Novel lipid-based colloidal dispersions as potential drug administration systems – expectations and reality

 Colloidal drug carriers offer a number of potential advantages as delivery systems for, for example, poorly soluble compounds. The first generation of colloidal carriers, in particular liposomes and sub-micron-sized lipid emulsions, are, however, associated with several drawbacks which so far have prevented the extensive use of these carriers in drug delivery. As an alternative colloidal delivery system melt-emulsified nanoparticles based on solid lipids have been proposed. Careful physicochemical characterization has demonstrated that these lipid-based nanosuspensions (solid lipid nanoparticles) are not just “emulsions with solidified droplets”. During the development process of these systems interesting phenomena have been observed, such as gel formation on solidification and upon storage, unexpected dynamics of polymorphic transitions, extensive annealing of nanocrystals over significant periods of time, stepwise melting of particle fractions in the lower-nanometer-size range, drug expulsion from the carrier particles on crystallization and upon storage, and extensive supercooling. These phenomena can be related to the crystalline nature of the carrier matrix in combination with its colloidal state. Observation of the supercooling effect has led to the development of a second new type of carrier system: nanospheres of supercooled melts. This novel type of colloidal lipidic carrier represents an intermediate state between emulsions and suspensions. Moreover, these dispersions are particularly suited to the study of the basic differences between colloidal triglyceride emulsions and suspensions. For many decades drug carriers have represented the only group of colloidal drug administration systems. Nowadays a fundamentally different group of dispersions is also under investigation: drug nanodispersions. They overcome a number of carrier-related drawbacks, such as limitations in drug load as well as side effects due to the matrix material of the carrier particles. Utilizing this concept virtually insoluble drugs can be formulated as colloidal particles, of solid or supercooled nature. For example, coenzyme Q₁₀ (Q₁₀) has been successfully processed into a dispersion of a supercooled melt. Droplet sizes in the lower nanometer range and shelf lives of more than 3 years can easily be achieved for Q₁₀ dispersions. The drug load of the emulsion particles reaches nearly 100%. Received: 15 July 1999/Accepted: 11 November 1999     

Semi-elastic core-shell nanoparticles enhanced the oral bioavailability of peptide drugs

The rigidity of nanoparticles was newly reported to influence their oral delivery. Semi-elastic nanoparticles can enhance the penetration in mucus and uptake by epithelial cells. However, it is still challenging and unclear that the semi-elastic core-shell nanoparticles can enhance the oral bioavailability of peptide drugs. This study was for the first time to validate the semi-elastic core-shell poly(lactic-co-glycolic acid) (PLGA)-lipid nanoparticles (LNPs) as the carrier of the oral peptide drug. The antihypertensive peptide Val-Leu-Pro-Val-Pro (VP5) loaded LNPs (VP5-LNPs) were prepared by a modified thin-film ultrasonic dispersion method. Uptake experiment was performed in Caco-2 and HT-29 cells and monitored by high content screening (HCS) and flow cytometric (FCM). Pharmacokinetics of VP5-LNPs was carried out in Sprague-Dawley (SD) rats and analyzed by DAS 2.0. The optimal VP5-LNPs had an average particle size of 247.3 ± 3.8 nm, zeta potential of −6.57 ± 0.45 mV and excellent entrapment efficiency (EE) of 89.88% ± 1.23%. Transmission electron microscope (TEM) and Differential scanning calorimeter (DSC) further confirmed the core-shell structure. VP5-LNPs could increase the cellular uptake in vitro and have a 2.55-fold increase in AUC0-72 h, indicating a great promotion of the oral bioavailability. The semi-elastic LNPs remarkably improved the oral availability of peptide and could be a promising oral peptide delivery system for peptide drugs in the future.     

Synthesis of silver nanoparticles using root extract of Duchesnea indica and assessment of its biological activities

Treatment of microbial infections and inflammatory conditions have many challenges in terms of efficacy and safety issues. Novel approaches such as nanoparticles based drug delivery system have shown promising results to solve some of these problems. The aim of this study was to exploit the efficacy of the synthesized silver nanoparticles. In this study, silver nanoparticles (AgNPs) were biosynthesized using root extract (aqueous) of Duchesnea indica. They were characterized using different techniques such as, ultraviolet–visible (UV–Vis) spectrophotometry, transmission and scanning electron microscopy (TEM and SEM), X-ray diffractometer (XRD), energy dispersive X-ray spectroscopy (EDX), fourier-transform infrared spectroscopy (FTIR) and zetasizer. The UV–Vis spectra gave a characteristic peak at 423 nm; XRD confirmed its crystalline structure; FTIR confirmed the involvement of phytochemicals in their capping and reduction; TEM images confirmed their spherical shape with average width of 20.49 nm and average area of 319.25 nm². Various biological activities were performed on these NPs, such as antimicrobial, anti-inflammatory, analgesic and muscle relaxant, which showed significant results as follow. Among bacterial strains, Salmonella typhi (MIC: 0.01 mg/ml) and Escherichia coli (MIC: 0.01 mg/ml), while among that of fungal Microsporum canis (MIC: 0.53 mg/ml) and Alternaria alternata (MIC: 0.51 mg/ml) were most susceptible. The AgNPs showed maximum anti-inflammatory activity (46.15 and 56.85%) at 20 mg/kg after 3 and 5 h of drug administration, comparable to that of standard. In-vivo model exhibited concentration dependent inhibition of both COX-2 and 5-LOX enzymes. Similarly, it exhibited maximum analgesic activity (54.24%) at 20 mg/kg dose after 60 min. of pain induction. Furthermore, they depicted maximum muscle relaxation (P < 0.01) after 60 and 90 min of drug administration. Above results suggest that these AgNPs can be studied further for the development of more effective and safe formulations.     

Formulation of Tioconazole and Melaleuca alternifolia Essential Oil Pickering Emulsions for Onychomycosis Topical Treatment

Onychomycosis is a disease that affects many adults, whose treatment includes both oral and topical therapies with low cure rates. The topical therapy is less effective but causes fewer side effects. This is why the development of an effective, easy to apply formulation for topical treatment is of high importance. We have used a nanotechnological approach to formulate Pickering emulsions (PEs) with well-defined properties to achieve site-specific delivery for antifungal drug combination of tioconazole and Melaleuca alternifolia essential oil. Silica nanoparticles with tailored size and partially hydrophobic surface have been synthesized and used for the stabilization of PEs. In vitro diffusion studies have been performed to evaluate the drug delivery properties of PEs. Ethanolic solution (ES) and conventional emulsions (CE) have been used as reference drug formulations. The examination of the antifungal effect of PEs has been performed on Candida albicans and Trichophyton rubrum as main pathogens. In vitro microbiological experimental results suggest that PEs are better candidates for onychomycosis topical treatment than CE or ES of the examined drugs. The used drugs have shown a significant synergistic effect, and the combination with an effective drug delivery system can result in a promising drug form for the topical treatment of onychomycosis.     

Topical Administration of Terpenes Encapsulated in Nanostructured Lipid-Based Systems

Terpenes are a group of phytocompounds that have been used in medicine for decades owing to their significant role in human health. So far, they have been examined for therapeutic purposes as antibacterial, anti-inflammatory, antitumoral agents, and the clinical potential of this class of compounds has been increasing continuously as a source of pharmacologically interesting agents also in relation to topical administration. Major difficulties in achieving sustained delivery of terpenes to the skin are connected with their low solubility and stability, as well as poor cell penetration. In order to overcome these disadvantages, new delivery technologies based on nanostructures are proposed to improve bioavailability and allow controlled release. This review highlights the potential properties of terpenes loaded in several types of lipid-based nanocarriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers) used to overcome free terpenes’ form limitations and potentiate their therapeutic properties for topical administration.     

Thermal analysis applied in the osmotic tablets pre-formulation studies

Osmotically controlled and oral drug delivery systems utilize osmotic pressure for controlled delivery of active agent(s). Drug delivery from these systems, to a large extent, is independent of the physiological factors of the gastrointestinal tract and these systems can be utilized for systemic as well as targeted delivery of drugs. We apply the thermal methods and IR spectroscopy to study compatibility between atenolol and several excipients usually found in the osmotic systems formulations (Polyethylene oxide, MW 3350, 100000, 200000 and 5000000; HPMC K4000, magnesium stearate and cellulose acetate. Cellulose acetate, HPMC K4000 and magnesium stearate have essentially no interaction with atenolol otherwise all Polyethylene oxide excipients modifies significantly the drug melting point indicating some extend of interaction.     

Injectable peptide-based hydrogel formulations for the extended in vivo release of opioids

To overcome drawbacks related to repeated opioid administration during the treatment of chronic pain, several controlled-drug delivery systems of opioids have been designed. In order to address some of the limitations of the existing systems, injectable peptide-based hydrogels represent a promising alternative. This work reports on the design and synthesis of short amphipathic peptide-based hydrogels as controlled-drug delivery systems for opioids. Based on the lead sequence H-FEFQFK-NH₂, a new set of peptide hydrogelators was designed including β-homo and d-amino acids, mainly aiming at enhancing proteolytic resistance of the peptides, and which hypothetically allows an extension of the drug release period. After self-assembly in aqueous media, the resulting hydrogels were characterized by dynamic rheometry, cryogenic transmission electronic microscopy and their cytotoxicity was assessed. The cryoTEM images of drug loaded hydrogels show the association of microcrystals of the loaded drug along the axes of the fibres, suggesting that the peptide fibres play a key-role as nucleating site for the drug crystals. Hydrogelators devoid of cytotoxicity were considered for further in vivo evaluation. Upon encapsulation of morphine and 14-methoxymetopon, two opioid analgesics, the applicability of the peptide hydrogels as controlled-drug delivery platforms was validated in vivo using the mouse tail-flick test. A sustained antinociceptive effect was observed after subcutaneous injection of the drug loaded gels and, in comparison with the lead sequence H-FEFQFK-NH₂, novel sequences revealed extension of the in vivo antinociception up to 72–96 h post injection.     

Inorganic hybrid nanoparticles in cancer theranostics: understanding their combinations for better clinical translation

Drug resistance, tumor heterogeneity, and poor selectivity make cancer treatment with current modalities a challenging and complicated task. Careful planning of diagnosis and therapy is required to build new strategies for treatment and management of cancer. The amalgamation of therapeutics and diagnostics in a single nano agent, known as theranostics is now possible due to the emergence of nanotechnology. Theranostics offers opportunities for personalized medicine by real-time monitoring of drug accumulation and dynamic modification of treatment depending on individual patient needs. Thus potential to reform disease management is held by theranostic nanoparticles. Amongst other nanosystems, inorganic nanoparticles have been widely used for developing theranostic drug delivery systems due to their favorable intrinsic properties. The last decade has seen a surge in development of such theranostic nanoparticles in which various inorganic materials in different combinations have been engineered to maximize the output with respect to specific applications. For example, Fe₃O₄@Au nanoparticles were developed for MRI, hyperthermia and magnetically controlled drug delivery. Several such combinations leading to innovative theranostic applications and their underlying mechanisms have been highlighted in this review. A review of patents and clinical trials of inorganic theranostic nanoparticles is also presented through which we understood that clinical translation still remains in the nascent stage. Thus, it is necessary to find and understand reasons for lack of clinical translations. Therefore, we have discussed the challenges associated with bench-to-bed translation of such inorganic nanoparticles which show immense potential in vitro but fail to deliver in long run.     

Magnetic Hybrid Wax Nanocomposites as Externally Controlled Theranostic Vehicles: High MRI Enhancement and Synergistic Magnetically Assisted Thermo/Chemo Therapy

To fight against cancer, smarter drugs and drug delivery systems are required both to boost the efficiency of current treatments while reducing deleterious side effects, and combine diagnosis/monitoring with therapy (theranosis) in the search for the final goal of personalized medicine. This work presents the design, preparation, and proof-of-principle validation of a novel hybrid organic–inorganic nanocomposite joining together non-invasive imaging capabilities through magnetic resonance imaging and externally actuated therapeutic properties through a combination of chemo- and thermotherapy. The lipidic matrix of the nanocomposite was composed of carnauba wax, which was simultaneously dual loaded with magnetite nanoparticles and the anticancer drug Oncocalyxone A. Obtained formulations were fully characterized and showed outstanding performances as T₂-contrast agents in magnetic resonance imaging (r₂>800 mm ⁻¹ s⁻¹), heat generating sources in magnetic hyperthermia (specific absorption rate, SAR>200 W g⁻¹_Fe), and magnetically responsive drug delivery vehicles. The potential of the designed formulations as theranostic agents was validated in vitro and results indicated a synergistic thermo/chemotherapeutic effect derived from heat generation and controlled drug delivery to cancer growth. Thereby, this external control over the drug delivery profile and the integrated imaging capability open the door to personalized cancer medicine and real-time monitoring of tumor progression.     

Calorimetric Evaluation of Glycyrrhetic Acid (GA)- and Stearyl Glycyrrhetinate (SG)-Loaded Solid Lipid Nanoparticle Interactions with a Model Biomembrane

Glycyrrhetic acid (GA) and stearyl glycyrrhetinate (SG) are two interesting compounds from Glycyrrhiza glabra, showing numerous biological properties widely applied in the pharmaceutical and cosmetic fields. Despite these appreciable benefits, their potential therapeutic properties are strongly compromised due to unfavourable physical-chemical features. The strategy exploited in the present work was to develop solid lipid nanoparticles (SLNs) as carrier systems for GA and SG delivery. Both formulations loaded with GA and SG (GA-SLNs and SG-SLNs, respectively) were prepared by the high shear homogenization coupled to ultrasound (HSH-US) method, and we obtained good technological parameters. DSC was used to evaluate their thermotropic behaviour and ability to act as carriers for GA and SG. The study was conducted by means of a biomembrane model (multilamellar vesicles; MLVs) that simulated the interaction of the carriers with the cellular membrane. Unloaded and loaded SLNs were incubated with the biomembranes, and their interactions were evaluated over time through variations in their calorimetric curves. The results of these studies indicated that GA and SG interact differently with MLVs and SLNs; the interactions of SG-SLNs and GA-SLNs with the biomembrane model showed different variations of the MLVs calorimetric curve and suggest the potential use of SLNs as delivery systems for GA.     

Paliperidone-Loaded Self-Emulsifying Drug Delivery Systems (SEDDS) for Improved Oral Delivery

The present research is aimed to improve the oral delivery of paliperidone by loading into self-emulsifying drug delivery systems (SEDDS). Oleic acid, Tween 80, and capmul MCM L8 were selected as oil, surfactant, and co-surfactant, respectively and phase diagram was constructed and the region was identified for the formation of SEDDS. The stable formulations were analyzed for globule size, robustness to dilution and in vitro drug release. The globule size of all the formulations was found to be in the range of 205 to 310 nm with good size uniformity and seems to be dependent on the proportion of oil in SEEDS formulation. The optimized formulation (F3) has been adsorbed onto neusilin and characterized. The DSC and XRD spectra unravel the presence of molecular state of paliperidone in solid SEDDS. The in vitro dissolution study indicates improved dissolution characteristics with higher dissolution efficiency for solid SEDDS (SEDDS-N) compared to pure drug. Further ex vivo permeation studies carried out using rat intestine suggest a 2- to 3-fold improvement in permeation for SEDDS compared to pure drug. In conclusion, SEDDS prove to be potential carriers for improved oral delivery of paliperidone.     

Pectin in controlled drug delivery – a review

Controlled drug delivery remains a research focus for public health to enhance patient compliance, drug efficiency and reduce the side effects of drugs. Pectin, an edible plant polysaccharide, has been shown to be useful for the construction of drug delivery systems for specific drug delivery. Several pectin derived formulations have been developed in our laboratory and tested in vitro, ex vivo, and in vivo for the ability to deliver bioactive substances for therapeutic purposes in the context of interactions with living tissues. Pectin derivatives carrying primary amine groups were more mucoadhesive and have shown potential in nasal drug delivery and other mucosal drug delivery. Pectin derivatives with highly esterified galacturonic acid residues are more hydrophobic and able to sustain the release of incorporated fragrances for a prolonged duration. Less esterified pectin derivatives are able to penetrate deeper into the skin and may be useful in aromatherapy formulations. Pectin, in combination with zein, a corn protein, forms hydrogel beads. The bound zein restricts bead swelling and retains the porosity of the beads; the pectin networks shield the zein from protease attack. The complex beads are ideal vehicles for colon-specific drug delivery. Studies presented in this paper indicate the flexibility and possibility to tailor pectin macromolecules into a variety of drug delivery systems to meet different clinical requirements. Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture.     

Nucleic Acid Delivery by Solid Lipid Nanoparticles Containing Switchable Lipids: Plasmid DNA vs. Messenger RNA

The development of safe and effective nucleic acid delivery systems remains a challenge, with solid lipid nanoparticle (SLN)-based vectors as one of the most studied systems. In this work, different SLNs were developed, by combination of cationic and ionizable lipids, for delivery of mRNA and pDNA. The influence of formulation factors on transfection efficacy, protein expression and intracellular disposition of the nucleic acid was evaluated in human retinal pigment epithelial cells (ARPE-19) and human embryonic kidney cells (HEK-293). A long-term stability study of the vectors was also performed. The mRNA formulations induced a higher percentage of transfected cells than those containing pDNA, mainly in ARPE-19 cells; however, the pDNA formulations induced a greater protein production per cell in this cell line. Protein production was conditioned by energy-dependent or independent entry mechanisms, depending on the cell line, SLN composition and kind of nucleic acid delivered. Vectors containing 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as unique cationic lipid showed better stability after seven months, which improved with the addition of a polysaccharide to the vectors. Transfection efficacy and long-term stability of mRNA vectors were more influenced by formulation-related factors than those containing pDNA; in particular, the SLNs containing only DOTAP were the most promising formulations for nucleic acid delivery.     

Liposomes as Antibiotic Delivery Systems: A Promising Nanotechnological Strategy against Antimicrobial Resistance

Antimicrobial drugs are key tools to prevent and treat bacterial infections. Despite the early success of antibiotics, the current treatment of bacterial infections faces serious challenges due to the emergence and spread of resistant bacteria. Moreover, the decline of research and private investment in new antibiotics further aggravates this antibiotic crisis era. Overcoming the complexity of antimicrobial resistance must go beyond the search of new classes of antibiotics and include the development of alternative solutions. The evolution of nanomedicine has allowed the design of new drug delivery systems with improved therapeutic index for the incorporated compounds. One of the most promising strategies is their association to lipid-based delivery (nano)systems. A drug’s encapsulation in liposomes has been demonstrated to increase its accumulation at the infection site, minimizing drug toxicity and protecting the antibiotic from peripheral degradation. In addition, liposomes may be designed to fuse with bacterial cells, holding the potential to overcome antimicrobial resistance and biofilm formation and constituting a promising solution for the treatment of potential fatal multidrug-resistant bacterial infections, such as methicillin resistant Staphylococcus aureus. In this review, we aim to address the applicability of antibiotic encapsulated liposomes as an effective therapeutic strategy for bacterial infections.     

Lipid-Based Nanostructures for the Delivery of Natural Antimicrobials

Encapsulation can be a suitable strategy to protect natural antimicrobial substances against some harsh conditions of processing and storage and to provide efficient formulations for antimicrobial delivery. Lipid-based nanostructures, including liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid nanocarriers (NLCs), are valuable systems for the delivery and controlled release of natural antimicrobial substances. These nanostructures have been used as carriers for bacteriocins and other antimicrobial peptides, antimicrobial enzymes, essential oils, and antimicrobial phytochemicals. Most studies are conducted with liposomes, although the potential of SLNs and NLCs as antimicrobial nanocarriers is not yet fully established. Some studies reveal that lipid-based formulations can be used for co-encapsulation of natural antimicrobials, improving their potential to control microbial pathogens.     

Polyacrylic Acid Modifies Local and Lateral Mobilities in Lipid Membranes

Polyacrylic acid (PAA) is a promising polymer for engineering lipid-based drug-delivery vesicles. Its unique properties allow lowering drug dose and delivery the drug close to the site of its release. To design a successful delivery scheme, however, it is important to understand on the molecular scale how the polymer interacts with lipids under various conditions in the human body. Some aspects of the PAA-lipid interaction can be revealed using physical methods, such as differential scanning microscopy, nuclear magnetic resonance spectroscopy, NMR-diffusometry, and infrared spectroscopy. This work discusses the use of these techniques as well as the peculiarities of preparing vesicular and microscopically aligned PAA-lipid systems.      

Central Composite Design for Formulation and Optimization of Solid Lipid Nanoparticles to Enhance Oral Bioavailability of Acyclovir

Treatment of herpes simplex infection requires high and frequent doses of oral acyclovir to attain its maximum therapeutic effect. The current therapeutic regimen of acyclovir is known to cause unwarranted dose-related adverse effects, including acute kidney injury. For this reason, a suitable delivery system for acyclovir was developed to improve the pharmacokinetic limitations and ultimately administer the drug at a lower dose and/or less frequently. In this study, solid lipid nanoparticles were designed to improve the oral bioavailability of acyclovir. The central composite design was applied to investigate the influence of the materials on the physicochemical properties of the solid lipid nanoparticles, and the optimized formulation was further characterized. Solid lipid nanoparticles formulated from Compritol 888 ATO resulted in a particle size of 108.67 ± 1.03 nm with an entrapment efficiency of 91.05 ± 0.75%. The analyses showed that the optimum combination of surfactant and solid lipid produced solid lipid nanoparticles of good quality with controlled release property and was stable at refrigerated and room temperature for at least 3 months. A five-fold increase in oral bioavailability of acyclovir-loaded solid lipid nanoparticles was observed in rats compared to commercial acyclovir suspension. This study has presented promising results that solid lipid nanoparticles could potentially be used as an oral drug delivery vehicle for acyclovir due to their excellent properties.     

The effect of the molecular weight of chitosan nanoparticles and its application on drug delivery

Nanoparticulate drug delivery systems offer several advantages over conventional forms of dosing, with polymer nanoparticles prepared from biomaterials being good candidates for use in drug delivery. We selected fluorouracil (5FU) as a model drug because it has been suggested that chitosan might prevent the side effects induced by 5FU. We have exploited the complexation between oppositely charged macromolecules to develop a safe and efficient method of preparation of chitosan bead formulations for use as drug delivery systems. In this study, we examined the effect that the molecular weight of chitosan had on the resulting nanoparticles' properties; the initial concentration of chitosan was held constant, but its molecular weight was decreased through the action of NaNO₂. FTIR spectroscopy suggested that no structural change occurred during the depolymerization process. The diameters of the nanoparticles—determined using dynamic light scattering and TEM techniques—decreased as the value of the viscosity of molecular weight (Mv) of chitosan decreased. In addition, we prepared fluorouracil-loaded chitosan nanoparticles and characterized them using NMR spectroscopy. The encapsulation efficiency increased as the value of Mv of chitosan decreased. The particles produced using 55-kDa chitosan had a mean diameter of 70.6 nm and a 66% drug loading.     

Whey protein: A functional and promising material for drug delivery systems recent developments and future prospects

Natural polymers have been extensively utilized in the past decades due to their outstanding features. Among these natural excipients, protein‐based polymers have superb features owing to their high drug binding capacity and biodegradability. Whey protein is a versatile protein‐based vehicle for drug delivery systems. It has been shown to be nontoxic, biocompatible, and biodegradable. Therefore, it has been considered as an ideal biomaterial for the design of advanced drug delivery systems. Protein‐based cargo acts as synthetic polymers counterpart for innovative delivery systems. The current review is mainly focused on application of whey proteins as an emerging carrier in drug delivery systems, achieved during the past.     

Recent advances in targeted stimuli-responsive nano-based drug delivery systems combating atherosclerosis

Atherosclerosis(AS), mainly caused by the changed immune system functions and inflammation, is the central pathogenesis of cardiovascular disease, which is a leading cause of death in the world. In modern medicine, the development of carriers precisely delivering the therapeutic agents to the target sites is the primary goal, which could minimize the potential adverse effects and be more effective in treating lesions. Due to the precise location, real-time monitoring, AS microenvironment respons...