Quality by design (QbD)–based fabrication of atazanavir-loaded nanostructured lipid carriers for lymph targeting: bioavailability enhancement using chylomicron flow block model and toxicity studies
TL;DR: A safe and promising drug targeting system was successfully developed to improve bioavailability and avoiding first-pass effect ensures to circumvent the acute-toxicity of liver.
Abstract: Atazanavir (ATV) is widely used as anti-HIV agent having poor aqueous solubility needs to modulate novel drug delivery system to enhance therapeutic efficiency and safety. The main objective of the present work was to fabricate ATV-loaded nanostructured lipid carriers (NLCs) employing quality by design (QbD) approach to address the challenges of bioavailability and their safety after oral administration. Herein, the main objective was to identify the influencing variables for the production of quality products. Considering this objective, quality target product profile (QTPP) was assigned and a systematic risk assessment study was performed to identify the critical material attributes (CMAs) and critical process parameter (CPP) having an influence on critical quality attributes (CQAs). Lipid concentrations, surfactant concentrations, and pressure of high-pressure homogenizer were identified as CMAs and CPP. ATV-NLCs were prepared by emulsification-high pressure homogenization method and further lyophilized to obtain solid-state NLCs. The effect of formulation variables (CMAs and CPP) on responses like particle size (Y1), polydispersity index (Y2), and zeta potential (Y3) was observed by central composite rotatable design (CCRD). The data were statistically evaluated by ANOVA for confirmation of a significant level (p < 0.05). The optimal conditions of NLCs were obtained by generating design space and desirability value. The lyophilized ATV-NLCs were characterized by DSC, powder X-ray diffraction, and FT-IR analysis. The morphology of NLCs was revealed by TEM and FESEM. In vitro study suggested a sustained release pattern of drug (92.37 ± 1.03%) with a mechanism of Korsmeyer-Peppas model (r2 = 0.925, and n = 0.63). In vivo evaluation in Wistar rats showed significantly higher (p < 0.001) plasma drug concentration of ATV-NLCs as compared to ATV-suspension using chylomicron flow block model. The relative bioavailability of ATV-NLCs was obtained to be 2.54 folds. Thus, a safe and promising drug targeting system was successfully developed to improve bioavailability and avoiding first-pass effect ensures to circumvent the acute-toxicity of liver.
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TL;DR: Nanostructured lipid carriers (NLCs) have emerged as a promising strategy for improving therapeutic compound oral bioavailability, not only due to nanomaterial advantages, but also due to lipid ingredients themselves, such as preventing enzyme degradation, taste masking, and especially favorable uptake by chylomicron pathways to the lymphatic drainage system as discussed by the authors .
10 citations
TL;DR: Various types of NLCs, formulation components, methods of preparation, characterization parameters, optimization strategies, toxicity, regulatory aspects, and their applications in oral, parenteral, ocular, pulmonary, nose-to-brain, tumor targeting, and transdermal drug delivery have been dealt in detail.
Abstract: Abstract The lipid-based colloidal carriers, such as nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), nanocapsules, liposomes, and microemulsion, are the latest and significant entrants in the development of drug delivery systems owing to their myriad advantages. The NLCs are second-generation SLNs having unstructured matrix, have high drug loading, and provide long-term drug stability in comparison to SLNs and other colloidal systems, which show lower drug loading and experience burst release/drug expulsion during storage. This review is aimed to summarize the formulation development and optimization strategies for NLCs as reported in the literature collected from authentic databases. Various types of NLCs, formulation components, methods of preparation, characterization parameters, optimization (statistical designs) strategies, toxicity, regulatory aspects, and their applications in oral, parenteral, ocular, pulmonary, nose-to-brain, tumor targeting, and transdermal drug delivery have been dealt in detail. Patents granted on the NLCs have also been enlisted.
7 citations
TL;DR: In this article, the concepts, mechanisms, and applications of Nanostructured Lipid Carriers that are considered feasible for transporting macromolecules via transdermal delivery system are thoroughly reviewed and presented along with their clinical perspective.
Abstract: Skin being the largest external organ, offers an enticing procedure for transdermal drug delivery, so the drug needs to rise above the outermost layer of the skin, i.e., stratum corneum. Small molecular drug entities obeying the Lipinski rule, i.e., drugs having a molecular weight less than 500Da, high lipophilicity, and optimum polarity, are favored enough to be used on the skin as therapeutics. Skin's barrier action properties prevent the transport of macromolecules at pre-determined therapeutic rates. Notable advancement in macromolecules' transdermal delivery occurred in recent years. Scientists have opted for liposomes, the use of electroporation or, low-frequency ultrasound techniques. Some of these have shown better delivery of macromolecules at clinically beneficial rates. These physical technologies involve complex mechanisms, which may irreversibly incur skin damage. Majorly, two types of lipid-based formulations, including Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) are widely investigated as a transdermal delivery system. In this review, the concepts, mechanisms, and applications of Nanostructured Lipid Carriers that are considered feasible for transporting macromolecules via transdermal delivery system are thoroughly reviewed and presented along with their clinical perspective.
4 citations
TL;DR: In this article , a Loratadine Nanostructured Lipid Carriers Ocugel was developed to enhance its solubility, trans-corneal penetrability, and bioavailability.
Abstract: Loratadine (LORA), is a topical antihistamine utilized in the treatment of ocular symptoms of COVID-19. The study aimed to develop a Loratadine Nanostructured Lipid Carriers Ocugel (LORA-NLCs Ocugel), enhance its solubility, trans-corneal penetrability, and bioavailability. full-factorial design was established with 24 trials to investigate the impact of several variables upon NLCs properties. LORA-NLCs were fabricated by using hot melt emulsification combined with high-speed stirring and ultrasonication methods. All obtained formulae were assessed in terms of percent of entrapment efficiency (EE%), size of the particle (PS), zeta potential (ZP), as well as in-vitro release. Via using Design Expert® software the optimum formula was selected, characterized using FTIR, Raman spectroscopy, and stability studies. Gel-based of optimized LORA-NLCs was prepared using 4% HPMC k100m which was further evaluated in terms of physicochemical properties, Ex-vivo, and In-vivo studies. The optimized LORA-NLCs, comprising Compritol 888 ATO®, Labrasol®, and Span® 60 showed EE% of 95.78 ± 0.67%, PS of 156.11 ± 0.54 nm, ZP of -40.10 ± 0.55 Mv, and Qh6% of 99.67 ± 1.09%, respectively. Additionally, it illustrated a spherical morphology and compatibility of LORA with other excipients. Consequently, gel-based on optimized LORA-NLCs showed pH (7.11 ± 0.52), drug content (98.62%± 1.31%), viscosity 2736 cp, and Q12% (90.49 ± 1.32%). LORA-NLCs and LORA-NLCs Ocugel exhibited higher ex-vivo trans-corneal penetrability compared with the aqueous drug dispersion. Confocal laser scanning showed valuable penetration of fluoro-labeled optimized formula and LORA-NLCs Ocugel through corneal. The optimized formula was subjected to an ocular irritation test (Draize Test) that showed the absence of any signs of inflammation in rabbits, and histological analysis showed no effect or damage to rabbit eyeballs. Cmax and the AUC0-24 were higher in LORA-NLCs Ocugel compared with pure Lora dispersion-loaded gel The research findings confirmed that NLCs could enhance solubility, trans-corneal penetrability, and the bioavailability of LORA.
3 citations
TL;DR: Overall, CRN-NLC nanoparticles were proved a suitable carrier for passive drug delivery and cancer treatment and demonstrated substantial tumour volume suppression with no weight loss compared to pure CRN (ethanolic solution).
Abstract: Nanostructure lipid carriers (NLCs) were developed for the delivery of curmumin (CRN), a potent anticancer agent with low bioavailability, for the treatment of prostate cancer. NLCs prepared using high pressure homogenization (HPH) with around 150 nm particle size, - 40 V ζ-potential and excellent long-term stability. Cellular uptake of CRN-SLN showed nanoparticle localization in the cytoplasm around the nucleus. CRN-NLCs were assessed using flow cytometry and found to cause early and late apoptotic events at 100 μg/ml CRN concentrations. CRN-NLC nanoparticles were administrated to nude mice with LNCaP prostate cancer xenografts and demonstrated substantial tumour volume suppression (40%) with no weight loss compared to pure CRN (ethanolic solution). Overall, NLCs were proved a suitable carrier for passive drug delivery and cancer treatment.
3 citations
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TL;DR: Relevant issues for the introduction of SLN to the pharmaceutical market, such as status of excipients, toxicity/tolerability aspects and sterilization and long-term stability including industrial large scale production are discussed.
3,260 citations
TL;DR: The biological activity of parenterally applied SLN and biopharmaceutical aspects such as pharmacokinetic profiles as well as toxicity aspects are reviewed.
1,302 citations
TL;DR: A wide discussion about preparation methods, advantages, disadvantages and applications of LNPs is presented by focusing on SLNs and NLCs, two major types of Lipid-based nanoparticles.
Abstract: Lipid nanoparticles (LNPs) have attracted special interest during last few decades. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are two major types of Lipid-based nanoparticles. SLNs were developed to overcome the limitations of other colloidal carriers, such as emulsions, liposomes and polymeric nanoparticles because they have advantages like good release profile and targeted drug delivery with excellent physical stability. In the next generation of the lipid nanoparticle, NLCs are modified SLNs which improve the stability and capacity loading. Three structural models of NLCs have been proposed. These LNPs have potential applications in drug delivery field, research, cosmetics, clinical medicine, etc. This article focuses on features, structure and innovation of LNPs and presents a wide discussion about preparation methods, advantages, disadvantages and applications of LNPs by focusing on SLNs and NLCs.
649 citations
TL;DR: Evidence is provided that SLNs are valuable as an oral delivery carrier to enhance the absorption of a poorly water soluble drug, quercetin.
576 citations
TL;DR: The results suggest that surfactants, which are commonly added to pharmaceutical formulations, may enhance the intestinal absorption of some drugs by inhibiting this apically polarized efflux system.
Abstract: Purpose It has recently been reported that the permeability of peptides across Caco-2 cells, an in vitro model of the intestinal mucosa, was limited by an apically polarized efflux mechanism Since surfactants (eg Cremophor EL, Polysorbate 80) have been reported to inhibit similar efflux systems in tumor cells, we determined whether they could enhance the permeability of peptides across monolayers of Caco-2 cells
308 citations