Lipophilic Carrier Research Articles

Comparative study between simple and optimized liposomal dispersion of quetiapine fumarate for diffusion through nasal route

Context: Nasal route of drug administration is preferred more and more for the targeted delivery to the brain in current drug development scenario due to its ease of use, reliability, quick action, and lesser side effects. Those CNS drugs which have limited oral bioavailability due to pharmacokinetic consequences and brain barrier repulsion are getting onto this direction.Objective: Quetiapine fumarate, an analogous to above and an antischizophrenic agent, is tested for its diffusion property with and without lipophilic carrier through sheep nasal membrane. Being a BCS class II' and high permeable candidate, it tends to crossover easily, so made up in a simple dispersion.Materials and methods: To improve its diffusion rate, it was embedded into liposomal dispersion, which has proven that it has advanced efficiency for diffusion. For this, both the formulations were checked and compared for their diffusion profile, as it is an essential property for bioavailability through nasal route. Comparison was made on the basis of % drug diffusion within 6 h, rate, mechanism, profile, and coefficient.Results: Liposomal dispersion has been proved superior with greater percentage diffusion of 32.61 ± 1.70 and very high permeability with a coefficient value of 4.1334 ± 0.7321 (× 10 − 5 cm/s). Diffusion profile comparison bearing dissimilarity of 18 and similarity of 74 indicated that the diffusion profiles of liposomal dispersions and simple dispersion were similar but not identical.Conclusion: Liposomal diffusion supremacy was further sustained by in vivo, ciliotoxicity, and gamma scintigraphy studies.

Synthesis of silica/metatitanic acid nanocomposite and evaluation of its catalytic performance for aquathermolysis reaction of extra-heavy crude oil

A lipophilic silica/metatitantic acid (denoted as SiO2/H2TiO3) nanocomposite was synthesized by hydrothermal reaction with surface-modified SiO2 as the lipophilic carrier. As-synthesized SiO2/H2TiO3 nanocomposite was used as a catalyst to promote the aquathermolysis reaction of extra-heavy crude oil thereby facilitating the recovering from the deep reservoirs at lowered temperature. The catalytic performance of the as-synthesized SiO2/H2TiO3 catalyst for the aquathermolysis reaction of the heavy oil at a moderate temperature of 150 °C was evaluated in relation to the structural characterizations by TEM, FTIR, XRD and FESEM as well as the determination of the specific surface area by N2 adsorption–desorption method. Findings indicate that as-synthesized SiO2/H2TiO3 nanocomposite exhibits an average size of about 20 nm as well as good lipophilicity and dispersibility in various organic solvents; and it shows good catalytic performance for the aquathermolysis reaction of the extra-heavy oil extracted from Shengli Oilfield of China. Namely, the as-synthesized SiO2/H2TiO3 catalyst is capable of significantly reducing the viscosity of the tested heavy oil from 58,000 cP to 16,000 cP (referring to a viscosity reduction rate of 72.41%) at a mass fraction of 0.5%, a reaction temperature of 150 °C and a reaction time of 36 h, showing potential application in downhole upgrading heavy crude oils.

Rapid synthesis of self-assembling 1,2-thiomannobioside glycoconjugates as potential multivalent ligands of mannose-binding lectins

Among the pathogen-associated carbohydrate patterns, the Man(α1→2)Man α disaccharide motif is of particular interest because its multivalent derivatives are considered as potential antiviral or antibacterial agents through interaction with mannose-binding lectins. We present a straightforward synthesis of amphiphilic compounds containing a hydrolytically stable S-linked 1,2-mannobioside residue, a tetraethylene glycol linker to ensure water solubility and various lipophilic carriers such as a hexadecyl chain and two pyrrolidinofullerene derivatives. According to a dynamic light scattering study, the obtained amphiphiles form nanoscale aggregates in water producing multivalent presentation of the thiomannobioside residue.

Antioxidant activity of idebenone-loaded neutral and cationic solid–lipid nanoparticles

Idebenone (IDE) is a lipophilic benzoquinone electron carrier synthetic analogue of coenzyme Q10, which behaves as an antioxidant and free radical scavenging molecule. Recently, the therapeutic application of IDE in Leber’s hereditary optic neuropathy has been discussed. This work was aimed at evaluating the encapsulation of IDE in solid–lipid nanoparticles (SLN). In particular, we tested the possibility of adapting the quasi-emulsion solvent diffusion technique, already proposed to produce polymeric nanoparticles, to prepare positively charged SLN with different compositions. Such a charge, due to the addition of a cationic lipid, would facilitate the interaction with the negatively charged eye surface epithelium, with a consequent longer pre-corneal residence time of the colloidal systems. In a preliminary evaluation of the produced IDE-loaded SLN, the antioxidant activity of the drug was demonstrated using an oxygen radical absorbance capacity assay. Encapsulation of the drug in the nanocarrier systems seems able to protect IDE from degradation and prolong its antioxidant potential.

DSC investigation of the effect of the new sigma ligand PPCC on DMPC lipid membrane.

The new sigma ligand cis-(±)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl) methyl]-1-(4-methylphenyl) cyclopropanecarboxylate [(±)-PPCC] is a promising tool for the treatment of various diseases. With the aim to investigate the absorption of (±)-PPCC by the cell membranes, in this study we evaluated the influence on thermotropic behavior of membrane model exerted by PPCC both as free base or as oxalic salt. To fulfill this purpose differential scanning calorimetry was used. The findings highlight that PPCC affects the thermodynamic parameters of phospholipids in different manner depending on whether it is in the salt or base form as well as function of the amount of drugs dispersed in the lipid matrix. The salt form of PPCC was uptaken by the membrane model faster than the free base. In addition, preliminary information on the use of a lipophilic carrier for PPCC was obtained.

Effect of Resveratrol-Related Stilbenoids on Biomembrane Models

The interactions of the two resveratrol analogues 2-hydroxy-3,5,3',5'-tetramethoxystilbene (4) and 2-hydroxy-3,5,3',4'-tetramethoxystilbene (5) with model biomembranes were studied. The aim of this investigation was to highlight possible differences in the interactions with such biomembranes related to the minimal structural differences between these isomeric stilbenoids. In particular, different experiments on stilbenoid/biomembrane model systems using both differential scanning calorimetry (DSC) and Langmuir-Blodgett techniques were carried out to evaluate stilbenoid/multilamellar vesicle and stilbenoid/phospholipid monolayer interactions, respectively. Dimyristoylphosphatidylcholine was used as constituent of the biomembrane models and permitted the experiments to be carried out at 37 °C, close to body temperature. Kinetic studies were also run by DSC to evaluate the uptake of the resveratrol derivatives by the biomembrane model in an aqueous medium and when transported by a lipophilic carrier. The results indicated that both of the resveratrol analogues influenced the behavior of multilamellar vesicles and monolayers, biomembrane models, with 4 producing a larger effect than 5. These results are useful for better understanding the mechanism of action of these compounds. Moreover, the kinetic results could be of importance for future design of lipophilic delivery systems for these stilbenoids.

DSC evidence of the interaction and absorption of 3,4-Secoisopimar-4(18),7,15-trien-3-oic acid by biomembrane model

3,4-Secoisopimar-4(18),7,15-trien-3-oic acid is a diterpenoid contained in the aerial parts of Salvia cinnabarina M. Martens et Galeotti which has been proved to inhibit the effect of some known mutagens, in several bacterial strains, acting as a desmutagenic agent. In order to evaluate if 3,4-Secoisopimar-4(18),7,15-trien-3-oic inactivate the mutagen in intra- or extracellular compartment, present work investigated the interaction between the test substance and the biological membrane in a model of biomembrane, represented by multilamellar vesicles of dimyristoylphosphatidylcholine, using differential scanning calorimetry. The results obtained indicate a strong interaction of the examined diterpenoid with the model of biomembrane and that its absorption is quite improved by a lipophilic carrier.

Ciprofloxacin Loaded Alginate/Chitosan and Solid Lipid Nanoparticles, Preparation, and Characterization

The aim of the present study was to develop controlled drug delivery systems based on nanotechnology. Two different nanocarriers were selected, chitosan-alginate nanoparticles as hydrophilic and solid lipid nanoparticles as lipophilic carriers. Nanoparticles were prepared and characterized by evaluating particle size, zeta potential, SEM pictures, DSC thermograms, percentage of drug loading efficiency, and drug release profile. The particle size of SLNs and Chi/Alg nanoparticles was 291 ± 5 and 520 ± 16. Drug loading efficiency of Chi/Alg and SLN particles were 68.98 ± 5.5% and 88 ± 4.5%. The drug release was sustained with chitosan-alginate system for about 45 hours whereas for SLNs >98% of the drug was released in 2 hours. Release profile did not change significantly after freeze drying of particles using cryoprotector. Results suggest that under in vitro condition chitosan/alginate systems can act as promising carriers for ciprofloxacin and may be used as an alternative system in sustained delivery of ciprofloxacin.

New potential prodrugs of aciclovir using calix[4]arene as a lipophilic carrier: synthesis and drug-release studies at the air–water interface

Two tetra-p-tert-butyl-calix[4]arene species bearing one or two anti-HSV aciclovir units tethered via carbodiester linkages at the lower rim were synthesized as possible antiviral prodrugs. The amphiphilic properties of these derivatives were studied using Langmuir balance at the air–water and air–carbonate buffer interfaces; the monolayers formed were stable on both subphases. Monolayers formed with these molecules on a carbonate buffer subphase at pH 10 and 37 °C were then used for monitoring hydrolysis of the diester linkage. The release of free aciclovir of around 30% in 3 days was observed with both derivatives, as shown with HPLC.

Synthesis of n-squalenoyl cytarabine and evaluation of its affinity with phospholipid bilayers and monolayers

Cytarabine (1-β- d-arabinofuranosylcytosine, Ara-C), a pyrimidine nucleoside analogue, is an attractive therapeutic agent for the treatment of both acute and chronic myeloblastic leukemias. 1,1′,2- tris- nor-Squalene acid (squaleneCOOH) has been conjugated to cytarabine with the formation of the squalenoyl-cytarabine prodrug, in order to improve the drug lipophilicity and, consequently, the affinity towards the environment of biological membranes, as well as of lipophilic carriers. The interaction of cytarabine and its prodrug with dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles and monolayers has been studied by the differential scanning calorimetry and the Langmuir–Blodgett techniques. The interaction has been evaluated considering the effect of the compounds on the DMPC MLV and monolayers behaviour. The aim was to have information on the interaction of the drug and the prodrug with the biological membranes and on the possibility to use liposomes as carriers for the prodrug. The results showed an improved affinity of the prodrug with MLV and monolayers with respect to the free drug.

Solid lipid nanoparticles self-assembled from electrosprayed polymer-based microparticles

A new strategy for manipulating molecular self-assembly to produce solid lipid nanoparticles (SLNs) in situ is reported. Microparticulate composites (consisting of the polymer PVP, naproxen and tristearin as a lipophilic carrier) were prepared using an elevated temperature electrospraying process. Tristearin/naproxen SLNs formed spontaneously when the composite microparticles were placed into water, as a result of the PVP polymer matrix dissolving. The self-assembled SLNs had average diameter of 376 ± 20 nm, a drug entrapment efficiency of 86.2% and provided sustained drug release over 24 h, with 87.6% of the total NAP freed into the dissolution medium in this time. These findings open a new route for developing novel biomaterials and nanoparticulate drug delivery systems, and for resolving problems associated with the formulation of poorly water-soluble drugs.

Isolation of lipocalin-type protein from rainbow trout seminal plasma and its localisation in the reproductive system

The lipocalin protein family is a large and diverse group of small extracellular proteins characterised by their ability to bind hydrophobic molecules. In the present study, we describe the isolation procedure for rainbow trout seminal plasma protein, characterised by a moderate migration rate during polyacrylamide gel electrophoresis, providing information regarding its basic features and immunohistochemical localisation. This protein was identified as a lipocalin-type protein (LTP). The molecular mass of LTP was found to be 18,848 Da and it was found to lack any carbohydrate components. Only a few Salmoniformes contain LTP in their seminal plasma. The abundance of LTP in the Sertoli and Leydig cells of the testes of the rainbow trout, as well as in secretory cells of the efferent duct, suggests that this protein is specific for rainbow trout milt, where it acts as a lipophilic carrier protein. Moreover, the specific localisation of LTP in the flagella of the spermatozoa suggests a role for LTP in sperm motility. Further experiments are necessary to identify the endogenous ligands for LTP in rainbow trout seminal plasma and to characterise the binding properties of this protein.

2-Hydroxypropyl-β-Cyclodextrin Removes All-TransRetinol from Frog Rod Photoreceptors in a Concentration-Dependent Manner

To determine whether a nonprotein lipophilic carrier, 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), can remove all-trans retinol from rod photoreceptor outer segments. All-trans retinol is generated in rod outer segments after light exposure. It is highly insoluble, and its efficient transport across extra- and intracellular aqueous space requires specialized carriers. Experiments were carried out with isolated frog rod photoreceptor cells. The removal of all-trans retinol by different concentrations of this carrier was measured by imaging its fluorescence in single-rod photoreceptors. HP-beta-CD concentrations >0.3 mM significantly increased the rate of all-trans retinol removal. The rate of removal increased linearly with carrier concentration, with a slope of 0.0058 min(-1)/mM. The effectiveness of HP-beta-CD shows that a specialized interaction with the cell membrane is not necessary for the efficient transfer of all-trans retinol between the cell membrane and the carrier. The transfer occurs through a collision-based mechanism, as indicated by the linear increase of the rate of removal with the carrier concentration.

The synthesis and characterization of lipophilic peptide-based carriers for gene delivery

Lipophilic carriers have shown great potential in improving the delivery of gene therapeutics. We have synthesized positively charged peptide-based carriers including lipoamino acids. The carriers were shown to interact with DNA by performing isothermal titration calorimetry and particle size and zeta potential experiments. An exothermic reaction resulted from the titration of carrier into DNA. The particle sizes of the carrier/DNA complexes varied over the different charge ratios from 200–800 nm. The zeta potential was negative at a low charge ratio but positive when the amount of carrier was increased. The utilisation of lipophilic carriers is a promising approach to improve the bioavailability of gene delivery.

Possible Fungistatic Implications of Betulin Presence in Betulaceae Plants and their Hymenochaetaceae Parasitic Fungi

Betulin and its derivatives (especially betulinic acid) are known to possess very interesting prospects for their application in medicine, cosmetics and as bioactive agents in pharmaceutical industry. Usually betulin is obtained by extraction from the outer layer of a birch bark. In this work we describe a simple method of betulin isolation from bark of various species of Betulaceae trees and parasitic Hymenochaetaceae fungi associated with these trees. The composition of the extracts was studied by GC-MS, whereas the structures of the isolated compounds were confirmed by FTIR and 1H NMR. Additionally, the significant fungistatic activity of betulin towards some filamentous fungi was determined. This activity was found to be strongly dependent on the formulation of this triterpene. A betulin-trimyristin emulsion, in which nutmeg fat acts as emulsifier and lipophilic carrier, inhibited the fungal growth even in micromolar concentrations--its EC50 values were established in the range of 15 up to 50 microM depending on the sensitivity of the fungal strain. Considering the lack of fungistatic effect of betulin applied alone, the application of ultrasonic emulsification with the natural plant fat trimyristin appeared to be a new method of antifungal bioassay of water-insoluble substances, such as betulin.

Defensive Effects of Fullerene-C60 Dissolved in Squalane Against the 2,4-Nonadienal-Induced Cell Injury in Human Skin Keratinocytes HaCaT and Wrinkle Formation in 3D-Human Skin Tissue Model

We dissolved fullerene-C60 in squalane (LipoFullerene; LF-SQ, C60-eq.: 500 ppm) and examined its defensive effects against 2,4-nonadienal (NDA)-induced cell injury in HaCaT keratinocytes and wrinkle formation in three dimensional (3D)-human skin tissue model. NDA is an analog of 4-hydroxynonenal, one of major causes for human body odor indicative of aging and a lipophilic cell injury factor. Cell viability (% of the control) decreased to 31.6% on treatment with NDA (40 microM), but it increased to 66.0-97.5% when LF-SQ of 1-4% (C60-eq.: 5-20 ppm) was administered for 5 hr before NDA addition. The defensive effect by LF-SQ was superior to that of "squalane" alone at the same doses. NDA-induced DNA-fragmentation in HaCaT cells was suppressed by LF-SQ administered for 5 hr before NDA treatment, and LF-SQ protected HaCaT cells against apoptosis-like cell death. LF-SQ did not appreciably defend against hydrogen peroxide, though LF-SQ effectively defended against tert-butylhydroperoxide, a type of the intermediate hydrophilicity-lipophilicity degree out of other reactive oxygen species. The scanning electron microscopy demonstrated that NDA caused wrinkles and abnormal scales on keratinocytes of 3D-human skin tissue model, and structural homogeneity of the interstratum was broken, any of which were, however, markedly suppressed with LF-SQ. Squalane alone exhibited defensive effect against the skin tissue injury to some extent, but which was inferior to LF-SQ. LF-SQ might effectively capture and scavenge lipid radicals generated inside the cell membrane, because squalane acts as a lipophilic carrier of C60. C60 dissolved in squalane can be expected to serve as a cosmeceutical ingredient for anti-wrinkle formation.

Fluorescent labeling of human mesenchymal stem cells by thiophene fluorophores conjugated to a lipophilic carrier

Fluorescent labeling of human mesenchymal stem cells (hMSCs) is essential for their study in vitro and in vivo. Here, we report a new chemical biodelivery method for labeling hMSCs using a series of very efficient and highly versatile thiophene-based fluorescent dyes. Such conjugates contribute to a stable and viable labeling of hMSCs and constitute a promising strategy for in vivo applications.

Cloning and characterization of a glucosyltransferase and a rhamnosyltransferase fromStreptomycessp. 139

Ste15 and ste22 present in the Ebosin biosynthesis gene cluster (ste) were previously shown to function in Ebosin biosynthesis and both of the protein products are predicted to be glycosyltransferases. In this study, their biochemical activities were confirmed. ste15 and ste22 were cloned and expressed in Escherichia coli. With a continuous coupled spectrophotometric assay and using the purified proteins, we now demonstrated that the protein Ste15 has the ability of catalysing the transfer of glucose specifically from UDP-glucose to an Ebosin precursor that lacks glucose, the lipid carrier located in the cytoplasmic membrane of the gene ste15 disrupt mutant Streptomyces sp. 139 (ste15(-)). The protein Ste22 can catalyse the transfer of rhamnose specifically from TDP-rhamnose to an Ebosin precursor that lacks rhamnose, a lipophilic carrier in the cytoplasmic membrane of the gene ste22 disrupt mutant Streptomyces sp. 139 (ste22(-)). The gene product of ste15 was identified to be a glucosyltransferase, and the protein encoded by ste22 was found to be a rhamnosyltransferase. Both of two enzymes play essential roles in the formation of repeating units of sugars during Ebosin biosynthesis. These are the first glucosyltransferase and rhamnosyltransferase in the biosynthesis of a Streptomyces exopolysaccharide to be characterized.

Lasalocid acid as a lipophilic carrier ionophore for allylamine: Spectroscopic, crystallographic and microbiological investigation

A new complex of lasalocid acid with allylamine (LAS–AM) is synthesised and studied by X-ray, FT-IR, 1H NMR and 13C NMR, ESI MS methods. In the solid state allylamine is protonated and all protons of NH 3 + are hydrogen bonded. We show that in the gas, liquid and solid states lasalocid forms 1:1 complexes with allylamine and that its structures of all states are comparable, which indicates that the complex LAS–AM is very stable. The stability of the LAS–AM complex is achieved by some intra-molecular hydrogen bonds. Due to these interactions the outside of the complex is hydrophobic enabling its transport across the biological membranes. This property of the complex is reflected in its anti-microbial activity, which is discussed.

Soluble filler as a dissolution profile modulator for slightly soluble drugs in matrix tablets

The purpose of this experimental work was the development of hydrophilic–lipophilic matrix tablets for controlled release of slightly soluble drug represented here by diclofenac sodium (DS). Drug dissolution profile optimization provided by soluble filler was studied. Matrix tablets were based on cetyl alcohol as the lipophilic carrier, povidone as the gel-forming agent, and common soluble filler, that is lactose or sucrose of different particle size. Physical properties of tablets prepared by melt granulation and drug release in a phosphate buffer of pH 6.8 were evaluated. In vitro studies showed that used filler type, filler to povidone ratio and sucrose particle size influenced the drug release rate. DS dissolution profile could be changed within a wide range from about 50% per 24 hours to almost 100% in 10 hours. The release constant values confirmed that DS was released from matrices by the diffusion and anomalous transport. The influence of sucrose particle size on the drug release rate was observed. As the particle size decreased, the drug release increased significantly and its dissolution profile became more uniform. Soluble fillers participated in the pore-forming process according to their solubility and particle size. Formulations containing 100 mg of the drug, 80 mg of cetyl alcohol, 40 mg of povidone, and 80 mg of either lactose or sucrose (particle size 250–125 μm) were considered optimal for 24-hour lasting dissolution of DS.