Lipid Liquid Crystals Research Articles

Preparation and characterization of injectable in-situ forming gel based on lipid liquid crystal for one month delivery of aripiprazole: In-vitro and in-vivo evaluations in rats

The present study developed a one-month sustained-release formulation of aripiprazole, used for the treatment of schizophrenia and bipolar disorder, based on lipid liquid crystal (LLC) using phosphatidylcholine (PC) and N-methyl-2-pyrrolidone (NMP) solvent with sorbitan monooleate (SMO) or derivative glycerol oleate (glycerol monooleate (GMO), glycerol di-oleate (GDO), and glycerol trioleate (GTO)). The best formulation was selected based on the minimum initial burst release and the highest release of aripiprazole during the 30-day period. So, the formulations containing GMO and SMO exhibited the best initial slow release, while the other two formulations showed a burst release within 24 h. Furthermore, the GMO formulation did not release the drug completely during the 30-day study period, and the formulation containing GTO released the drug completely in less than a month. Therefore, the two formulations containing SMO and GDO were selected for further tests. The prepared liquid crystals had a hexagonal structure, indicating the creation of a suitable formulation structure with slow and controlled release. The area under the curve for the LLC-SMO formulation was higher than for other formulations, supporting the sustained release of aripiprazole and improving the long-term bioavailability of the drug. Moreover, this formulation was found to be safe and did not cause any damage to the skin at the injection site or vital organs such as the spleen, kidney, brain, heart, and liver. Hence, it can be considered a suitable option for developing an extended-release LLC formulation of aripiprazole.

Sustain-release lipid-liquid crystal formulations of pexiganan against Helicobacter pylori infection: in vitro evaluation in C57BL/6 mice

IntroductionThe Gram-negative bacterium Helicobacter pylori, H. pylori, is associated with significant digestive disorders. However, the effectiveness of bacterial eradication is declining due to drug resistance. A potent anti-H. pylori activity is shown by the natural antimicrobial peptide pexiganan.ObjectiveThe current study aimed to evaluate the effectiveness of pexiganan and its lipid-liquid crystals (LLCs) in inducing Helicobacter pylori in mice.MethodsIn this experimental study, H. pylori infection was first induced in C57BL/6 mice. Secondly, the antibacterial efficacy of pexiganan and its LLCs formulations was investigated to eliminate H. pylori infection.ResultsThe H. pylori infection could not be completely eradicated by pexiganan peptide alone. However, incorporating pexiganan within the LLC formulation resulted in an increased elimination of H. pylori. Under the H&E strain, the pexiganan-LLCs formulation revealed minimal mucosal alterations and a lower amount of inflammatory cell infiltration in the stomach compared to the placebo.ConclusionClarithromycin was more effective than pexiganan at all tested concentrations. Furthermore, the pexiganan-loaded LLCs exhibited superior efficacy in curing H. pylori infection in a mouse model compared to pexiganan alone. This formulation can enhance H. pylori clearance while mitigating the adverse effects, typically associated with conventional drugs, leading to a viable alternative to current treatment options.

Development of Sustained Release Formulations Based on Lipid-Liquid Crystal to Control the Release of Deoxycholate: In Vitro and In Vivo Assessment

Subcutaneous injections of phosphatidylcholine (PC), sodium deoxycholate (NADC), and a mixture of them were found to be an effective option for treating cellulite. However, it is noteworthy that the injection of NADC may result in inflammation as well as necrosis in the injection area. The preparation of a sustained release formulation based on lipid-liquid crystal that controls the release of NADC could be a potential solution to address the issue of inflammation and necrosis at the site of injection. To present a practical and validated approach for accurately determining the concentration of NADC in LLC formulations, spectrofluorimetry was used based on the International Council for Harmonization (ICH) Q2 guidelines. Based on the validation results, the fluorometric technique has been confirmed as a reliable, efficient, and economical analytical method for quantifying NADC concentrations. The method demonstrated favorable attributes of linearity, precision, and accuracy, with an r2 value of 0.999. Furthermore, it exhibited excellent interday and intraday repeatability, with RSD values below 4%. The recovery percentages ranged from 97 to 100%, indicating the method’s ability to accurately measure NADC concentrations. The subcutaneous injection of the LLC-NADC demonstrated a reduction in inflammation and tissue necrosis in skin tissue, along with an increase in fat lysis within 30 days, when compared to the administration of only NADC solution. Moreover, the histopathological assessment confirmed that the use of the LLC formulation did not result in any detrimental side effects for kidney or heart tissue.

Preparation and Physicochemical Evaluation of Injectable Sustained-Release Risperidone by Lipid Liquid Crystal Vehicle

Introduction: Risperidone is a highly effective medicine in patients with mental disorders. Since maintaining blood concentrations of risperidone within the therapeutic index is pivotal during treatment, these patients should receive medication daily and continuously. Method: In this study, an optimal lipid liquid crystal was designed according to the maximum release for 60 days based on different ratios of phosphatidylcholine (PC) to sorbitan monooleate (PC:SMO), tween 80 (w/w%), and tocopherol acetate (w/w%) using Design Expert software with the Central Composite Design (CCD) method. Release evaluations were conducted in vitro to compare the effects of lipid liquid crystal and Risperdal CONSTA®. The structure evaluation was also tested using polarized electron microscopy and in vitro assessment via cell culture. Results: The optimal formulation was selected based on the maximum release (100%) of the drug obtained within 2 months with a PC: SMO ratio of 58.6%, tween 0.82% (w/w), and tocopherol acetate 3.6% (w/w). A hexagonal mesophase with a dihedral structure was observed in the liquid crystal structure. No toxicity was observed in the cell culture test. Conclusion: The comparison of the results of in vitro studies of the liquid crystal formulation containing risperidone and the commercial formulation, Risperdal CONSTA®, showed that the liquid crystal system provides better and more uniform drug release for 60 days. Therefore, it can increase patient compliance and ease the problems of oral administration

Prolonged local delivery of doxorubicin to cancer cells using lipid liquid crystalline system

Exploring efficient strategies to eradicate the tumor tissue and enhance patient outcomes still remained a serious challenge. Systemic toxicity of the current chemotherapeutics and their low concentration in the tumor site limited reaching a practical approach in their administration and combinational therapy. Besides, complicated delivery platforms could not receive the marketing approval due to difficulties in scale up procedures. To this aim, we developed a simple injectable local delivery platform which provided a sufficient dose of the chemotherapeutic in the cancerous tissue with sustained release properties. Herein, various injectable in situ forming LLC formulations loaded with doxorubicin (DOX) were developed. Although there were many previous studies on lipid liquid crystal (LLC) based formulations, their performance as an injectable intratumoral depot system for local chemotherapy has not been extensively investigated yet. In the current study we developed 18 formulations of DOX loaded LLCs using Box-Behnken method via different ratios of phosphatidyl choline: sorbitan monooleate (PC: SMO), N-Methyl-2-pyrrolidone (NMP), and tween 80. The physicochemical properties of the formulations were investigated and their in vivo tumor inhibition efficiencies in C26 tumor bearing mouse model was further studied. The results indicated that DOX loaded PC: SMO/NMP/Tween 80 (50:50/50/2 w/w%) and DOX loaded PC: SMO/NMP (50:50/50 w/w%) formulations were syringeable with pseudoplastic behavior. Also, they could release the cargo in a sustained manner for 60 days. Compared to intravascular administration of DOX, intratumoral injection of the developed formulations led to a significant decrease in tumor volume and enhancement of the survival rate in murine tumor model. Additionally, animal imaging studies proved their prolonged accumulation in the tumor site. Histopathological studies showed that treatment with the DOX-loaded LLC formulations did not cause any systemic toxicity to vital organs. Taken together, we believe that the developed simple and efficient local delivery platform can be further used in combinational therapies and treatment of various solid tumors.

In-vitro and in-vivo evaluation of sustained-release buprenorphine using in-situ forming lipid-liquid crystal gels

AimsSustained-release systems reduce the incidence of drug side effects and the need for frequent drug consumption, thus increasing patient compliance with treatment. In this study, we aimed to produce sustained-release buprenorphine (BP) using lipid-liquid crystal gels. Main methodsThe three experimental groups in this study included: group I: lipid-liquid crystal formulation 5 (F5) containing BP, group II: BP-free F5, group III: BP solution in NMP, and group IV: control (no treatment). The formulations were injected subcutaneously into the rabbits' back neck. Key findingsThe results showed that the time required to reach the drug's maximum concentration (Tmax) was longer in group I than in group III. The maximum BP concentration (Cmax) and the constants of the drug removal rate and drug absorption rate (Ka) were significantly higher in group III compared to group I. The half-life (t1/2) of the drug in blood circulation was significantly longer in group I than in group III. Histopathological analysis revealed no histological abnormalities in the skin and heart in group I (BP-containing F5); however, mild hyperemia was observed in interstitial vessels in group III (BP-containing NMP). The kidney and liver tissues showed normal structure in the control group, as well as groups I and II. However, in the group receiving BP-containing NMP, significant congestion, tissue damage, necrosis, and fibrosis were observed in the kidney and liver. SignificanceThe results showed that the lipid-liquid crystal system can be used to design slow-release platforms for BP, minimizing the side effects associated with the use of its conventional forms.

Liquid crystalline lipid nanoparticle promotes the photodynamic activity of gallium protoporphyrin against S. aureus biofilms.

Antimicrobial photodynamic therapy (aPDT) has emerged as an innovative strategy to combat antibiotic resistant microbes; yet aPDT efficacies against biofilms are sub-optimal due to inability of photosenstizers to reach microbes embedded in biofilm matrix. To overcome this challenge, liquid crystal lipid nanoparticles (LCNP) were employed in this study as a smart, biocompatible and triggerable delivery system for the new photosensitizer gallium protoporphyrin (GaPP), due to their capabilities in promoting efficient antimicrobial delivery to biofilms. The relationship between GaPP loading of LCNP, reactive oxygen species (ROS) production and the in vitro antibacterial activity against two antibiotic resistant Staphylococcus aureus strains was established. LCNP substantially improved the antibacterial activity of GaPP, completely eradicating S. aureus and MRSA planktonic cultures, using a GaPP concentration of 0.8μM and light dose 1.9J/cm2. At the same concentration and light dose, unformulated GaPP triggered only a 4 log10 and 2 log10 reduction in respective planktonic cultures. Most importantly, the activity of GaPP against biofilms was enhanced by 2-fold compared to unformulated GaPP, reducing the viability of S. aureus and MRSA biofilms by 8 log10 and 5 log10, respectively. The biosafety of photoactivated GaPP-LCNP was evaluated against human fibroblasts, which indicated a high safety profile of the treatment. Therefore, these findings encourage further investigations of GaPP-LCNP as a potential treatment for localized chronic infections.

A sustain-release lipid-liquid crystal containing risperidone based on glycerol monooleate, glycerol dioleate, and glycerol trioleate: In-vitro evaluation and pharmacokinetics in rabbits

The present study intends to develop an in-situ forming gel (ISFG) vehicle for the sustained and gradual delivery of risperidone to schizophrenic patients for longer drug dosing intervals. Initial burst release (IBR) was evaluated for the lipid liquid crystals (LLCs) containing glycerol monooleate (GMO), glycerol dioleate (GDO), and glycerol trioleate (GTO), along with different percentages of phosphatidylcholine (PC) as the oil phase, and N-methyl-2-pyrrolidone (NMP) as the solvent. In vitro evaluations, pharmacokinetics, and histopathological studies in rabbits were done to find the optimal LLC formulation. The formulation containing GDO had lower IBR in comparison with the other formulations, including Risperdal CONSTA®. Microscopy assessment indicated that the structures of LLC formulations containing GMO, GDO, and GTO cubic (Q2) were hexagonal (HII) and an intermediate form of HII and Q2, respectively. Comparison of the pharmacokinetic data showed that the optimal LLC containing GDO/PC with the ratio of 2.2:1 and 30% NMP created more consistent release profiles in vitro and in vivo during 60 days. Histopathology results in rabbits showed almost no side effects for the formulations. This study emphasized the better drug delivery potential of GDO-based gel-forming systems compared to Risperdal CONSTA®, which would increase patient compliance and decrease the inconvenience of frequent drug oral administrations.

Lipid-liquid crystals for 2 months controlled risperidone release: In-vitro evaluation and pharmacokinetics in rabbits

In this study, a drug delivery system based on lipid liquid crystal (LLC) was developed for the long-term delivery of risperidone to improve psychological treatment. Optimal LLC formulation was achieved based on maximum release after 60 days with different ratios of phosphatidylcholine (PC) to sorbitol monooleate (PC: SMO), tween grade 80 (w/w %), and tocopherol acetate (TA) (w/w %) using the Box-Behnken method. In vitro and ex vivo studies, pharmacokinetics, and histopathological examination in rabbits were conducted to compare the optimal LLC with Risperdal CONSTA®. The optimum formulation containing the PC to SMO ratio of 58.6%, tween 0.82% w/w, and TA 3.6% w/w was selected because it had the highest drug release percentage (100%) during about two months. Polarized optical microscopy (POM) revealed HII mesophase with a 2-dimensional structure. Cell culture also revealed moderate cytotoxicity for LLC-risperidone. Pharmacokinetic data displayed that the optimal LLC created a more consistent drug serum level within 60 days, and histopathology results demonstrated slight to moderate damage in rabbits’ organs. Furthermore, the accelerated stability test confirmed optimum stability for LLC and risperidone. This study confirmed the better pharmacokinetic potentials of SMO-based LLC systems compared with Risperdal CONSTA®, which would promote patient compliance and obviate the difficulties of additional oral therapy.

Liquid Crystal Nanoparticles Enhance Tobramycin Efficacy in a Murine Model of Pseudomonas aeruginosa Biofilm Wound Infection.

Chronic Pseudomonas aeruginosa wound infections are highly prevalent and often untreatable due to biofilm formation, resulting in high antimicrobial tolerance. Standard antibiotic therapy for P. aeruginosa infections involves tobramycin, yet it is highly ineffective as monotherapy as tobramycin cannot penetrate the biofilm to elicit its antimicrobial effect. Lipid liquid crystal nanoparticles (LCNPs) have previously been shown to increase the antimicrobial efficacy and penetration of tobramycin against P. aeruginosa biofilms in vitro and ex vivo. Here, for the first time, we have developed a chronic P. aeruginosa biofilm infection in full-thickness wounds in mice to examine the potential of LCNPs to improve the effect of tobramycin, preclinically. After three doses, administered once a day, tobramycin-LCNPs significantly reduced the P. aeruginosa bacterial load in murine wounds 1000-fold more than unformulated tobramycin, which in turn showed no significant difference to the saline control treatment. Consistent with the improved P. aeruginosa eradication, the tobramycin-LCNPs promoted wound healing. In comparison to previous in vitro and ex vivo data, we show a strong in vitro-in vivo correlation between P. aeruginosa biofilm infection models. The enhanced activity of tobramycin-LCNPs in vivo in the preclinical murine model demonstrates the strong potential of LCNPs as a next-generation formulation approach to improve the efficacy of tobramycin against P. aeruginosa biofilm wound infections.

Comparison of lipid liquid crystal formulation and Vivitrol® for sustained release of Naltrexone: In vitro evaluation and pharmacokinetics in rats

Camurus’ FluidCrystal® injection depot is a lipid liquid crystal (LLC) phase formation-based method, comprising of glycerol dioleate (GDO) and soy phosphatidylcholine (SPC), together with minute quantities of N-methyl-2-pyrrolidone solvent (NMP). The present study aimed to develop a method for LLC using sorbitan monooleate (LLC-SMO) instead of GDO to prepare a one-month sustained-release formulation of naltrexone (NTX) that is applied for the treatment of autism and treating alcohol dependence. The optical characteristics of the LLC were assessed by polarizing light microscopy (PLM) to reveal the presence of lamellar, hexagonal, and cubic mesophases. Furthermore, in vitro release of NTX and NMP, degradation, pharmacokinetics, and histopathology of LLC-GDO and LLC-SMO in rats were evaluated and compared to those of Vivitrol®. The PLM images revealed that the structure of LLC-SMO is hexagonal, similar to LLC-GDO. The in vitro release of NTX and its pharmacokinetic results in rats indicted that the LLC-SMO system is more uniform than LLC-GDO and Vivitrol® during 35 days. Histopathological results of LLC-GDO and LLC-SMO confirmed the biocompatibility of our LLC delivery systems. Taken together these data demonstrate that the LLC-SMO-based method, was efficient enough to sustain the release of NTX in vitro and in vivo, confirming the biocompatible nature of this delivery system.

Tobramycin Liquid Crystal Nanoparticles Eradicate Cystic Fibrosis-Related Pseudomonas aeruginosa Biofilms.

Pseudomonas aeruginosa biofilms cause persistent and chronic infections, most known clinically in cystic fibrosis (CF). Tobramycin (TOB) is a standard anti-pseudomonal antibiotic; however, in biofilm infections, its efficacy severely decreases due to limited permeability across the biofilm matrix. Herewith, a biomimetic, nanostructured, lipid liquid crystal nanoparticle-(LCNP)-formulation is discovered to significantly enhance the efficacy of TOB and eradicate P. aeruginosa biofilm infections. Using an advanced, biologically-relevant co-culture model of human CF bronchial epithelial cells infected with P. aeruginosa biofilms at an air-liquid interface, nebulized TOB-LCNPs completely eradicated 1× 109 CFU mL-1 of P. aeruginosa after two doses, a 100-fold improvement over the unformulated antibiotic. The enhanced activity of TOB is not observed with a liposomal formulation of TOB or with ciprofloxacin, an antibiotic that readily penetrates biofilms. It is demonstrated that the unique nanostructure of the LCNPs drives the enhanced penetration of TOB across the biofilm barrier, but not through the healthy lung epithelium barrier, significantly increasing the available antibiotic concentration at the site of infection. The LCNPs are an innovative strategy to improve the performance of TOB as a directed pulmonary therapy, enabling the administration of lower doses, reducing the toxicity, and amplifying the anti-biofilm activity of the anti-pseudomonal antibiotic.

Protective Liquid Crystal Nanoparticles for Targeted Delivery of PslG: A Biofilm Dispersing Enzyme.

The glycoside hydrolase, PslG, attacks and degrades the dominant Psl polysaccharide in the exopolymeric substance (EPS) matrix of Pseudomonas aeruginosa biofilms and is a promising therapy to potentiate the effect of antibiotics. However, the need for coadministration with an antibiotic and the potential susceptibility of PslG to proteolysis highlights the need for an effective delivery system. Here, we compared liposomes versus lipid liquid crystal nanoparticles (LCNPs) loaded with PslG and tobramycin as potential formulation approaches to (1) protect PslG from proteolysis, (2) trigger the enzyme's release in the presence of bacteria, and (3) improve the total antimicrobial effect in vitro and in vivo in a Caenorhabditis elegans infection model. LCNPs were an effective formulation strategy for PslG and tobramycin that better protected the enzyme against proteolysis, triggered and sustained the release of PslG, improved the antimicrobial effect by 10-100-fold, and increased the survival of C. elegans infected with P. aeruginosa. Digestible LCNPs had the advantage of triggering the enzyme's release in the presence of bacteria. However, compared to nondigestible LCNPs, negligible differences arose between the LCNPs' ability to protect PslG from proteolysis and potentiate the antimicrobial activity in combination with tobramycin. In C. elegans, the improved antimicrobial efficacy was comparable to tobramycin-LCNPs, although the PslG + tobramycin-LCNPs achieved a greater than 10-fold reduction in bacteria compared to the unformulated combination. Herewith, LCNPs are showcased as a promising protective delivery system for novel biofilm dispersing enzymes combined with antibiotics, enabling infection-directed therapy and improved performance.

On the thermotropic and magnetotropic phase behavior of lipid liquid crystals containing magnetic nanoparticles.

The inclusion of superparamagnetic iron oxide nanoparticles (SPIONs) in lipid mesophases is a promising strategy for drug-delivery applications, combining the innate biocompatibility of lipid architectures with SPIONs' response to external magnetic fields. Moreover, the organization of SPIONs within the lipid scaffold can lead to locally enhanced SPIONs concentration and improved magnetic response, which is key to overcome the current limitations of hyperthermic treatments. Here we present a Small-Angle X-ray Scattering (SAXS) structural investigation of the thermotropic and magnetotropic behavior of glyceryl monooleate (GMO)/water mesophases, loaded with hydrophobic SPIONs. We prove that even very low amounts of SPIONs deeply alter the phase behavior and thermotropic properties of the mesophases, promoting a cubic to hexagonal phase transition, which is similarly induced upon application of an Alternating Magnetic Field (AMF). Moreover, in the hexagonal phase SPIONs spontaneously self-assemble within the lipid scaffold into a linear supraparticle. This phase behavior is interpreted in the framework of the Helfrich's theory, which shows that SPIONs affect the mesophase both from a viscoelastic and from a structural standpoint. Finally, the dispersion of these cubic phases into stable magnetic colloidal particles, which retain their liquid crystalline internal structure, is addressed as a promising route towards magneto-responsive drug-delivery systems (DDS).

Characterization of a Liquid Crystal System for Sustained Release of a Peptide BMS-686117.

Liquid crystal lipid-based formulations are an effective approach to prolong pharmacokinetics and reduce burst release of a drug on subcutaneous delivery. The objective of this paper was to investigate the influence of phase structures of a lipid-based liquid crystal delivery system and its associated mechanical properties on the release profile of a peptide. It was hypothesized that release of drug molecules are closely related to the mechanical properties that are controlled by phase structures. Experimentally, the relationship between phase structures of lipid liquid crystal system-soy phosphatidyl choline (SPC) and glycerol dioleate (GDO) in water were characterized by polarized light microscopy and small angle X-ray diffraction. Their rheological properties were evaluated with a rheometer and the in vitro release of the peptide as a measure drug release from the LC-depot injection. Three phases: disordered phase, lamellar phase, mixtures of cubic, lamellar, and hexagonal phases were detected by varying formulation compositions. A significant difference in rheological behavior was observed. The disordered phase displayed some attributes of typical Newtonian fluid with lowest viscosity while the lamellar phase showed a shear thinning behavior. Regarding the mechanical strength, the lamellar phase presents the highest storage modulus due to its layer structure followed by mixed phases. Comparing release profiles, the lamellar phase produced a fast release followed by the mixture of phases. In conclusion, this study demonstrates the ability to characterize LC phase structures with microscopy, small angle X-ray diffraction, and rheological measurements and their link to modulating a peptide release profile.

Behavior of lysozyme adsorbed onto biological liquid crystal lipid monolayer at the air/water interface**Project supported by the National Natural Science Foundation of China (Grant Nos. 21402114 and 11544009), the Natural Science Basic Research Plan in Shaanxi Province of China (Grant No. 2016JM2010), the Fundamental Research Funds for the Central Universities of China (Grant No. GK201603026), and the National University Science

The interaction between proteins and lipids is one of the basic problems of modern biochemistry and biophysics. The purpose of this study is to compare the penetration degree of lysozyme into 1,2-diapalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethano-lamine (DPPE) by analyzing the data of surface pressure–area (π–A) isotherms and surface pressure–time (π–T) curves. Lysozyme can penetrate into both DPPC and DPPE monolayers because of the increase of surface pressure at an initial pressure of 15 mN/m. However, the changes of DPPE are larger than DPPC, indicating stronger interaction of lysozyme with DPPE than DPPC. The reason may be due to the different head groups and phase state of DPPC and DPPE monolayers at the surface pressure of 15 mN/m. Atomic force microscopy reveals that lysozyme was absorbed by DPPC and DPPE monolayers, which leads to self-aggregation and self-assembly, forming irregular multimers and conical multimeric. Through analysis, we think that the process of polymer formation is similar to the aggregation mechanism of amyloid fibers.

Liquid crystal based sensors monitoring lipase activity: A new rapid and sensitive method for cytotoxicity assays

In this work we present liquid crystal (LC) based sensor devices to monitor cell viability. The sensing layer is composed by the LC and a planar monolayer of phospholipids. In the presence of minute traces of phospholipases, which hydrolyze enzymatically phospholipids, the LC–lipid interface is disintegrated. This event causes a change in orientation of the LC, which was followed in a polarized microscope. The lipase activity can be used to measure the cell viability, since members of this enzyme family are released by cells, as they undergo necrosis. The described sensor was used to monitor the presence of the lipases released from three different cell lines, which were either exposed to highly cytotoxic model compounds (sodium azide and paracetamol) or subjected to freeze-thaw cycles to induce cell death by a non-chemical based inducer for apoptosis, such as temperature. Finally, the comparison of lipase activity detected by a state-of-the-art fluorescence assay to the LC based system resulted in the superiority of the LC system concerning incubation time and sensitivity.

Amphiphilic designer nano-carriers for controlled release: from drug delivery to diagnostics

Our review highlights lipid liquid crystal nanocarriers, essentially their design considerations and sugar-based materials for specific targeted delivery.

Drug delivery applications of non-lamellar liquid crystalline phases and nanoparticles

Abstract Lipid liquid crystal (LC) phases are fascinating structures formed spontaneously in aqueous media through molecular self-assembly. The resulting three-dimensional architectures with supra-molecular order are governed by the effective molecular geometries of the participating lipid building blocks. LC structures vary from normal “oil-in-water” phases to reversed “water-in-oil” phases, where the lipid and aqueous domains can be isolated, continuous or biocontinuous depending on the phase morphology. As is intuitively understood, this imposes different degrees of restriction to diffusive transport within LC phases; a property that can be effectively utilized for controlling the release of active pharmaceutical ingredients (API) in drug products. Aside from controlling release, LC phases can also be used for protecting sensitive substances such as peptides and proteins from enzymatic degradation, and for solubilization of sparingly soluble compounds into the lipid and/or aqueous nano-domains. LC phases can furthermore, with the aid of swelling and stabilization aids such as amphiphilic surfactants and copolymers, be fragmented into well-defined and kinetically stable nanoparticles (LCNP) with more or less retained inner phase structure. Due to their often very high solubilizing and encapsulating abilities, LCNPs are interesting carrier systems for a broad range of API, from small sparingly soluble substances to larger peptides or proteins. Here we discuss the interplay between structure and function of LC systems and also their different uses in commercial and pipeline products.

Phytantriol and glyceryl monooleate cubic liquid crystalline phases as sustained-release oral drug delivery systems for poorly water-soluble drugs II. In-vivo evaluation

Abstract Objectives Lipid-based liquid crystals formed from phytantriol (PHY) and glyceryl monooleate (GMO) retain their cubic-phase structure on dilution in physiologically relevant simulated gastrointestinal media, suggesting their potential application as sustained-release drug-delivery systems for poorly water-soluble drugs. In this study the potential of PHY and GMO to serve as sustained-release lipid vehicles for a model poorly-water-soluble drug, cinnarizine, was assessed and compared to that of an aqueous suspension formulation. Methods Small-angle X-ray scattering was used to confirm the nanostructure of the liquid-crystalline matrix in the presence of the selected model drug, cinnarizine. Oral bioavailability studies were conducted in rats, and disposition of lipid and drug in segments of the gastrointestinal tract was determined over time. Differences in the digestibility and stability of formulations under digestion conditions were investigated using an in-vitro lipolysis model. Key findings The oral bioavailability of cinnarizine using the PHY formulation was 41%, compared to 19% for the GMO formulation and 6% for an aqueous suspension. The PHY formulation provided a Tmax for cinnarizine of 33 h, with absorption apparent up to 55 h after administration. In contrast, the Tmax for the GMO formulation was only 5 h. The PHY formulation was retained in the stomach for extended periods of time, with 56% of lipid remaining in the stomach after 24 h, in contrast to less than 1% of the GMO formulation after 8 h, suggesting that gastric retention was a key aspect of the prolonged period of absorption, which correlated with the formulations' relative susceptibility to in-vitro lipolysis and degradation. Conclusions PHY provides a dramatic sustained-release effect for cinnarizine on oral administration, which is linked to gastric retention of the formulation and its ability to resist digestive processing. Poorly digested liquid crystal lipid formulations therefore offer a novel class of sustained-release matrices for oral administration.