Lovastatin Nanoparticle Synthesis and Characterization for Better Drug Delivery

Abstract: Zerumbone, a natural dietary lipophilic compound with low water solubility (1.296 mg/L at 25°C) was used in this investigation. The zerumbone was loaded into nanostructured lipid carriers using a hot, high-pressure homogenization technique. The physicochemical properties of the zerumbone-loaded nanostructured lipid carriers (ZER-NLC) were determined. The ZER-NLC particles had an average size of 52.68 ± 0.1 nm and a polydispersity index of 0.29 ± 0.004 μm. Transmission electron microscopy showed that the particles were spherical in shape. The zeta potential of the ZER-NLC was −25.03 ± 1.24 mV, entrapment efficiency was 99.03%, and drug loading was 7.92%. In vitro drug release of zerumbone from ZER-NLC was 46.7%, and for a pure zerumbone dispersion was 90.5% over 48 hours, following a zero equation. Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay in human T-cell acute lymphoblastic leukemia (Jurkat) cells, the half maximal inhibitory concentration (IC50) of ZER-NLC was 5.64 ± 0.38 μg/mL, and for free zerumbone was 5.39 ± 0.43 μg/mL after 72 hours of treatment. This study strongly suggests that ZER-NLC have potential as a sustained-release drug carrier system for the treatment of leukemia.

Abstract: An analysis of the important intermolecular interactions of the active pharmaceutical ingredient lovastatin which contribute to the surface chemistry and attachment energy morphology is presented. The analysis is supported by a recent redetermination of the single-crystal structure (orthorhombic space group P212121) and targets the understanding and potential control of the morphology of lovastatin, which tends to crystallize in a needle-like morphology, where the aspect ratio varies depending on the nature of the solvent. The lattice energy was calculated to be −38.79 kcal mol−1 with a small contribution of −2.73 kcal mol−1 from electrostatic interactions. The lattice structure is significantly stabilized by the hexahydronaphthalene ring of the molecule, which contributes 43.39% of the lattice energy. Synthon analysis shows that the dominant intermolecular interaction within the lattice structure of lovastatin is found to be along the a crystallographic axis, associated with a dispersive stacking interaction due to the close packing of 2 hexahydronaphthalene rings resulting in a total interaction energy of −6.46 kcal mol−1. The attachment energy morphology correlates well with the observed crystal morphology which exhibits a needle-like habit dominated by {0 1 1}, {0 2 0}, {0 0 2}, and {1 0 1} crystal forms. The needle capping faces are found to contain the short stacks of hexahydronaphthalene rings where the strong intermolecular synthon is found to contribute positively to the attachment energy and hence growth at this surface. This dominant intermolecular synthon is concluded to be the major cause of enhanced growth along the crystallographic a axis leading to the formation of a needle-like morphology. A habit modification strategy is discussed which uses recrystallization from apolar solvents to reduce the effective growth rate at the needle-capping surfaces. This is supported through experimental data which shows that crystals obtained from crystallization in hexane and methyl-cyclohexane have significantly reduced aspect ratios in comparison to those grown from the more polar methanol and ethyl acetate solutions. Crystals obtained from nitromethane solutions were also found to have a very large reduction in aspect ratio to a prismatic morphology reflecting this solvent's propensity to interact with hydrophobic surfaces, critically with no polymorph change.

Abstract: Hyperlipidemia is a prevailing risk factor that leads to development and progression of atherosclerosis and consequently cardiovascular diseases. Several antihyperlipidemic drugs are having various disadvantages such as low water solubility and poor bioavailabilty due to presystemic gastrointestinal clearance. Thus, there is a considerable need for the development of efficient delivery methods and carriers. This review focuses on the importance and role of various nanoparticulate systems as carrier for antihyperlipidemic drugs in the treatment of hyperlipidemia. Some nanoparticle technology-based products are approved by FDA for effective treatment of hyperlipidemia, namely Tricor® by Abbott Laboratories (Chicago, IL, USA) and Triglide® by Skye Pharma (London, UK). Efforts to address each of these issues are going on, and should remain the focus on the future studies and look forward to many more clinical products in the future.

Abstract: Reconstituted high density lipoprotein (rHDL) is a biomimetic nanoparticle with plaque targeting and anti-atherosclerotic efficacy. In this work, we report on a strategy to rational design of lovastatin (LOV)-loaded spherical rHDL (LOV-s-rHDL) for efficient and safe anti-atherosclerotic therapy. Briefly, three LOV-s-rHDLs were formulated with LOV/s-rHDL at ratios of 8:1, 10:1, and 15:1 upon their respective median-effect values (Dm). The combined inhibitory effect between LOV and s-rHDL of different LOV-s-rHDL formulations on DiI-labeled oxLDL internalization was systemically investigated in RAW 264.7 cells based on the median-effect principle. Median-effect analysis demonstrated that the optimized LOV-s-rHDL was formulated with a ratio of 10:1 (Dm LOV:Dm s-rHDL), in which LOV and s-rHDL carrier showed the best synergistic effect, presumably ascribed to their inhibitory effect on CD36 and SR-A expression according to the Western blot analysis. In vivo pharmacodynamics studies showed that the optimized LOV...

Abstract: Low dissolution of drugs in the intestinal fluid can limit their effectiveness in oral therapies. Here, a novel porous silica-supported solid lipid system was developed to optimize the oral delivery of drugs with limited aqueous solubility. Using lovastatin (LOV) as the model poorly water-soluble drug, two porous silica-supported solid lipid systems (SSL-A and SSL-S) were fabricated from solid lipid (glyceryl monostearate, GMS) and nanoporous silica particles Aerosil 380 (silica-A) and Syloid 244FP (silica-S) via immersion/solvent evaporation. SSL particles demonstrated significantly higher rate and extent of lipolysis in comparison with the pure solid lipid, depending on the lipid loading levels and the morphology. The highest lipid digestion was observed when silica-S was loaded with 34% (w/w) solid lipid, and differential scanning calorimeter (DSC) analysis confirmed the encapsulation of up to 2% (w/w) non-crystalline LOV in this optimal SSL-S formulation. Drug dissolution under non-digesting intestinal conditions revealed a three- to sixfold increase in dissolution efficiencies when compared to the unformulated drug and a LOV-lipid suspension. Furthermore, the SSL-S provided superior drug solubilization under simulated intestinal digesting condition in comparison with the drug-lipid suspension and drug-loaded silica. Therefore, solid lipid and nanoporous silica provides a synergistic effect on optimizing the solubilization of poorly water-soluble compound and the solid lipid-based porous carrier system provides a promising delivery approach to overcome the oral delivery challenges of poorly water-soluble drugs.

Abstract: This review describes the use of nanoparticles based on solid lipids for the parenteral application of drugs. Firstly, different types of nanoparticles based on solid lipids such as "solid lipid nanoparticles" (SLN), "nanostructured lipid carriers" (NLC) and "lipid drug conjugate" (LDC) nanoparticles are introduced and structural differences are pointed out. Different production methods including the suitability for large scale production are described. Stability issues and drug incorporation mechanisms into the particles are discussed. In the second part, the biological activity of parenterally applied SLN and biopharmaceutical aspects such as pharmacokinetic profiles as well as toxicity aspects are reviewed.

Abstract: Solid lipid nanoparticles (SLN) are distinguishable from nanostructured lipid carriers (NLC) by the composition of the solid particle matrix. Both are an alternative carrier system to liposomes and emulsions. This review paper focuses on lipid nanoparticles for dermal application. Production of lipid nanoparticles and final products containing lipid nanoparticles is feasible by well-established production methods. SLN and NLC exhibit many features for dermal application of cosmetics and pharmaceutics, i.e. controlled release of actives, drug targeting, occlusion and associated with it penetration enhancement and increase of skin hydration. Due to the production of lipid nanoparticles from physiological and/or biodegradable lipids, this carrier system exhibits an excellent tolerability. The lipid nanoparticles are a "nanosafe" carrier. Furthermore, an overview of the cosmetic products currently on the market is given and the improvement of the benefit/risk ratio of the topical therapy is shown.

Abstract: In recent years, various nanotechnology platforms in the area of medical biology, including both diagnostics and therapy, have gained remarkable attention. Moreover, research and development of engineered multifunctional nanoparticles as pharmaceutical drug carriers have spurred exponential growth in applications to medicine in the last decade. Design principles of these nanoparticles, including nano-emulsions, dendrimers, nano-gold, liposomes, drug-carrier conjugates, antibody-drug complexes, and magnetic nanoparticles, are primarily based on unique assemblies of synthetic, natural, or biological components, including but not limited to synthetic polymers, metal ions, oils, and lipids as their building blocks. However, the potential success of these particles in the clinic relies on consideration of important parameters such as nanoparticle fabrication strategies, their physical properties, drug loading efficiencies, drug release potential, and, most importantly, minimum toxicity of the carrier itself. Among these, lipid-based nanoparticles bear the advantage of being the least toxic for in vivo applications, and significant progress has been made in the area of DNA/RNA and drug delivery using lipid-based nanoassemblies. In this review, we will primarily focus on the recent advances and updates on lipid-based nanoparticles for their projected applications in drug delivery. We begin with a review of current activities in the field of liposomes (the so-called honorary nanoparticles), and challenging issues of targeting and triggering will be discussed in detail. We will further describe nanoparticles derived from a novel class of amphipathic lipids called bolaamphiphiles with unique lipid assembly features that have been recently examined as drug/DNA delivery vehicles. Finally, an overview of an emerging novel class of particles (based on lipid components other than phospholipids), solid lipid nanoparticles and nanostructured lipid carriers will be presented. We conclude with a few examples of clinically successful formulations of currently available lipid-based nanoparticles.

Abstract: The first generation of lipid nanoparticles was introduced as solid lipid nanoparticles (SLN), the second, improved generation as nanostructured lipid carriers (NLC). Identical to the liposomes, the lipid nanoparticles (NLC) appeared as products first on the cosmetic market. The article gives an overview of the cosmetic benefits of lipid nanoparticles, that means enhancement of chemical stability of actives, film formation, controlled occlusion, skin hydration, enhanced skin bioavailability and physical stability of the lipid nanoparticles as topical formulations. NLC are on the market as concentrates to be used as cosmetic excipients, special formulation challenges for these products are discussed. NLC appeared also in a number of finished cosmetic products world-wide. An overview of these products is provided including their special effects due to the lipid nanoparticles, lipids used for their production and incorporated cosmetic actives.

Abstract: Brain is a delicate organ, isolated from general circulation and characterized by the presence of relatively impermeable endothelial cells with tight junctions, enzymatic activity and the presence of active efflux transporter mechanisms (like P-gp efflux). These formidable obstacles often impede drug delivery to the brain. As a result several promising molecules (showing a good potential in in vitro evaluation) are lost from the market for a mere consequence of lack of in vivo response probably because the molecule cannot reach the brain in a sufficient concentration. The options to tailor make molecules for brain, though open to the medical chemist, are a costly proposition in terms of money, manpower and time (almost 50 years). The premedial existing approaches for brain delivery like superficial and ventricular application of chemical or the application of chemicals to brain parenchyma are invasive and hence are less patient friendly, more laborious and require skill and could also damage the brain permanently. In view of these considerations novel drug delivery systems such as the nanoparticles are presently being explored for their suitability for targeted brain delivery. Nanoparticles are solid colloidal particles ranging in size from 1 to 1000 nm (<1 microm) and composed of macromolecular material. Nanoparticles could be polymeric or lipidic (SLNs). SLNs are taken up readily by the brain because of their lipidic nature. The bioacceptable and biodegradable nature of SLNs makes them less toxic as compared to polymeric nanoparticles. Supplemented with small size which prolongs the circulation time in blood, feasible scale up for large scale production and absence of burst effect makes them interesting candidates for study. In the present review we will discuss about the barriers to CNS drug delivery, strategies to bypass the blood-brain barrier and characterization methods of SLNs and their usefulness. The proposed mechanism of uptake, methods of prolonging the plasma retention and the in vivo and in vitro methods for assessment will also be discussed in some details.