Current Pharmaceutical Design - Volume 23, Issue 43, 2017

Background: Current treatments for neurodegenerative diseases are challenging, due to the absence of fully effective medicines. One of the major problems associated to these is the occurrence of non-targeting events, which leads to adverse effects and requires frequent dose administration. Methods: Researches have been performed to develop new drug delivery systems administrated by alternative routes. For example, the direct nose-to-brain delivery of drugs by means of lipid nanoparticles, such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has been showing promising results. Results: Among the advantages of intranasal administration is the avoidance of passing the blood-brain barrier (BBB) to reach the central nervous system (CNS), allowing the direct delivery of drugs to the brain by a noninvasive way, minimizing systemic exposure and prolonging residence time. This review article discusses the advantages of using SLN and NLC for direct nose-to-brain drug delivery. A brief reference to other lipid-based carriers (liposomes, nanoemulsions and microemulsions) is also provided. Conclusion: The benefits of using SLN and NLC for improve nasal drug delivery have been demonstrated by in vitro, ex vivo and in vivo experiments. However, more in vivo animal studies are needed for advance to human clinical trials and reach clinics.

Background: Cancer stem cells (CSCs) have been described as a relevant contributor to tumorigenicity, metastasis, tumor recurrence and drug resistance, making this cell population a relevant target in solid tumors. Methods: This has stimulated the development of different therapeutic strategies often targeting surface markers (CD44, epithelial cell adhesion molecule (EpCAM), aldehyde dehydrogenase (ALDH) and nucleolin) and/or signaling pathways that are aberrantly activated and contribute to CSCs proliferation and survival. Results: There are a variety of signaling pathways often involved in physiological processes of cell function that aberrantly regulate CSCs, including Notch, Hedgehog, Wnt, PI3K/Akt, JAK/STAT and Ras/ERK signaling pathways. The inhibition of these pathways usually depletes CSC population and increases tumor sensitivity to chemotherapy. However, the recognition of the potential of cells to interconvert in response to environmental stimulus, turned both CSCs and non-stem cancer cells into two relevant therapeutic targets. Therefore, the use of drug combinations is increasingly needed. These drugs with different mechanisms of action often characterized by distinct pharmacokinetics profiles and, as such, will present distinct biodistribution patterns, following systemic administration. To synchronize pharmacokinetics, one can encapsulate synergistic drug combinations into lipidbased nanoparticles, assuring tumor delivery of the selected drug ratio. Conclusion: This review will focus on the multiple strategies to target CSCs, as well as on the potential of lipidbased nanoparticles to target both CSCs and non-stem cancer cells

Background: Solid lipid nanoparticles (SLN) are colloidal drug carrier systems that contribute several properties required from a sophisticated drug delivery system for increasing drug bioavailability and providing effective therapy. Many advantages of SLN have been reported over traditional dosage forms and their colloidal counterparts since the early 1990s. They were optimized for oral drug delivery for the first time. The first SLN formulations were produced by reducing particle size of solid lipid microparticles by spray congealing technique in the late 1980s. Then, studies have been continued investigating for their different administration routes else including parenteral, transdermal, ocular, nasal, respiratory etc. Methods: Their foremost qualifications such as their biocompatible nature and high drug entrapment efficiency make them promising colloidal drug carrier systems for effective treatment of serious disasters like genetic disorders and cancer. Conclusion: In this review, therapeutic potential of drug delivery of SLN and nanostructured lipid carriers (NLC, the second generation of SLN) are summarized considering researches and patents on their administration via different routes and their preparations in the pharmaceutical market.

Background: SLNs and NLCs have remarkably wide range of properties which make them useful for several potential applications in drug delivery, clinical medicine, and research, as well as in parenteral, dermal, pulmonary and topical delivery of drugs. The unique size-dependent properties of the solid lipid nanoparticles make them at the forefront of the rapidly developing field of nanotechnology offering development of new therapeutics having reduced toxic side effects and increased treatment efficacy. Methods: SLNs and NLCs are very attractive drug delivery candidates, primarily due to their relatively stable constituents and probable ease of drug encapsulations. The incorporation of drugs into nanocarriers like SLNs and NLCs for several levels of drug targeting offers good potential in gene transfer, cosmetic and food industry with great promise for reaching the goal of controlled and site-specific drug delivery. Lipid nanoparticle drug delivery technology presents considerable opportunities for improving medical therapeutics, but the technology's potential remains unrealized. Results: The review has focused on the various effective delivery routes and strategies for SLNs and NLCs, and their applicability in the encapsulation of therapeutics. Number of research works has been successfully carried out in this area. It would result in a simultaneous improvement in the quality, efficacy, and safety profile of drugs. Conclusion: However, because of mentioned limitations and difficulties related to them, the total number of products on the market is still limited. Although the concept of PEGylation to increase half-life of nanoparticles revolutionized the nanoparticle-mediated drug-delivery field, significant improvements are warranted in this area.

Background: Lipid nanoparticles have attracted increased degree of scientific and commercial attention in the last decade. The lipidic nanoparticles have emerged as a potential alternative to other nano-scale systems due to their various advantages over them and also due to overcoming the shortcomings of the already available colloidal systems like liposomes, niosomes and polymeric nanoparticles. Description: These have been investigated for delivery of macromolecules, genes, siRNA and other therapeutic agents for oral, topical, parenteral administration and target site specific delivery for various diseases like cancer, ocular diseases and brain disorders. The lipid nanoparticles have evolved from SLNs, then NLCs and lipid drug conjugates overcoming any issues related to production and formulation and adding advantages, if any. The current review article focuses on the lipid nanoparticles, their formulation approaches and current advancements in the field through recent clinical trials and patents. This manuscript embodies various patents, preclinical and clinical aspects related to the lipidic nanocarriers. Conclusion: Over the years the lipidic nanoparticulate systems have evolved as significant carriers for improved therapeutics and in diagnostic field. The large number of patents and preclinical trials in the recent years suggests that these systems will find immense potential in near future.

Background: Lipid based nanocarriers have gained recently enormous interest for pharmaceutical application. They have the potential to provide controlled drug release and to target the drug to a specific area. In addition, lipid based nanocarriers can improve the bioavailability of drugs suffering from high hepatic first-pass metabolism, by enhancing their transport via the lymphatic system. The main components of lipid based nanocarriers are lipids and surfactants. Both have great influence on the prepared lipid based systems characteristics. The criteria for their selection are much related to physicochemical properties of the drug and the required administration route. This work gives an overview on the effect of both the type and amount of lipids and surfactants used in the manufacture of lipid based nanocarriers on their behavior and characteristics. Conclusion: Recent studies revealed that the properties of the final product including; particle size, homogeneity, drug loading capacity, zeta potential, drug release profile, stability, permeability, pharmacokinetic properties, crystallinity and cytotoxicity, may be significantly influenced not only by the type but also the amount of the lipids and/or surfactants included in the formulation of the lipid based nanocarriers.

Background: Solid lipid nanoparticles (SLN) and the next generation of nanostructured lipid carriers (NLC) seem to be a very promising alternative to other colloidal carriers, such as liposomes, microemulsions, and polymeric nanoparticles. These combine the advantages of the cited nanocarriers and can improve the dissolution rate in biological fluids, increase the drug absorption, improve the tissue distribution in the target organ, enhance the drug bioavailability and ensure controlled drug release. SLN and NLC can ensure higher drug stability in the harsh environment, cover the bitter taste of the drug, and reduce the first-pass effect after oral administration. However, these carriers suffer from some disadvantages such as low drug loading capacity, drug expulsion, and unpredictable gelation tendency. Methods: This article aims to provide detail information about the process of complex characterization of SLN and NLC to produce an effective, quality and safe colloidal DDS with desired properties, based on the literature published in the period from 2000 to 2017. Results: Characterization techniques in terms of size and particle size distribution; surface morphology, functionalization, and zeta potential; structure, depending on the degree of crystallinity, lipid modification, drug incorporation and loading capacity; drug release; co-existence of other nano- and microstructures; and toxicity assessment according to the process of production, lipids and surfactants used and route of administration are discussed in the article. Conclusion: The precise characterization of lipid nanocarriers as drug delivery systems ensures guarantees for the quality of the product as an effective and safe form. The typical composition of SLN and NLC requires a comprehensive approach of characterization and in-depth analysis of the results to perform a drug delivery system with desired properties.

Background: Lipid nanoparticles are considered one of the most promising systems for controlled release of therapeutic molecules highly hydrophobic and with low biodisponibility. Solid lipid nanoparticles and nanostructured lipids carriers are widely seen as the workhorses of drug delivery systems because of low toxicity, enhanced encapsulation capacity, controlled drug kinetic release, easy tailoring and targeting and practicable scale up. Conclusions: A new generation of hybrid lipid nanoparticles has emerged by combining the lipidic properties with polymers, proteins and metallic structures. The main features of hybrid lipid nanoparticles including popular methods for synthesis and characterization, biological and toxicological properties, administration routes, drug encapsulation strategies, tailoring and targeting, and potential systems for use in biomedicine are described in the present review.

Background: Topical drug administration offers an attractive route with minimal invasiveness. It also avoids limitations of intravenous administration such as the first pass metabolism and presystemic elimination within the gastrointestinal tract. Furthermore, topical drug administration is safe, have few side effects, is easy to apply, and offers a fast onset of action. However, the development of effective topical formulations still represents a challenge for the desired effect to be reached, locally or systemically. Solid lipid nanoparticles and nanostructured lipid carriers are particular candidates to overcome the problem of topical drug administration. The nanometric particle size of lipid nanoparticles favors the physical adhesion to the skin or mucosal, what can also be attained with the formation of hybrid (nanoparticles/polymer) systems. Methods: In this review, we discuss the major challenges for lipid nanoparticles formulations for topical application to oral mucosa, skin, and eye, highlighting the strategies to improve the performance of lipid nanoparticles for topical applications. Next, we critically analyzed the in vitro and in vivo approaches used to evaluate lipid nanoparticles performance and toxicity. Conclusion: We addressed some major drawbacks related to lipid nanoparticle topical formulations and concluded the key points that have to be overcome to help them to reach the market in topical formulations to oral mucosa, skin, and eye.

Background: The eyes are among the most readily accessible organs in terms of location in the body, yet drug delivery to eye tissues is particularly problematic. The anatomy, physiology and biochemistry of the eye limit the ophthalmic delivery of drugs. Numerous strategies in ophthalmic drug delivery have been made to expand the bioavailability and to prolong the remaining time of drugs treated topically to eye. Methods: Designing a novel delivery vehicles that can proficiently target the diseased eye tissue, generate high drug levels, and keep sustained and effective concentrations with no or minimum side effects is the main concentration of present examination. One of the encouraging approaches currently is the use of lipidic nanoparticle vehicles categorized by a submicron-meter dimension. Due to their properties and numerous advantages, solid lipid nanoparticles and nanostructure lipid carriers are promising systems for ocular drug delivery. Conclusion: The focus of this review is on the recent developments in ophthalmic lipid nanoparticles, the rationale for their use, drug loaded SLNs and NLCs, and the characteristic advantages, limitations of this system and recent studies.

Background: Lipid nanoparticles have been extensively studied for drug delivery of antifungal drugs, especially for dermatophytosis treatments. They can accumulate in skin appendages and release drugs in a controlled manner and also increase skin moisture, due to the formation of an occlusive film. Since moisture heavily influences nail and skin permeability, these systems seem to pose great potential for antifungal drug delivery. Methods: We therefore compare skin and nail physiopathological structure and discuss the potential use of lipid nanoparticles in managing skin and nail mycoses, highlighting their unexplored use in onychomycosis. Results: Structural features become particularly relevant when treating local skin/nail disorders. Nail plate represents the most resistant barrier to the penetration of molecules. In recent years, at least 55 researches have been reported about lipid nanoparticles and, antifungal drugs. They have focused on production methods and nanoparticle ingredients influence on entrapment efficiency, fungal activity in vitro, stability, and drug release. Lipid nanoparticles such as SLN and NLC have shown great results in permeating the skin. Currently, however, there is just one study published using NLC applied directly to the nail plate. NLC containing voriconazole had a noteworthy impact on the penetration depth of a nanoencapsulated drug, which allowed its deeper penetration into porcine hooves than the unloaded drug. Conclusion: Evidence of the success of SLN and NLC in achieving high encapsulation efficiencies of antifungals and promoting cutaneous delivery indicates the potential of the systems in enhancing nail hydration and drug penetration into the nail plate.

Background: The class of fluoroquinolone antibiotics, due to its core chemical modifications, is considered as wide-spectrum antibacterial drugs with useful pharmacokinetic and pharmacodynamic properties. However, because of their poor solubility in water, they are used as salts (lactates or hydrochlorides). Fluoroquinolones, bacterial membranes and eukaryotic cell membranes interactions are well known and their permeation properties are well investigated. In fact, they are concentrated inside the cells and intracellular compartments. Nanotechnology in Drug Delivery has developed many supra-molecular structures that have been used to improve both pharmacokinetic and pharmacodynamic properties. The main results of the published papers showed reduction of toxicity, higher intracellular concentrations (both bacteria and eukaryotic), enhancement of antimicrobial activity, prolonged drug release, decreased mortality in animal model studies, improved water solubility and improved in vitro efficacy against intracellular pathogens. Methods: a literature search was performed in the NCBI-PUBMED database, with no time range, using the keywords "solid lipid nanoparticles" and ‘quinolones’ or the name of single antibiotics. Results: the most important aspects of lipid-based nanocarrier technology used for fluoroquinolones have been highlighted, with a focus on the latest formulation developments that have led to significant improvements of pharmacokinetics and pharmacodynamics. Both technological and microbiological aspects of published papers have been discussed. Conclusion: the potentiality of using lipid nanoparticles to improve the efficacy and potency of quinolone antibiotics has been supported by recent scientific publications, although some criticism appeared due to the microbiological investigative methods used and because of lack of systematic evaluation about the influence of technological approaches to the in vitro and in vivo drug activity.

Background: Thousands of bioactive compounds are identified and isolated from the medicinal plants every year, of which many possess significant health benefits. However, the overwhelming majority of entities suffer from poor water solubility and membrane permeability that impedes them approaching the clinical stage. Methods: Lipid nanoparticles have shown to be a versatile platform for advanced delivery of various therapeuticals, including the oral, topical and systemic routes. Lipid nanoparticles are able to significantly improve the oral bioavailability, pharmacokinetic profile, skin permeability, and ocular residence time of drugs, demonstrating considerable potential in pharmaceutical or medical practice. Results: This article profoundly reviews important applications of lipid nanoparticles in active natural medicines. Special concerns focus on solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for their training in the oral, intravenous, percutaneous and ocular drug delivery. Conclusion: The survey shows that lipid nanoparticles are promising vehicles for the delivery of various natural actives and may address some intractable problems associated with delivery thereof.

Background: Multidrug resistance in cancer is the ability of a cancer cell to resist treatment with a wide range of structurally and functionally dissimilar chemotherapeutics. The resistant phenotype could arise in response to several cellular changes that ultimately result in a decrease in intracellular drug accumulation (or effectiveness), either by limiting cellular drug entry, or by expulsion of those molecules that have made it into the cell. Both blocking drug cellular entry and its expulsion are mostly brought about by the cell membrane. Several pharmaceutical excipients (mainly lipids, surfactants and amphililc copolymers) have been reported to reverse multidrug resistance by addressing cell membrane related changes resulting in low intracellular drug levels in resistant cells. These excipients are routinely used in the preparation of lipid based nanoparticles endowing inherent multidrug resistance reversing properties to these nanoparticles. Methods: In this review, cell membrane alterations resulting in multidrug resistance will be initially reviewed, followed by a discussion of the different types of lipid NPs and the potential held by the excipients used in their preparation in multidrug resistance reversal. Finally, a discussion on how lipid nanoparticles have been engineered and used in different occasions to enable multidrug resistance reversal is included. Conclusion: The superior role held by lipid nanoparticles in comparison to free excipients will be highlighted.