Medium-chain Glycerides Research Articles

The influence of components on the rectal absorption of cefazolin in rats.

A study has been made to identify the component(s) responsible for the absorption-promoting effect of MGK medium chain glyceride preparation commercially available as a mixture of glyceryl-1-monooctanoate, glyceryl-1,3-dioctanoate, glyceryl-1,2-dioctanoate, glyceryl trioctanoate, octanoic acid and glycerol. The action of the individual constituents has been evaluated on the rectal absorption of cefazolin in conscious rats. The results indicate that the action of MGK can be completely explained by the effect of glyceryl-1-monooctanoate, which both enhanced the extent and rate of cefazolin uptake.

Rate-controlled absorption enhancement of rectally administered cefazolin in rats by a glyceride mixture (MGK).

The enhancing effect of the medium chain glyceride preparation MGK on the rectal absorption of the cephalosporin antibiotic cefazolin sodium was evaluated in relation to the rate of delivery. Cefazolin sodium proved to be absorbed to a small extent (15 to 27%) after rectal administration without MGK. Bolus administration with MGK enhanced rate and extent of cefazolin sodium absorption, resulting in a bioavailability of 57 +/- 26%. Linear infusion of 3 mg cefazolin sodium with MGK in 32 min produced complete absorption of the antibiotic (102 +/- 7%), but absorption occurred slower in comparison with bolus delivery. The rate of administration proved to be an important variable of the absorption enhancing effect of MGK.

Peptide and Protein Delivery at a Glance

Peptide and Protein Delivery at a Glance

The Effect of Media Composition, pH, and Formulation Excipients on the In Vitro Lipolysis of Self-Emulsifying Drug Delivery Systems (SEDDS)

The objective of the present work was to investigate the effects of pH, ions, and excipients on the in vitro lipolysis of self-emulsifying drug delivery systems (SEDDS). Studies were performed in bio-relevant media using a pH stat autotitrator for analysis. The results demonstrated that alkaline media were essential for lipolysis, which was enhanced by divalent CaCl2 ions and medium chain glycerides. Monovalent NaCl and the hydrophile-lipophile balance (HLB) of the surfactant had insignificant effect on lipolysis. Consequently, it was concluded that the activity of lipase, at an optimum pH of 6.5, is the predominant factors for digestion of SEDDS.

Design of Lipid-Based Formulations for Oral Administration of Poorly Water-Soluble Drugs: Precipitation of Drug after Dispersion of Formulations in Aqueous Solution

This study was designed to investigate the precipitation of a lipophilic drug following dispersion of lipid formulations in water. The model drug fenofibrate was formulated in representative lipid delivery systems designed for oral administration, using medium chain glycerides, polysorbates, and propylene glycol as excipients. Aqueous dispersion of water-insoluble self-emulsifying lipid formulations resulted in turbid emulsions, followed subsequently by very slow precipitation of 3–7% of the dose of fenofibrate. Self-emulsifying formulations that included water-soluble surfactants, which dissolved a lower mass of drug in solution at equilibrium, nevertheless typically maintained drugs in a metastable state, following dilution with water, for several hours or even days. Formulations with higher contents of hydrophilic materials resulted in more rapid precipitation. Extensive precipitation of fenofibrate from oil-free formulations, comprising of only surfactants and cosolvents, took place within 30 min. The results indicated that most of the lipid systems were supersaturated with respect to the drug on dilution, but the extent of precipitation varied significantly between formulations and was influenced by the extent of supersaturation after dilution. The study suggests that the use of hydrophilic formulations for delivery of lipophilic drugs may result in a greater extent of drug precipitation in the stomach. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3582–3595, 2009

Microemulsions Containing Medium-Chain Glycerides as Transdermal Delivery Systems for Hydrophilic and Hydrophobic Drugs

We evaluated the ability of microemulsions containing medium-chain glycerides as penetration enhancers to increase the transdermal delivery of lipophilic (progesterone) and hydrophilic (adenosine) model drugs as well as the effects of an increase in surfactant blend concentration on drug transdermal delivery. Microemulsions composed of polysorbate 80, medium-chain glycerides, and propylene glycol (1:1:1, w/w/w) as surfactant blend, myvacet oil as the oily phase, and water were developed. Two microemulsions containing different concentrations of surfactant blend but similar water/oil ratios were chosen; ME-lo contained a smaller concentration of surfactant than ME-hi (47:20:33 and 63:14:23 surfactant/oil/water, w/w/w). Although in vitro progesterone and adenosine release from ME-lo and ME-hi was similar, their transdermal delivery was differently affected. ME-lo significantly increased the flux of progesterone and adenosine delivered across porcine ear skin (4-fold or higher, p < 0.05) compared to progesterone solution in oil (0.05 +/- 0.01 microg/cm(2)/h) or adenosine in water (no drug was detected in the receptor phase). The transdermal flux of adenosine, but not of progesterone, was further increased (2-fold) by ME-hi, suggesting that increases in surfactant concentration represent an interesting strategy to enhance transdermal delivery of hydrophilic, but not of lipophilic, compounds. The relative safety of the microemulsions was assessed in cultured fibroblasts. The cytotoxicity of ME-lo and ME-hi was significantly smaller than sodium lauryl sulfate (considered moderate-to-severe irritant) at same concentrations (up to 50 microg/mL), but similar to propylene glycol (regarded as safe), suggesting the safety of these formulations.

A new self-emulsifying drug delivery system (SEDDS) for poorly soluble drugs: Characterization, dissolution, in vitro digestion and incorporation into solid pellets

The aim of the current study was the development of a new pellet based self-emulsifying (SE) drug delivery system for the oral delivery of poorly soluble drugs. Furthermore, we wanted to investigate the influence of physiological dilution media and enzymatic digestion on the solubilization capacity of the formulation for the model drug Progesterone. Lipid mixtures composed of Solutol ® HS 15 and medium chain glycerides were optimized with respect to their self-emulsifying properties. The liquid SE lipid was mixed with microcrystalline cellulose and transformed into pellets by extrusion/spheronization. The pellets were characterized for size, shape, surface characteristics and friability. In vitro dissolution and digestion experiments were carried out using physiological dissolution media. The droplet diameter of the dispersed SE mixtures was largely affected by changing the oil to Solutol ® HS 15 ratio. Moreover, digestion of SE mixtures changed the solubilization capacity for Progesterone. Pellets with good properties (size, shape and friability) have been produced through the incorporation of a selected SE mixture into MCC. In conclusion, extrusion/spheronization is a suitable process to produce solid self-emulsifying pellets with up to 40% load of a liquid SE mixture. Digestion induces a change in lipid composition which affects the solubilization capacity of the lipid phase.

ESR studies on the influence of physiological dissolution and digestion media on the lipid phase characteristics of SEDDS and SEDDS pellets

The aim of the current study is the evaluation of a recently optimized SEDDS, composed of Solutol ® HS15 and medium chain glycerides, and self-emulsifying pellets by means of ESR. Tempol-benzoate (TB)-loaded SEDDS were produced and electron spin resonance (ESR) spectroscopy was used to evaluate the diluted self-emulsifying mixtures. Moreover, ESR in vitro digestion experiments were carried out to have an insight on the characteristics of the different phases formed during the digestion process and to evaluate the distribution and the localization of TB in these phases. In addition, self-emulsifying pellets were produced using nitroxide-loaded SEDDS and the microenvironment within the pellets during release process was monitored in an online process using ESR spectroscopy. After dilution of nitroxide-loaded SEDDS, the percent of TB localized in the lipophilic compartment was decreasing with increasing the surfactant fraction in the mixture. Moreover, it was found that different phases with variable viscosity and polarity were produced as a result of the enzymatic digestion of SEDDS in physiologically relevant media. This change in lipid composition has largely affected the distribution and the localization of the spin probe during the digestion process. A rapid increase in the mobility of the spin probe inside the pellets was noticed after exposure to the release media. Additionally, TB was localized within the self-emulsifying mixture environment for the time of the experiment. ESR is considered a powerful non-invasive tool to assess the microenvironment of the diluted SEDDS and to monitor in vitro digestion process. Digestion induces a change in lipid composition which can affect the solubilization capacity of the administered drug. Therefore, monitoring in vitro digestion process using ESR spectroscopy will help in providing greater understanding of the interaction between the administered drug and the digested lipid vehicles.

Process intensification of synthesis process for medium chain glycerides using cavitation

Abstract Cavitation results in conditions of local hot spots, turbulence and liquid circulation in the reactor which can result into intensification of chemical reactions. The present work investigates the effect of cavitating conditions on the synthesis process of medium chain glycerides (MCG) based on the esterification reaction between the fatty acids and glycerol. Effect of molar ratio and temperature on the rate of reaction and equilibrium conversion in the presence of ultrasound has been studied. It has been conclusively established that cavitation indeed results in substantial degree of intensification as compared to the conventional approach reported in the literature. Under optimized operating conditions of mole ratio (1:3) and temperature (90 °C), equilibrium conversion of 98.5% has been obtained in about 6 h of reaction time using cavitation.

The Use of Lipid-Based Formulations to Increase the Oral Bioavailability of Panax Notoginseng Saponins Following a Single Oral Gavage to Rats

Purpose: This article was intended to improve the absorption of ginsenoside Rg1 and Rb1 of Panax notoginseng saponins (PNS). Methods: PNS-Phospholipid complex and a lipid-based formulation by dissolving the complex in the medium chain fattyglycerides were prepared, and their oral relative bioavailability was determined in rats and compared with an aqueous solution of PNS for each component. Results: The study gave evidence that the phospholipids could combine with the two active constitutes of PNS and form a PNS-phospholipid complex. The complex efficiently increased the solubility of hydrophilic ginsenoside Rg1 and Rb1 in some selected hydrophobic esters, such as fatty glycerides, and constructed the lipid-based formulations of PNS. The experimental result in rats in vivo showed that the oral relative bioavailability was enhanced remarkably by these lipid-based formulations composed of the PNS-Phospholipid complex and various esters. The absorption enhancement of the medium-chain glyceride (Labrafac cc and Capmul MCM (3:1)) was somewhat greater than that of other fatty glyceride. The area under the plasma concentration-time curve (AUC) of ginsenoside Rg1 and Rb1 of the PNS-complex in the medium-chain glyceride were 27.38 μg.mL-1.h and 600.08 μg.mL-1.h, compared with 2.52 μg.mL-1.h and 92.29 μg.mL-1.h of the PNS aqueous solution, respectively. Conclusions: The oral relative bioavailability of ginsenoside Rg1 and Rb1 of PNS was enhanced remarkably by the lipid-based formulations. These findings reveal a new strategy to increase oral bioavailability by lipophilicity enhancement for some highly water-soluble but poorly absorbed drugs.

Optimization and evaluation of amoxicillin medium chain fatty acids/salts microemulsions: intestinal absorption and cytotoxicity

Pseudoternary microemulsions have been developed which, in addition to non-ionic medium-chain glycerides and fatty acids such as caprylic (C 8 ) and capric acids (C 10 ), incorporate ionic lipids, i.e. the sodium salts of fatty acids. The permeability, absorption enhancing activity were evaluated using phenol red as a marker molecule and the cytotoxicity of these lipid microemulsions were investigated in rats by measuring the amount of proteins and lactate dehydrogenase enzyme released in the intestinal fluids. The histopathological follow up of colonic membranes after administration of microemulsions was used to assess tissue damage. In vitro permeability and absorption studies showed that caprate-based systems containing captex 200 (20%), surfactant mixture of polysorbate 80: sodium caprate 4:1 (60%), capmul MCM C 8 : capric acid 1:1(20%) significantly (P

Comparative study on digestive lipase activities on the self emulsifying excipient Labrasol®, medium chain glycerides and PEG esters

Labrasol® is a lipid-based self-emulsifying excipient used in the preparation of lipophilic drugs intended for oral delivery. It is mainly composed of PEG esters and glycerides with medium acyl chains, which are potential substrates for digestive lipases. The hydrolysis of Labrasol® by porcine pancreatic extracts, human pancreatic juice and several purified digestive lipases was investigated in the present study. Classical human pancreatic lipase (HPL) and porcine pancreatic lipase, which are the main lipases involved in the digestion of dietary triglycerides, showed very low levels of activity on the entire Labrasol® excipient as well as on separated fractions of glycerides and PEG esters. On the other hand, gastric lipase, pancreatic lipase-related protein 2 (PLRP2) and carboxyl ester hydrolase (CEH) showed high specific activities on Labrasol®. These lipases were found to hydrolyze the main components of Labrasol® (PEG esters and monoglycerides) used as individual substrates, whereas these esters were found to be poor substrates for HPL. The lipolytic activity of pancreatic extracts and human pancreatic juice on Labrasol® is therefore mainly due to the combined action of CEH and PLRP2. These two pancreatic enzymes, together with gastric lipase, are probably the main enzymes involved in the in vivo lipolysis of Labrasol® taken orally.

Evaluation of Hydroperoxides in Common Pharmaceutical Excipients

While the physical properties of pharmaceutical excipients have been well characterized, impurities that may influence the chemical stability of formulated drug product have not been well studied. In this work, the hydroperoxide (HPO) impurity levels of common pharmaceutical excipients are measured and presented for both soluble and insoluble excipients. Povidone, polysorbate 80 (PS80), polyethylene glycol (PEG) 400, and hydroxypropyl cellulose (HPC) were found to contain substantial concentrations of HPOs with significant lot-to-lot and manufacturer-to-manufacturer variation. Much lower HPO levels were found in the common fillers, like microcrystalline cellulose and lactose, and in high molecular weight PEG, medium chain glyceride (MCG), and poloxamer. The findings are discussed within the context of HPO-mediated oxidation and formulating drug substance sensitive to oxidation. Of the four excipients with substantial HPO levels, povidone, PEG 400, and HPC contain a mixture of hydrogen peroxide and organic HPOs while PS80 contains predominantly organic HPOs. The implications of these findings are discussed with respect to the known manufacturing processes and chemistry of HPO reactivity and degradation kinetics. Defining critical HPO limits for excipients should be driven by the chemistry of a specific drug substance or product and can only be defined within this context.

Profiling of medium chain glycerides used in pharmaceutical formulation development by reversed-phase HPLC

Medium chain length (C8, C10) mono-, di- and triacylglycerols (MCGs) are used in pharmaceutical formulation development of poorly soluble compounds, as a means to increase their oral bioavailability. The ratios of C8 and C10 fatty acid components along with the ratio of monoglycerides, diglycerides and triglycerides can significantly impact overall solubilizing characteristics both in vitro and in vivo. Existing literature methods either do not have the desired selectivity or simplicity to adequately characterize these MCGs. A reversed-phase HPLC method has been developed utilizing a Waters Symmetry C18 (150 mm × 4.6 mm, 3.5 μm particle size) column with a gradient of acetonitrile and water. The effluent was monitored using a UV detector at 220 nm and relative response factors were determined for all components with available standards to allow for accurate quantitation. The RP-HPLC method was optimized for selectivity, sensitivity and efficiency and was successfully applied to the characterization of commercial samples yielding superior sensitivity and ease of preparation compared to existing compendial methods.

Production of medium chain glycerides from coconut and palm kernel fatty acid distillates by lipase-catalyzed reactions

Medium chain glycerides (MCGs) containing C 8:0 and C 10:0 fatty acids is very much important for medicinal and nutritional applications. Coconut and palm kernel fatty acid distillates (FADs) can be utilized to produce MCGs by a combination of lipase-catalyzed hydrolysis and esterification reactions. The neutral glycerides present in coconut and palm kernel FADs are hydrolyzed by Candida rugosa lipase. The hydrolysates were then subjected to steam distillation under vacuum (at 120–140 °C) to get fractions rich in medium chain fatty acids (MCFAs). The fractions, from coconut and palm kernel FADs (75.2 and 76.2% MCFAs, respectively), were esterified with Rhizomucor miehei (Lipozyme RM IM) lipase to produce MCGs. Products from coconut FAD contained 64.7–67.5% diacylglycerol (DG), followed by 18.8–22.9% monoacylglycerol (MG) and 9.8–9.3% triacylglycerol (TG). Similarly, products from palm kernel FAD contained 63.5–66.7% DG, 19.1–23.6% MG and 9.5–10.1% TG.

Formulation and Physicochemical Characterization of Microemulsion System Using Isopropyl Myristate, Medium-Chain Glyceride, Polysorbate 80 and Water

The phase behavior of the system isopropyl myristate/medium-chain glyceride/polysorbate 80/water forming both w/o and o/w microemulsions has been studied to develop microemulsion comprising of pharmaceutical excipients. The pseudo-ternary phase diagrams with large monophasic zones and gel formation were realized and several compositions were identified in the phase diagram for rheological, dynamic light scattering (DLS) and calorimetric measurements. The identified systems at different temperatures behaved as Newtonian fluid and the activation parameters for their viscous flow were evaluated. From DLS measurements, hydrodynamic diameter, polydispersity and diffusion coefficient of the microheterogeneous dispersions were determined. The free energy, enthalpy and entropy of solution of the w/o and o/w microemulsions were determined from calorimetric measurements.

Production of Medium Chain Glycerides and Monolaurin from Coconut Acid Oil by Lipase-Catalyzed Reactions

Medium chain glycerides (MCGs) containing C8:0 and C10:0 fatty acids have got commercial importance by considering their medicinal and nutritional applications. Monolaurin is also a value added commercial product. Coconut acid oil, which is mainly utilized in soap manufacturing process, can be effectively utilized to produce MCGs and monolaurin by a combination of lipase-catalyzed hydrolysis and esterification. Coconut acid oil containing 68% free fatty acid (as lauric acid), and 31.4% neutral glycerides are hydrolyzed by Candida rugosa lipase. The hydrolyzed acid oil was then subjected to steam distillation under atmospheric pressure to get a fraction (yield, 5%) rich in medium chain fatty acids (C8:0, 46.2%, C10:0, 19.2%), and the residual fraction was fractionally distilled under vacuum to get a fraction rich in lauric acid (68.4%). These two fractions were esterified with glycerol with Rhizomucor miehei (Lipozyme RM IM) lipase to produce MCGs from the first fraction and monolaurin from the second fraction.

Evaluation of the in-vitro digestion profiles of long and medium chain glycerides and the phase behaviour of their lipolytic products.

An evaluation of the in-vitro digestion profile and phase behaviour of the common formulation lipids Miglyol 812 (medium chain triglyceride, MCT), Capmul MCM (C8/C10 monoglyceride/ diglyceride mixture), soybean oil (long chain triglyceride, LCT) and Maisine 35-1 (C18 monoglyceride/diglyceride mixture), is described. Experiments were conducted using titrimetric, high-performance thin-layer chromatographic (HPTLC) and ultracentrifugational techniques under model fasted and post-prandial intestinal conditions. The rate and extent of digestion of the medium chain lipids was greater than the corresponding long chain lipids, and independent of bile salt concentration, with complete conversion to monoglyceride and fatty acid occurring after 30 min digestion. The long chain lipid digests separated into an oily phase (containing undigested triglyceride and diglyceride), an aqueous phase (containing bile salt, fatty acid and monoglyceride) and a pellet phase (containing approximately 5 mm of fatty acid, presumably as an insoluble soap) after ultracentrifugation. Higher proportions of long chain fatty acid and monoglyceride were dispersed into the aqueous phase with increasing bile salt concentrations. In contrast, medium chain lipolytic products separated only into an aqueous phase and a pellet fraction in a bile-salt-independent manner. The digestion of both the C8/C10 and C18 monoglyceride/diglyceride lipid mixtures was more rapid than the corresponding triglyceride, especially at early time points. This investigation provides insight into the relative digestion kinetics of medium chain and long chain lipids and provides information regarding the phase behaviour of their lipolytic products under conditions modelled on those expected after oral administration. The data also provide a background for improved understanding of the potential utility of long chain and medium chain lipid-based formulations.

Synthesis of medium‐chain glycerides using lipase from Candida rugosa

AbstractEnzymatic synthesis of medium‐chain glycerides (MCG) from capric acid and glycerol was studied using lipase from Candida rugosa. The effects of various reaction parameters such as time, molar ratio of substrates (mmol capric acid/mmol glycerol), amount of lipase, type of organic solvents, and initial water activity (aw) were studied. The best conditions tested for MCG synthesis at 37°C were, respectively, time, 24 h; molar ratio of substrates, 2.5; and amount of lipase, 100.0 mg. The use of organic solvents greatly influenced the activity of lipase in the synthesis of MCG. Generally, activity of lipase was high in nonpolar solvents with log P values from 3.50 to 4.50, where P is the partition coefficient between water and 1‐octanol. The enzymatic synthesis of MCG was preferably carried out at an initial aw of 0.328, which resulted in maximal yield. Analysis of the products of reaction using gas chromatography showed that lipase from Candida rugosa seemed to produce more dicaprin and tricaprin than monocaprin.

Preparation of biodegradable insulin nanocapsules from biocompatible microemulsions.

To prepare poly(ethyl 2-cyanoacrylate) nanocapsules containing insulin by interfacial polymerization of spontaneously forming, biocompatible microemulsions. A pseudo-ternary phase diagram of a mixture of medium chain glycerides (caprylic/capric triglycerides and mono-/diglycerides), a mixture of surfactants (polysorbate 80 and sorbitan mono-oleate) and water was constructed. Polarizing light microscopy was used to identify combinations forming microemulsions. Microemulsions were characterized by conductivity and viscosity to select systems suitable for the preparation of poly(ethyl 2-cyanoacrylate) nanocapsules by interfacial polymerization. Nanocapsules were prepared by addition of 100 mg of ethyl 2-cyanoacrylate to a stirred water-in-oil microemulsion containing 1 g of water, 7.6 g of oil, and 1.4 g of surfactant. The nanocapsules formed were characterized by photon correlation spectroscopy, freeze fracture transmission and scanning electron microscopy. Insulin nanocapsules were prepared by using an aqueous solution of insulin (100 units/ml) as the dispersed phase of the microemulsion. The entrapment and the release of insulin from the nanocapsules were determined. Three regions were identified in the pseudo-ternary phase diagram; a microemulsion region, a region in which liquid crystalline structures were present and a coarse emulsion region. All systems in the microemulsion region were water-in-oil dispersions. Poly(ethyl 2-cyanoacrylate) nanocapsules having a mean particle size of 150.9 nm were formed upon interfacial polymerization of the microemulsion. Nanocapsules were found to have a central cavity surrounded by a polymer wall. In excess of 80% of the insulin present in the microemulsion was encapsulated upon interfacial polymerization. Interfacial polymerization of spontaneously forming water-in-oil microemulsions represents a convenient method for the preparation of poly(alkylcyanoacrylate) nanocapsules suitable for the entrapment of bioactive peptides.