Self-assembled Liquid Crystalline Nanoparticles Research Articles

Formation of Self-Assembled Liquid Crystalline Nanoparticles and Absorption Enhancement of Ω-3s by Phospholipids and Oleic Acids.

This study aimed to optimize and evaluate self-assembled liquid crystalline nanoparticles (SALCs) prepared from phospholipids and oleic acid for enhancing the absorption of Ω-3s. We explored the structure and optimal formulation of SALCs, which are composed of Ω-3 ethyl ester (Ω-3 EE), phospholipids, and oleic acid, using a ternary diagram and evaluated the improvement in Ω-3 dissolution, permeation, and oral bioavailability. The in vitro dissolution and pharmacokinetics of Ω-3 SALCs were compared with those of Omacor soft capsules (as the reference). The shape of the liquid crystal was determined according to the composition of phospholipids, oleic acids, and Ω-3s and was found to be in cubic, lamellar, and hexagonal forms. The dissolution rates of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) obtained from Ω-3 SALCs were 1.7 to 2.3-fold higher than those of the Omacor soft capsules. Furthermore, a pharmacokinetic study in male beagle dogs revealed that Ω-3 SALCs increased the oral bioavailability of Ω-3 EE by 2.5-fold for EPA and 3.1-fold for DHA compared with the reference. We found an optimal formulation that spontaneously forms liquid crystal-based nanoparticles, improving the bioavailability of EPA and DHA, not found in the existing literature. Our findings offer insight into the impact of nanoparticle phase on the oral delivery of oil-soluble drugs and provide a novel Ω-3 EE formulation that improves the bioavailability of EPA and DHA.

Novel small self-assembled resveratrol-bearing cubosomes and hexosomes: preparation, charachterization, and ex vivo permeation

The study aims to elaborate novel self-assembled liquid crystalline nanoparticles (LCNPs) of resveratrol which has neuro-protective, anti-aging, and anticancer activity. Resveratrol loaded LCNPs fabrication and optimization for transdermal delivery was assessed via a quality by design approach based on 23 full factorial designs. The cubic phase of LCNPs was successfully prepared using GMO (glyceryl monooleate) via the emulsification technique. Based on the factorial design, the independent operating variables significantly affected the five dependent responses. The cubosomes and hexosomes hydrodynamic diameters were in the nanometer range (135–256 nm) with narrow particle size distribution, high negative zeta potential ≥ −27.9 mV, and entrapment efficiency ≥73.5%. The LCNPs succeeded in sustaining resveratrol release for almost 24 h, following a non-fickian transport of drug diffusion mechanism. Ex-vivo study revealed a significant enhancement up to six folds in the transdermal permeation of resveratrol-loaded LCNPs compared to its suspension. The selected LCNPs exhibited a high physical stability while retaining the cubic structure for at least 3 months. Quality by design approach successfully accomplished a predictable mathematical model permitting the development of novel LCNPs for sustained transdermal delivery of resveratrol.

Self-assembled nano-architecture liquid crystalline particles as a promising carrier for progesterone transdermal delivery

The study aims to elaborate novel self-assembled liquid crystalline nanoparticles (LCNPs) for management of hormonal disturbances following non-invasive progesterone transdermal delivery.Fabrication and optimization of progesteroneloaded LCNPs for transdermal delivery were assessed via a quality by design approach based on 23 full factorial design. The design includes the functional relationships between independent processing variables and dependent responses of particle size, polydispersity index, zeta potential, cumulative drug released after 24h and ex-vivo transdermal steady flux. The developed nanocarrier was subjected to TEM (transmission electron microscope) for morphological elucidation and stability study within a period of three months at different storage temperatures.The cubic phase of LCNPs was successfully prepared using glyceryl monooleate (GMO) via the emulsification technique. Based on the factorial design, the independent operating variables significantly affected the five dependent responses. The cubosomes hydrodynamic diameters were in the nanometric range (101–386nm) with narrow particle size distribution, high negative zeta potential ≥−30mV and entrapment efficiency ≥94%. The LCNPs succeeded in sustaining progesterone release for almost 24h, following a non-fickian transport of drug diffusion mechanism. Ex-vivo study revealed a significant enhancement up to 6 folds in the transdermal permeation of progesterone-loaded LCNPs compared to its aqueous suspension. The optimized LCNPs exhibited a high physical stability while retaining the cubic structure for at least three months.Quality by design approach successfully accomplished a predictable mathematical model permitting the development of novel LCNPs for transdermal delivery of progesterone with the benefit of reducing its oral route side effects.

Self-assembled liquid crystalline nanoparticles as an ophthalmic drug delivery system. Part II: optimization of formulation variables using experimental design

In the field of keratoconus treatment, a lipid-based liquid crystal nanoparticles system has been developed to improve the preocular retention and ocular bioavailability of riboflavin, a water-soluble drug. The formulation of this ophthalmic drug delivery system was optimized by a simplex lattice experimental design. The delivery system is composed of three main components that are mono acyl glycerol (monoolein), poloxamer 407 and water and two secondary components that are riboflavin and glycerol (added to adjust the osmotic pressure). The amounts of these three main components were selected as the factors to systematically optimize the dependent variables that are the encapsulation efficiency and the particle size. In this way, 12 formulas describing experimental domain of interest were prepared. Results obtained using small angle X-rays scattering (SAXS) and cryo-transmission electron microscopy (cryo-TEM) evidenced the presence of nano-objects with either sponge or hexagonal inverted structure. In the zone of interest, the percentage of each component was determined to obtain both high encapsulation efficiency and small size of particles. Two optimized formulations were found: F7 and F1. They are very close in the ternary phase diagram as they contain 6.83% of poloxamer 407; 44.18% and 42.03% of monoolein; 46.29% and 48.44% of water for F7 and F11, respectively. These formulations displayed a good compromise between inputs and outputs investigated.

Self-assembled liquid crystalline nanoparticles as an ophthalmic drug delivery system. Part I: influence of process parameters on their preparation studied by experimental design

To develop self-assembled liquid crystalline nanoparticles as a drug delivery system for keratoconus treatment, a formulation containing riboflavin a water-soluble drug, two surfactants (poloxamer 407 and mono acyl glycerol – monoolein-) and water was optimized and prepared by emulsification and a homogenization process. A fractional factorial design was applied to estimate the main effects and interaction effects of five parameters on two responses, namely particle size and encapsulation efficiency. The five parameters are the temperature of the two phases, the duration of emulsification, the presence of heating during homogenization, the number of passes and pressure. The most influent parameters are the presence of heating during the homogenization and the pressure that led to the production of nanoparticles with an average size of 145 nm and an average encapsulation efficiency of 46%.

Protein-Bearing Cubosomes Prepared by Liquid Precursor Dilution: Inner Ear Delivery and Pharmacokinetic Study Following Intratympanic Administration

This study aims to design self-assembled cubic liquid crystalline nanoparticles (cubosomes) to enhance inner ear bioavailability of earthworm fibrinolytic enzyme (EFE). The cubosomes were prepared using a liquid precursor mixture containing glyceryl monooleate, hydrotrope propylene glycol, and F127 as stabilizer. Submicron-size particles (100 nm to 200 nm) with slight negative charge formed spontaneouly upon dilution of the liquid precursors. Small-angle X-ray scattering (SAXS) results demonstrated that the formation of cubsomses largely depended on the hydration level of liquid precursor and the encapsulation of highly hydrophilic EFE induced the phase transition of the cubosome. The encapsulatoin efficiency of EFE in cubosomes was 79.6% and their cubic ultrastructure were confirmed by TEM. In vitro cell toxicity results showed that the viability of L929 cells decreased by increasing the concentration of nanoparticles. Octadecyl rhodamine B chloride (R18) labeled cubosomes were identified in the basal turn of the scala tympani and middle portion of the cochlea after 30 min post intratympanic administration, indicating that cubosomes could permeate through the RWM. The AUC(0 h-24 h) of EFE administrated as EFE cubosomes was 2.6-fold in cochlear fluid compared to those applied by free drug via the intratympanic route. In conclusion, self-assembled liquid crystalline nanoparticles provide a promising protein vehicle for effective inner ear drug delivery.

Enhanced oral absorption of 20(S)-protopanaxadiol by self-assembled liquid crystalline nanoparticles containing piperine: in vitro and in vivo studies

Background20(S)-protopanaxadiol (PPD), similar to several other anticancer agents, has low oral absorption and is extensively metabolized. These factors limit the use of PPD for treatment of human diseases.MethodsIn this study, we used cubic nanoparticles containing piperine to improve the oral bioavailability of PPD and to enhance its absorption and inhibit its metabolism. Cubic nanoparticles loaded with PPD and piperine were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel and verified using transmission electron microscopy and differential scanning calorimetry. We evaluated the in vitro release of PPD from these nanoparticles and its absorption across the Caco-2 cell monolayer model, and subsequently, we examined the bioavailability and metabolism of PPD and its nanoparticles in vivo.ResultsThe in vitro release of PPD from these nanoparticles was less than 5% at 12 hours. PPD-cubosome and PPD-cubosome loaded with piperine (molar ratio PPD/piperine, 1:3) increased the apical to basolateral permeability values of PPD across the Caco-2 cell monolayer from 53% to 64%, respectively. In addition, the results of a pharmacokinetic study in rats showed that the relative bioavailabilities of PPD-cubosome [area under concentration–time curve (AUC)0–∞] and PPD-cubosome containing piperine (AUC0–∞) compared to that of raw PPD (AUC0–∞) were 166% and 248%, respectively.ConclusionThe increased bioavailability of PPD-cubosome loaded with piperine is due to an increase in absorption and inhibition of metabolism of PPD by cubic nanoparticles containing piperine rather than because of improved release of PPD. The cubic nanoparticles containing piperine may be a promising oral carrier for anticancer drugs with poor oral absorption and that undergo extensive metabolism by cytochrome P450.

Self-assembled liquid crystalline nanoparticles as a novel ophthalmic delivery system for dexamethasone: Improving preocular retention and ocular bioavailability

The object of this study was to design novel self-assembled liquid crystalline nanoparticles (cubosomes) as an ophthalmic delivery system for dexamethasone (DEX) to improve its preocular retention and ocular bioavailability. DEX cubosome particles were produced by fragmenting a cubic crystalline phase of monoolein and water in the presence of stabilizer Poloxamer 407. Small angle X-ray diffraction (SAXR) profiles revealed its internal structure as Pn3 m space group, indicating the diamond cubic phase. In vitro, the apparent permeability coefficient of DEX administered in cubosomes exhibited a 4.5-fold (F1) and 3.5-fold (F2) increase compared to that of Dex-Na phosphate eye drops. Preocular retention studies revealed that the retention of cubosomes was significantly longer than that of solution and carbopol gel, with AUC 0→180 min of Rh B cubosomes being 2–3-fold higher than that of the other two formulations. In vivo pharmacokinetics in aqueous humor was evaluated by microdialysis, which indicated a 1.8-fold (F1) increase in AUC 0→240 min of DEX administered in cubosomes relative to that of Dex-Na phosphate eye drops, with about an 8-fold increase compared to that of DEX suspension. Corneal cross-sections after incubation with DEX cubosomes demonstrated an unaffected corneal structure and tissue integrity, which indicated the good biocompatibility of DEX cubosomes. In conclusion, self-assembled liquid crystalline nanoparticles might represent a promising vehicle for effective ocular drug delivery.