hydrolysis rate constants calculated under in vivo conditions were considerably larger than those obtained in the skin homogenate and in vitro penetration experiments. Conclusions. The present skin diffusion/bioconversion model combined with computer analysis enables us to comprehensively account for diffusion, partitioning and metabolism during in vivo percutaneous absorption. Nevertheless, different enzymatic hydrolysis rate constants obtained under bothin vivo and in vitro conditions demonstrate the difficulty of obtaining accurate values for in vivo enzymatic activity from related in vitro experiments.     

LIPID EMULSIONS OF PALMITOYLRHIZOXIN: EFFECTS OF PARTICLE SIZE ON BLOOD DISPOSITIONS OF EMULSION LIPID AND INCORPORATED COMPOUND IN RATS

Emulsion formulations of various particle sizes for the highly lipophilic antitumour agent, RS-1541 (13-O-palmitoylrhizoxin), were prepared using dioctanoyldecanoyl-glycerol (ODO) as lipids and polyoxyethylene-(60)-hydrogenated castor oil (HCO-60) as a surfactant. These emulsions were evaluated as injectable drug carriers and compared with a colloidal solution. Both in vitro and in vivo after i.v. administration, RS-1541 was distributed into lipoproteins from the colloidal solution. When applied as emulsions of various particle sizes (124–419 nm) in vitro, RS-1541 was retained and stabilized within the emulsions. In the in vivo study, however, retention of RS-1541 in the emulsions after i.v. injection depended on their size. The small-particle emulsions (94–112 nm) resulted in long retention, and the large-particle emulsions (415–474 nm) led to short retention. Lipolysis rates of emulsion particles by lipoprotein lipase also depended on their size, indicating rapid lipolysis for small-particle emulsions (133 nm). However, the lipolysis was not such an extensive one, showing 10–30% release of capric acid from ODO within 6 h. Blood dispositions of capric acids approximately paralleled those of RS-1541 after i.v. injection of various particle size emulsions (130–368 nm) to rats, although relatively rapid eliminations of capric acids compared with RS-1541 were observed for the small-particle size emulsions (130 nm). These results suggest that when injected as emulsion formulations, the highly lipophilic antitumour agent, RS-1541, has behaviour similar to that of the emulsion particles in the body, which is dependent on the size of the latter. Thus, by properly selecting the particle size, lipid emulsions consisting of ODO and HCO-60 are expected to be effective and useful DDS carriers for RS-1541.     

In Silico Prediction of Optimal in Vivo Delivery Properties Using Convolution-Based Model and Clinical Trial Simulation

Purpose. To develop a new strategy for the in silico evaluation of the optimal in vivo delivery properties of a drug, minimizing a cost function defined by the brain receptor occupancy obtained in positron-emission tomography experiments. Methods. A convolution-based model was formulated to link in vivo delivery rate to plasma concentrations whereas a second-stage model was used to link plasma concentrations to the pharmacodynamic effect. A feedback control approach was applied to identify the optimal in vivo delivery rate given an appropriate optimality criterion. Finally, clinical trial simulation was used as a supportive tool for decision-making by evaluating different scenarios accounting for pharmacokinetic/pharmacodynamic parameter uncertainty, inter-subject variability, and drug potency. Results. The results revealed that the mean in vivo delivery time significantly affects brain receptor occupancy whereas the fraction of the dose available for the systemic circulation shows the highest influence on brain receptor occupancy for a givenin vivo delivery rate. Finally, variability on receptor occupancy seems to be more affected by the inter-individual variability on the disposition PK parameters. Conclusion. The integration of convolution-based model, feedback control approach, and clinical trial simulation offers a unique tool for in ilico improvement of the drug development process by identifying critical issues on drug properties, optimal in vivo delivery rate, and potential problems related to the inter-individual variability.     

Improving Correlations Between Drug Solubilization and In Vitro Lipolysis by Monitoring the Phase Partitioning of Lipolytic Species for Lipid-Based Formulations

Solution proton nuclear magnetic resonance analysis was used in conjunction with in vitro lipolysis to elucidate the time-dependent speciation and release of lipolytic products during the digestion of lipid-loaded inorganic particles, allowing correlations to be made between the phase partitioning of lipolytic products and an encapsulated poorly soluble drug. Silicon dioxide, montmorillonite, and laponite were used to encapsulate medium chain triglycerides into solid-state lipid-based formulations (LBFs), and coumarin 102 was selected as a model poorly soluble compound. The specific inorganic carrier material used to encapsulate medium chain triglycerides significantly impacted the release and partitioning of the solubilizing lipolytic products, that is, diglycerides, monoglycerides, and fatty acids. A strong linear correlation was obtained between drug solubilization and fatty acid release to the aqueous phase (R² = 0.996), indicating fatty acids to be the most important lipid species for enabling solubilization and potential drug absorption in vivo. This method was developed to improve upon the use of pH-stat titration for characterizing LBF digestion during in vitro lipolysis studies and is demonstrated herein to provide useful insights into how the selected inorganic carrier material impacts LBF performance when solid-state LBF powders are fabricated via adsorption.     

In Vivo Model for Ciclosporin Intestinal Absorption in Lipid Vehicles

The influence of lipid vehicles on the intestinal absorption of Ciclosporin was studied in vivo. The model takes into account the effect of the intestinal lipid digestion on the absorption after intraduodenal administration of [³H]Ciclosporin in olive oil or middle-chain triglyceride (MCT) to the bile duct-cannulated rat. Digested vehicles significantly promoted the absorption compared to nondigested vehicles. In the nondigested state, olive oil was a significantly better vehicle than MCT, whereas the difference between both lipids was only a trend in the digested state. Further studies with variants of this in vivo model should determine the influence of abnormalities of fat digestion and absorption on the pharmacokinetics and pharmacodynamics of a drug with a low therapeutical index.     

Surface Lipids of Seeds Support Both Aspergillus Parasiticus Growth and Aflatoxin Production

Abstract

Seed surface lipids (SSL) play a key role in supporting aflatoxin (AFT) output in oily and starchy seeds following infection with Aspergillus parasiticus. On oily seeds, fungal growth and AFT production occur when the levels of SSL are higher than 0.15% of total oil content of seeds, with a ratio between triglycerides and free fatty acids (TG/FFA) of SSL > 1. If FFA prevail over TG, growth can be inhibited because of the toxicity towards Aspergillus of unsaturated FFA of SSL. Defatted meals of sunflower seeds support a reduced AFT biosynthesis. On starchy seeds, A. parasiticus proliferates in the germ region, the area richest in lipids.     

Glycerides as prodrugs. 1. Synthesis and antiinflammatory activity of 1,3-bis(alkanoyl)-2-(O-acetylsalicyloyl)glycerides (aspirin triglycerides).

A series of 1,3-bis(alkanoyl)-2-(O-acetylsalicyloyl)glycerides (aspirin triglycerides) having aspirin at the 2 position of glycerol and fatty acids at the 1 and 3 positions was prepared. The compounds were administered orally and tested for efficacy in the rat paw edema test, and the stomachs were examined for the presence of lesions. The results showed that the members of this series in which the fatty acids are of intermediate chain length (C4-C12) do not cause gastric lesions and have essentially all the systemic activity associated with aspirin.     

Effect of Curcumin and its Analogue on Lipids in Carbon Tetrachloride–Induced Hepatotoxicity: A Comparative Study

Abstract

Curcumin and its analogue (bis.demethoxy curcumin analogue [BDMC-A]) were studied for their possible lipid-lowering properties in carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. Carbon tetrachloride (3 ml kg^?1 wk^?1) administration to albino Wistar rats increased the levels of hepatic marker enzymes such as aspartate transaminase (AST), alkaline phosphatase (ALP), and γ.-glutamyl transferase (GGT) in the plasma. The levels of lipids cholesterol, triglycerides, and free fatty acids were also increased in plasma and tissues (liver, kidney, heart, and brain). Phospholipid levels increased in plasma, heart, and brain but decreased in liver and kidney. Curcumin (80 mg/kg) and BDMC-A (80 mg/kg) administration to CCl₄-treated rats for a period of 3 months significantly decreased the lipid levels. The effect exerted by BDMC-A was more prominent than that of curcumin. Studies on the histopathology of the liver are also in line with the biochemical parameters studied. These observations show the lipid-lowering efficacy of curcumin and its analogue in CCl₄-induced hepatotoxicity.     

Differential effects of a gelatinase inhibitor on adipocyte differentiation and adipose tissue development

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Drug Targeting by Polyalkylcyanoacrylate Nanoparticles Is Not Efficient Against Persistent Salmonella

Purpose. We have investigated the efficacy of colistin and ciprofloxacin, free or bound to polyalkylcyanoacrylate nanoparticles, for the targeting and eradication of Salmonella persisting in the organs of the mononuclear phagocyte system. Methods. A model of persistent S. typhimurium infection was developed in C57BL/6 mice using IV inoculation of the plasmid-cured strain C53. Results. In vivo and ex vivoexperiments showed that the persisting bacteria seem to evolve to a nongrowing state during experimental salmonellosis. In vivo treatment with free or nanoparticle-bound colistin did not significantly reduce the number of viable Salmonella C53, either in the liver or the spleen of infected mice. In contrast, in vivo treatment with ciprofloxacin led to a significant decrease of bacterial counts in the liver whatever the stage of infection and the form used. However, none of the treatments were able to sterilize the spleen or the liver. In ex vivo experiments, colistin was only active against bacteria recovered during the early phase of infection, whereas ciprofloxacin exerted its activity at all times postinfection. Conclusions. We suggest that the micro-environment in which the bacterial cells persist in vivo probably causes dramatic changes in their susceptibility to antimicrobial agents.