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Psoriasis is an inflammatory skin which is chronic disorder with epidermal (acanthosis) hyperplasia and extreme inflammation as erythematous lesions. The penetration and neovascularization of inflammatory cells resulting from epidermis hyperproliferation with incomplete keratinocyte differentiation irregular horn cell formation are characterized by an erythematous scaly skin plaque. The purpose of the work entitled was to increase the penetration of the drug and develop nanoparticle loaded gel for better in-vitro release. Erlotinib belongs to BCS class II that stands for high permeability and less solubility. On physicochemical evaluation, melting point of erlotinib had been established to be 229.4 ± 254.6 °C. On UV analysis absortion maxima was found to be 341 nm in 0.1 N HCl. The Erlotinib shown very good solubility in ethanol, diethyl ether in contrast showed less solubility in phosphate buffer and water. An attempt is made to prepare nanoparticle gel of erlotinib using lipid such as cetyl palmitate poloxamer 188. The method of preparation of nanoparticles was found to be simple and reproducible. The formulated nanoparticles had been specified for its particle size and it comes out to be 81.57 ± 9.6 nm and zeta potential was found to be −29.3 ± 1.21mV. Percentage entrapment efficiency was found in a range of 89.2 ± 21% and loading efficiency was found to be 13.45 ± 0.72. The in vitro drug release of erlotinib from method ET-NLC15 become satisfactory give an explanation for with the aid of using Higuchi equation. This indicates that ET-NLC15 gel follow matrix diffusion-based release kinetics and the highest regression coefficient (R2) value was 0.968 through Higuchi model. Hence from all aspects; we concluded that the release of drug Erlotinib can provide drug release in a controlled manner by proper designing of the formulation and selection of a suitable method of preparation.

The purpose of this study is to produce nanostructured lipid carrier (NLC) that can solubilize poorly water-soluble velutin and verify an improved tyrosinase synthesis inhibition. A solubility test for velutin was conducted. Cetyl palmitate and caprylic/capric triglyceride were selected as solubilizer. The lipid matrix was produced using the ultrasound dispersion method. The morphology and size distribution of the produced NLC was analyzed through scanning electron microscopy (SEM) and dynamic light scattering (DLS), and the release and tyrosinase inhibition of velutin was evaluated through the Franz diffusion cell method and tyrosinase inhibition assay. Lipid matrix nanoparticles showed an average size of approximately 250 nm and polydispersity of 0.2, and it was confirmed that the velutin incorporated within nanoparticles sustained release at a constant rate over 36 hours. Due to extremely low aqueous solubility, the tyrosinase synthesis inhibition of velutin suspension was 0%, and the value of velutin incorporated within the NLC formulation was greatly improved 56.5% (40 μg/mL). As a result, it was verified that lipid-based NLC nanoparticles are an efficient formulation for the topical delivery of poorly water-soluble flavonoids such as velutin.

In recent years, several studies have shown that the use of solid lipid nanoparticles (SLN) as a colloidal drug delivery system was more advantageous than lipid emulsions, liposomes and polymeric nanoparticles. SLNs have numerous advantages of different nanosystems and rule out many of their drawbacks. Despite the numerous advantages of SLNs, translation from the preclinical formulation to the industrial scale-up is limited. In order to provide a reproducible and reliable method of producing nanoparticles, and thus, obtain an industrial scale-up, several methods of synthesis of nanoparticles by microfluidic have been developed. Microfluidic technique allows a good control and a continuous online synthesis of nanosystems compared to synthesis in bulk, leading to a narrow size distribution, high batch-to-batch reproducibility, as well as to the industrial scale-up feasibility. This work described the optimization process to produce SLNs by microfluidics. The SLNs produced by microfluidics were characterized by complementary optical and morphological techniques and compared with those produced by bulk method. SLNs were loaded with paclitaxel and sorafenib, used as model drugs. The anti-cancer efficiency of the SLNs formulation was estimated with 2D and 3D tumour models of two different cell lines, and the cellular uptake was also studied with fluorescence-assisted measurements. Statement of significance In this work, we describe the production of a single step continuous production for solid lipid nanoparticles (SLNs) via glass capillary-based microfluidic-chip. Comparing to conventional bulk methods, the current synthesis method showed several advantages, including a continuous production with high yield, good reproducibility and precise control over the properties of SLNs, which are critical pre-conditions for its successful industrialization. The superiority of this microfluidic-based method was confirmed by an overall physicochemical characterization of the produced SLNs. The size of the SLNs was controlled by altering the microfluidic parameters, and SLNs with dimensions ca. 100 nm were feasibly fabricated through parameters optimization. The microfluidics production of SLNs offered a good encapsulation efficiency and drug loading degree for a sustained release manner . (c) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Indexación Scopus Anesthetic failure is common in dental inflammation processes, even when modern agents, such as articaine, are used. Nanostructured lipid carriers (NLC) are systems with the potential to improve anesthetic efficacy, in which active excipients can provide desirable properties, such as anti-inflammatory. Coupling factorial design (FD) for in vitro formulation development with in vivo zebrafish tests, six different NLC formulations, composed of synthetic (cetyl palmitate/triglycerides) or natural (avocado butter/olive oil/copaiba oil) lipids were evaluated for loading articaine. The formulations selected by FD were physicochemically characterized, tested for shelf stability and in vitro release kinetics and had their in vivo effect (anti-inflammatory and anesthetic effect) screened in zebrafish. The optimized NLC formulation composed of avocado butter, copaiba oil, Tween 80 and 2% articaine showed adequate physicochemical properties (size = 217.7 ± 0.8 nm, PDI = 0.174 ± 0.004, zeta potential = − 40.2 ± 1.1 mV, %EE = 70.6 ± 1.8) and exhibited anti-inflammatory activity. The anesthetic effect on touch reaction and heart rate of zebrafish was improved to 100 and 60%, respectively, in comparison to free articaine. The combined FD/zebrafish approach was very effective to reveal the best articaine-in-NLC formulation, aiming the control of pain at inflamed tissues. © 2020, The Author(s). https://www-nature-com.recursosbiblioteca.unab.cl/articles/s41598-020-76751-6

Cetyl palmitate was produced by the esterification of palmitic acid with cetyl alcohol using n-hexane as solvent and a fermented solid of Burkholderia contaminans as catalyst. Effects of temperature (35–55 °C) and alcohol:acid molar ratio (0.5:1–2:1) on the reaction kinetics were evaluated for a fixed amount of catalyst (10 wt% related to the total mass of substrates) and a stirring speed (600 rpm) that was sufficiently high to avoid convective mass transfer limitations in the bulk phase. The temperature did not to influence the reaction rates and conversions above 90% were obtained for all temperatures after 12 h of reaction using a stoichiometric ratio (1:1) between the substrates. The prepared catalyst was recycled and reused in seven consecutive reactions of 8 h each and lost around 40% of its initial activity during the process. A Ping-Pong Bi–Bi kinetic model was proposed to represent the system reactions and was satisfactorily fitted to the experimental data.

Solid lipid nanoparticles (SLN) are colloidal lipid carriers, which used for improving the bioavailability of lipophilic and hydrophilic drugs. SLN are composed of biodegradable lipids such as hard fats, highly purified triglycerides, monoglycerides, complex glyceride mixtures or waxes which are solid at room temperature. In the present study, different formulation variables, including the type and quantity of lipid and surfactant were optimized for the preparation of SLN. SLN were prepared by a modified micro emulsion-based method and their particle size was evaluated. Two types of surfactants Tween 80 and Poloxamer 188 were used. Also, the monoglyceride (Glyceryl monostearate) and wax (Cetyl palmitate) were used as lipid. The optimum SLN formulae were at lipid concentration 5%. The optimum surfactant concentration was 6%. SLN with a surfactant Tween 80 were smaller in size than Poloxamer 188 SLN. Glyceryl monostearate formed a smaller size SLN than Cetyl palmitate. Increasing Glyceryl monostearate concentration in the lipid ratio resulted in the formation of small size SLN.

Background:It was shown that curcumin (Cur) has anti-plasmodium activity, however, its weak bioavailability, rapid metabolism, and limited chemical stability has restricted its application in clinical usages. Nanostructured lipid carriers (NLCs) are a type of drug-delivery systems (DDSs) which their core matrix is composed of both solid and liquid lipids.Objective:The aim of the current study was to prepare and characterize curcumin-loaded nanostructured lipid carriers (Cur-NLC) for malaria treatment.Methods:For the production of NLC, coconut oil and cetyl palmitate were selected as a liquid and solid lipid, respectively. In order to prepare the Cur-NLC, the microemulsion method was applied. General toxicity assay on Artemia salina and also hemocompatibility was investigated. Antimalarial activity was studied on mice infected with Plasmodium berghei.Results:The NLCs mean particle size and polydispersity index (PI) was 145 nm and 0.3, respectively. Moreover, the zeta potential of the Cur-NLC was −25 mV, as well as, the NLCs showed pseudo-spherical shape which revealed via transmission electron microscopy (TEM). The loading capacity and encapsulation efficacy of the obtained Cur-NLC were 3.1 ± 0.015% and 74 ± 3.32%, respectively. In vitro, Cur release profiles showed a sustained-release pattern up to 5 days in synthesized Cur-NLC. The results of in vivo anti-plasmodial activity against P. berghei revealed that antimalarial activity of Cur-NLC was high 2-fold compared with bare Cur at the tested dosage level.Conclusion: :The results of this study showed that NLC would be used as a potential nanocarrier for the treatment of malaria.

Repaglinide, a member of the meglitinide class of drugs, is a new anti-diabetic agent that is utilized as an oral hypoglycemic agent. Using glyceryl monostearate, cetyl palmitate, and tristearin as lipids and poloxamer 188 as a surfactant, repaglinide-loaded solid lipid nanoparticles were created. Solid lipid nanoparticles were prepared utilizing an o/w microemulsion technique, which included the lipids glyceryl monostearate and tristearin, as well as waxes such as cetyl palmitate and the surfactant poloxamer 188. The mean particle size of the solid lipid nanoparticles formed was around 339 nm, with an entrapment efficiency of 82.20%. In-vitro release studies continued to be conducted using the dialysis bag diffusion technique. Within 12 h, the cumulative drug release was 88.4%. The results indicate that repaglinide was released more slowly from solid lipid nanoparticles made from tristearin and glyceryl monostearate in an equal ratio. Tristearin found the controlled release and extreme entrapment from other lipid carriers like glyceryl monostearate and cetyl palmitate. Differential scanning calorimetry demonstrates that repaglinide is entangled in amorphous or molecular state within solid lipid nanoparticles. SEM microscopy revealed that the produced repaglinide solid lipid nanoparticles had a spherical shape. After one month of storage at 2-8 °C, short-term stability testing revealed no significant alteration.

Nanostructured lipid carriers (NLC) belong to youngest lipid-based nanocarrier class and they have gained increasing attention over the last ten years. NLCs are composed of a mixture of solid and liquid lipids, which solubilizes the active pharmaceutical ingredient, stabilized by a surfactant. The miscibility of the lipid excipients and structural changes (polymorphism) play an important role in the stability of the formulation and are not easily predicted in the early pharmaceutical development. Even when the excipients are macroscopically miscible, microscopic heterogeneities can result in phase separation during storage, which is only detected after several months of stability studies. In this sense, this work aimed to evaluate the miscibility and the presence of polymorphism in lipid mixtures containing synthetic (cetyl palmitate, Capryol 90®, Dhaykol 6040 LW®, Precirol ATO5® and myristyl myristate) and natural (beeswax, cocoa and shea butters, copaiba, sweet almond, sesame and coconut oils) excipients using Raman mapping and multivariate curve resolution – alternating least squares (MCR-ALS) method. The results were correlated to the macroscopic stability of the formulations. Chemical maps constructed for each excipient allowed the direct comparison among formulations, using standard deviation of the histograms and the Distributional Homogeneity Index (DHI). Lipid mixtures of cetyl palmitate/Capryol®; cetyl palmitate/Dhaykol®; myristyl myristate/Dhaykol® and myristyl myristate/coconut oil presented a single histogram distribution and were stable. The sample with Precirol®/Capryol® was not stable, although the histogram distribution was narrower than the samples with cetyl palmitate, indicating that miscibility was not the factor responsible for the instability. Structural changes before and after melting were identified for cocoa butter and shea butter, but not in the beeswax. Beeswax + copaiba oil sample was very homogenous, without polymorphism and stable over 6 months. Shea butter was also homogeneous and, in spite of the polymorphism, was stable. Formulations with cocoa butter presented a wider histogram distribution and were unstable. This paper showed that, besides the miscibility evaluation, Raman imaging could also identify the polymorphism of the lipids, two major issues in lipid-based formulation development that could help guide the developer understand the stability of the NLC formulations.

Excipient interaction has become essential knowledge for rational formulation design of nanoparticles. Nanostructured lipid carriers (NLCs) include at least three types of excipient, which enhance excipient interaction possibilities and relevance. The present article introduces an alternative approach for evaluating a great number of excipients with few samples, using NLC as a model delivery system. This approach is based on two sequential experiments using Hall-2 experimental design and analysis of excipient interactions in respect to their physicochemical properties by multilevel statistics. NLCs were prepared using a hot emulsification-ultrasonication method with lidocaine and nine excipients (solid lipids, oils and surfactants). The evaluated parameters were z-average size (DLS), dispersity (DLS), zeta potential (electrophoretic mobility) and entrapment efficiency (HPLC). Cetyl palmitate, beeswax, castor oil, capric/caprylic acid and polysorbate 80 all presented larger effects amongst the studied factors as well as a clear pattern of synergistic interactions. Following the verified trends, we produced an optimized NLC that exhibited all desirable physicochemical characteristics and a modified drug release profile. Our results demonstrate the methodology’s robustness, which can be applied to other nanoparticles and establish a cost-effective excipient evaluation.

Multi-resistant pathogens are one of the main challenges in health care as resistance genes vastly spread globally. One of the major causes for the dissemination of nosocomial infections is the contamination of medical devices. However, the common authorized sterilization processes are not suitable for heat sensitive medical devices. Against that background, a coating technique has been developed, which deposits a renewable layer on the surface of a medical device. For that reason, nanostructured coatings with cetyl palmitate (CTP) and silicium (Sicarstar) -nanoparticles have been tested. The different types of nanoparticles have been applied on polyethylene (PE) surfaces. PE is a material, which has been frequently used for medical devices like angiographic catheters. Before every coating, the surfaces have been treated in an anisothermal physical plasma, which has been carried out in a low-pressure discharge regime. The freshly coated specimens have been tested by several physical methods and biological techniques to obtain surface parameters such as the layer coverage of the substrate or the roughness and the cytotoxicity or the antimicrobial efficacy, respectively. First investigations confirm that the coatings considerably decrease the adsorption of microbial deposits. The coatings can be detached in a subsequent cleaning process. This process could be embedded in the reprocessing process as well as into an industrial context.

Methotrexate-loaded cubosomes (MTCs) were developed to provide relief from pain/joint stiffness, by affording stable methotrexate concentration at the targeting sites through sustained pattern by non-invasive skin route with enhanced permeation upon skin, for the treatment of rheumatoid arthritis. Non-ionic surfactant poloxamer 188 works to enhance the permeation of methotrexate. The results of FT-IR analysis indicates the compatibility nature of methotrexate (MT), poloxamer 188 and cetyl palmitate selected for the formulation. Different ratios of poloxamer 188 and cetyl palmitate were utilized to formulate using emulsification process. The selected MTCs showed particle size of around 626.13 ± 14.15 nm with charge of around − 6.29 ± 1.07 mV with cubic morphology. The encapsulation efficiency of MTCs was found to be 92.94 ± 0.9%. The in vitro MT release from MTCs conducted for 12 h revealed a sustained release pattern. The non-crystalline nature of MTCs was confirmed by XRD analysis. The in vitro anti-inflammatory effect of MTCs showed enhanced anti-inflammatory effect 11.9% compared to diclofenac sodium 10.4%. Ex vivo skin permeation analysis in excised skin of wistar albino rats showed 2.50 ± 0.3 ng of MT permeation within 2 h followed by 8.80 ± 5.2 ng within 12 h without any skin irritation. In addition, histopathological evaluation supported with fluorescent microscopic analysis of FITC-labeled MTCs confirmed the superior permeation enhancement of MTCs. The thermal stimulus time (TST) as studied by rat tail flick method indicates the enhancement of TST in case of MTCs (5.63 ± 0.21 s) compared to standard diclofenac gel (2.70 ± 0.20 s)/blank formulation (2.45 ± 0.23 s), which indicates the superior analgesic effect of the developed MTCs. The inflammed paw thicknesses were measured for CFA-induced arthritic rats which get reduced from day 1 (1.47 cm) to (1.03 cm) day 15 for MTCs-treated groups that were imaged by animal imaging system. Thus, the MTCs may act as a promising system for the treatment of RA upon topical application.

In the present study, the phase behaviour and reactivity of sulfonic acid-functionalised imidazolium- and phosphonium-based ionic liquid catalysts (ILCs) have been investigated for Fischer esterification reactions between alcohols and carboxylic acids with different alkyl chain lengths. Suitable design of ILCs enabled the control of phase behaviour with the reactants/products, and various wax esters derived from long-chain fatty acids and long-chain fatty alcohols underwent phase separation with the ILCs. Upon relating the phase behaviour and conversion (X), it has been revealed that higher X values were observed in the products that were phase-separated from the ILCs, as compared to the products that remained in the homogeneous phase with the ILCs. Furthermore, an excellent conversion of over 99% was achieved for production of cetyl palmitate, a typical wax ester, even at moderate temperature (60 °C) by removing water via bubbling dry N2 gas into the mixture or under reduced pressure.

Indirubin, an ingredient in traditional Chinese medicine, is considered as an anti-cancer agent. However, due to its hydrophobic nature, clinical efficiency has been limited. Drug delivery via nanotechnology techniques open new windows toward treatment of cancerous patients. Glioblastoma multiforme (GBM) is the most severe and common type of brain primary tumors. Of common problems in targeting therapies of glioblastoma is the availability of drug in tumoric tissues. In this study, Indirubin loaded solid lipid nanoparticles were prepared and their therapeutic potentials and antitumoric effects were assessed on GBM cell line (U87MG). The SLNs were prepared with Cetyl palmitate and Polysorbat 80 via high-pressure homogenization (HPH) methods in hot mode. Then, properties of SLNs including size, zeta potential, drug encapsulation efficacy (EE %) and drug loading were characterized. SLNs morphology and size were observed using SEM and TEM. The crystalinity of formulation was determined by different scattering calorimetry (DSC). The amount of drug release and antitumor efficiency were evaluated at both normal brain pH of 7.2 and tumoric pH of 6.8. The prapared SLNs had mean size of 130 nm, zeta potential of -16 mV and EE of 99.73%. The results of DSC showed proper encapsulation of drug into SLNs. Drug release assessment in both pH displayed sustain release property. The result of MTT test exhibited a remarkable increment in antitumor activity of Indirubin loaded SLN in comparison with free form of drug and blank SLN on multiform GB. This study indicated that Indirubin loaded SLNs could act as a useful anticancer drugs.

Nanostructured lipid carriers (NLCs) are gaining attention as the new generation of lipid vehicles. These carriers consist of saturated lipids with small drops of liquid oil dispersed into the inner lipid matrix and are stabilized by a surfactant. Conventionally, NLC-based drug delivery systems have been widely studied, and many researchers are looking into the composition of NLC properties to improve the performance of NLCs. The membrane fluidity and polarity of self-assembling lipids are also essential properties that must be affected by membrane compositions; however, such fundamental characteristics have not been studied yet. In this study, NLCs were prepared from cetyl palmitate (CP), caprylic triglyceride (CaTG), and Tween 80 (T80). Structural properties, such as particle size and ζ-potential of the CP/CaTG/T80 ternary mixtures, were investigated. Then, the systematic characterization of self-assembly properties using fluorescence-based analysis was applied for the first time to the NLC system. As a final step, the ternary diagram was developed based on the self-assembly properties to summarize the possible structures formed at different compositions. The results showed four states: micelle-like, oil-in-water (O/W) emulsion-like, solid lipid nanoparticle-like, and intermediate (solid-liquid coexistence). For the purpose of making the lipid matrix more liquified, the heterogeneous state and the disordered state of the O/W emulsion-like structure might fulfill the criteria of NLCs. Finally, the ternary diagram provides new information about the assembly state of NLC constituents that could become an important reference for developing high-performance NLCs.

Semisolids constitute a significant proportion of topical pharmaceutical dosage forms available on the market, with creams being considered profitable systems for releasing active substances into the skin. This work aimed at the development of a generic Clotrimazole topical cream, based on the assumptions that assist the development of such formulations. First, the critical parameters to obtain a final formulation as similar as possible to the reference product were defined. Then, the percentages of cetyl palmitate and octyldodecanol were identified as critical variables and chosen for optimization in further studies. A “quality by design” approach was then used to identify the effect of process variability on the structural and functional similarity (Q3) of the generic product qualitatively (Q1) and quantitatively (Q2). A two-factor central composite orthogonal design was applied and eleven different formulations were developed and subjected to physicochemical characterization and product performance studies. The results were used to estimate the influence of the two variables in the variation of the responses, and to determine the optimum point of the tested factors, using a design space approach. Finally, an optimized formulation was obtained and analysed in parallel with the reference. The obtained results agreed with the prediction of the chemometric analysis, validating the reliability of the developed multivariate models. The in vitro release and permeation results were similar for the reference and the generic formulations, supporting the importance of interplaying microstructure properties with product performance and stability. Lastly, based on quality targets and response constraints, optimal working conditions were successfully achieved.

The aim of this study was the preparation of solid lipid nanoparticles (SLN) formed from cetyl palmitate with having targeting molecules for monocarboxylate transporter-1 (MCT-1): p-hydroxybutyric acid and anticancer agents: carmustine (BCNU) and temozolomide (TMZ) for enhanced anti-proliferation against glioblastoma multiforme (GBM). Properties including size, morphology, chemical structure, zeta potential, drug encapsulation efficacy, drug release, biocompatibility, stability were determined, and in vitro studies were done. BCNU and TMZ loaded SLNs had a hydrodynamic size of 227 nm +/- 46 a zeta potential of -25 mV +/- 4 with biocompatible features. The data showed rapid drug release at first and then continuous release. Nanoparticles could be stored for nine months. BCNU and TMZ loaded SLNs exhibited a remarkable increment in the antitumor activity compared to the free-drugs and induced apoptosis on U87MG cells. In addition, targeted nanoparticles were more uptaken by MCT-1 expressing brain cells. This study indicated that BCNU and TMZ loaded SLNs could act as a useful anticancer system for targeted GBM therapy., Scientific and Technological Research Council of Turkey, TUBITAK [117S241]; Ege University [2019/17444], This work was supported by the Scientific and Technological Research Council of Turkey, TUBITAK (grant number: 117S241). The authors would like to acknowledge to Ege University Center for Drug Research, Development, and Pharmacokinetic Applications (ARGEFAR) for laboratory support and Dursun Demiroz for his illustration and help. We are grateful to Ege University Planning and Monitoring Coordination of Organizational Development and Directorate of Library and Documentation for their support in editing and proofreading service of this study. Patent applications in the national and international areas have been filed for this invention, which have been supported by Ege University (application number 2019/17444).

This study aimed to evaluate the effect of solid lipid and oil structures on the physicochemical properties, kinetic release, photostability, and photoprotection of nanostructured lipid carriers (NLC) containing octyl methoxycinnamate (OMC). OMC was used as a model compound since it is an effective sunscreen agent and is widely used in sunscreen products; however, it is unstable after ultraviolet radiation (UVR) exposure. OMC-loaded NLC were prepared from different solid lipids (cetyl palmitate (CP) or tristearin) and oils (caprylic/capric triglyceride, isopropyl myristate or isononyl isononanoate) at a 4:1 ratio. After production, the particle size (z-ave) and polydispersity index (PDI) of OMC-loaded NLC ranged from 190 to 260 nm and were lower than 0.25, respectively, and the zeta potential (ZP) values were higher than |50 mV|. The Fourier transform infrared (FTIR) spectroscopy results indicated no interaction among the components. Data obtained from differential scanning calorimetry (DSC) and X-ray diffraction showed that the incorporation of oil into solid lipids disturbed the crystallinity of the lipid matrix, depending on the structure of the oil molecule. OMC loaded in tristearin-based NLC (OMC-tristearin-NLC) showed higher release of OMC than OMC loaded in CP-based NLC (OMC-CP-NLC). For photostability properties, OMC-CP-NLC prepared from isononyl isononanoate showed the highest stability owing to the less-ordered structure, providing space for accommodation of OMC, whereas the percentage of OMC remaining in tristearin-based NLC was comparable. Therefore, the degree of protection was dependent on the type of solid lipid and oil. As a result, branched-chain fatty acids provided a higher degree of disturbance than linear-chain fatty acid.

Aerosolization is a non-invasive approach in drug delivery for localized and systemic effect. Nanostructured lipid carriers (NLCs) are new generation versatile carriers, which offer protection from degradation and enhance bioavailability of poorly water soluble drugs. The aim of this study was to develop and optimize NLC formulations in combination with optimized airflow rates (i.e. 60 and 15 L/min) and choice of medical nebulizers including Air jet, Vibrating mesh and Ultrasonic nebulizer for superior aerosolization performance, assessed via a next generation impactor (NGI). Novel composition and combination of NLC formulations (F1 – F15) were prepared via ultrasonication method, employing five solid lipids (glycerol trimyristate (GTM), glycerol trilaurate (GTL), cetyl palmitate (CP), glycerol monostearate (GMS) and stearic acid (SA)); and three liquid lipids (glyceryl tributyrate (GTB), propylene glycol dicaprylate/dicaprate (PGD) and isopropyl palmitate (IPP)) in 1:3 w/w ratios (i.e. combination of one solid and one liquid lipid), with Beclomethasone dipropionate (BDP) incorporated as the model drug. Out of fifteen BDP-NLC formulations, the physicochemical properties of formulations F7, F8 and F10 exhibited desirable stability (one week at 25 °C), with associated particle size of ~241 nm, and >91% of drug entrapment. Post aerosolization, F10 was observed to deposit notably smaller sized particles (from 198 to 136 nm, 283 to 135 nm and 239 to 157 nm for Air jet, Vibrating mesh and Ultrasonic nebulizers, respectively) in all stages (i.e. from stage 1 to 8) of the NGI, when compared to F7 and F8 formulations. Six week stability studies conducted at 4, 25 and 45 °C, demonstrated F10 formulation stability in terms of particle size, irrespective of temperature conditions. Nebulizer performance study using the NGI for F10 identified the Air jet to be the most efficient nebulizer, depositing lower concentrations of BDP in the earlier stages (1–3) and higher (circa 82 and 85%) in the lateral stages (4–8) using 60 and 15 L/min airflow rates, when compared to the Vibrating mesh and Ultrasonic nebulizers. Moreover, at both airflow rates, the Air jet nebulizer elicited a longer nebulization time of ~42 min, facilitating aerosol inhalation for prophylaxis of asthma with normal tidal breathing. Based on characterization and nebulizer performance employing both 60 and 15 L/min airflow rates, the Air jet nebulizer offered enhanced performance, exhibiting a higher fine particle dose (FPD) (90 and 69 µg), fine particle fraction (FPF) (70 and 54%), respirable fraction (RF) (92 and 69%), and lower mass median aerodynamic diameter (MMAD) (1.15 and 1.62 µm); in addition to demonstrating higher drug deposition in the lateral parts of the NGI, when compared to its counterpart nebulizers. The F10 formulation used with the Air jet nebulizer was identified as being the most suitable combination for delivery of BDP-NLC formulations.

The fluorescence dye-loaded nanoparticles are widely used as bioimaging agents in the field of nanotheranostics. However, the nanoparticles for nanotheranostics usually consist of synthetic materials, such as metal, silica, and organic polymers, which are often biologically incompatible and may arouse toxicity issues. Herein, the potential of near-infrared probe DiR-containing solid lipid nanoparticle suspensions (DiR-SLNS) as the bioimaging agent, which was prepared by lipids and surfactants with excellent biocompatibility, was investigated in this study. The nanostructure of DIR-SLNS system and the distribution of DiR were studied by dissipative particle dynamics (DPD) simulations. The stability of physicochemical properties and fluorescence spectra of DIR-SLNS system were investigated using dynamic laser scattering (DLS), nanoparticle tracking analysis (NTA), and fluorescence spectra. The fluorescence intensity-concentration correlation of DIR-SLNS was also evaluated. As a result, DiR-SLNS demonstrated a "core-shell"-like nanostructure and DiR was mainly distributed in the cetyl palmitate (CP) core rather than the surface of SLNS, which was beneficial to its potential applications in bioimaging. DiR-SLNS exhibited remarkable physicochemical stability as the nanoparticles maintained ~ 90% fluorescence intensity during the 10-day storage time. The correlation between fluorescence intensity and concentration was established and validated using a linear regression model. This study proposed a type of promising candidates in nano-scale with higher safety and fluorescence stability for bioimaging.

In this work, a novel enteric coating based on natural waxes and alginate was reported. Initially, theophylline tablets were coated with emulsified ceresin wax in heated aqueous alginate solution using a fluidised bed coating technology. A coating level of 10% proved sufficient to prevent tablets from uptalking gastric medium (< 5%) and produced a delayed release profile that complies to the pharmacopeial criteria of enteric coating release. Then, a wide range of emulsions based on other natural waxes (white beeswax, yellow beeswax, cetyl palmitate, carnauba wax or rice bran wax) yielded coatings with similar disintegration times and release profiles. Interestingly, the ceresin-based coating showed a superior performance at inhibiting acid uptake and enabling highly pH-responsive drug release in comparison to different commercially available GRAS enteric coating products (Eudraguard® Control, Swanlac® ASL10, and Aquateric™ N100). The coating was stable for 6 months at 30°C and 65% RH. This innovative approach of applying hot O/W emulsion of natural waxes yielded an aesthetically attractive and stable coating with gastric protection and pH-sensitive release properties. The novel coating can be an efficient and promising alternative to overcome the shortcomings of current GRAS grade enteric coating products. [Abstract copyright: Copyright © 2020. Published by Elsevier B.V.]

Aims: The present study was aimed to improve the permeability of Luliconazole (LZ) and to localize high drug concentrations at skin layers by Quality by Design (QbD) based Nanostructured lipid carriers (NC) based gel. Methods: Quality Target Product Profile was set, and Critical Quality attributes were identified. FT-IR and DSC studies confirmed compatibility. Risk assessment was carried out by screening the factors using 2IV7-2 fractional factorial design and optimization by Box Behnken design. Cholesterol: Cetyl Palmitate, PEG 200 and probe sonication time were identified as factors, Particle size (80%) and % Cumulative Drug release (% CDR, >95%) as responses. Contour plots, overlay plots and desirability, were utilized to create design space. Results: The quadratic polynomial equations showed increased lipid content, PEG 200 and optimum sonication time reduced particle size, PDI, improved % EE and % CDR. The optimized formula was formulated into a gel. Ex-vivo permeation studies performed using pig ear pinna skin revealed that developed LZ NC gel exhibited greater permeation 272.98±8.57 (μg/cm2) and 32.11 ±4.7 (μg/cm2/h) flux than plain drug dispersed gel. Dermatokinetic parameters of LZ NC gel revealed that a highly significant amount of LZ was permeated, distributed and transported through the skin layers. The better linear correlations were obtained by LZ permeation through a synthetic membrane (in-vitro) and pig ear pinna skin (ex-vivo). Conclusion: The above findings revealed that developed LZ NC gel exhibited better permeation and localization at skin layers in treating fungal infections.

Chemotherapy fails to eradicate cancer cells, mainly due to the lack of selective drug accumulation into the tumor site, which can affect healthy cells, as well. In this research, we studied the magnetite nanostructured lipid carriers (NLCs) for targeted delivery of curcumin into breast cancer cells. Superparamagnetic iron oxide nanoparticles (SPIONs) were prepared using coprecipitation method by mixing FeCl2 and FeCl3 in a suitable ratio in alkaline media. The resultant ferrofluid was very stable and possessed high magnetic properties. To prepare SPIONs containing NLCs (NLC-SPIONs), cetyl palmitate and cod-liver oil, Tween 80 and span60 were used as solid lipid, liquid lipid, surfactant, and co-surfactant, respectively. Curcumin as an anticancer drug was loaded into NLC-SPIONs (CUR-NLC-SPIONs) and its characteristics, including particle size, zeta potential, polydispersity index (PDI), drug entrapment efficacy, drug-loading capacity, and thermal stability were evaluated. The results showed that CUR-NLC-SPIONs had a mean particle size of 166.7 ± 14.20 nm, mean zeta potential of -27.6 ± 3.83 mv, and PDI of 0.24 ± 0.14. Encapsulation efficiency for all prepared nanoparticles (NPs) was 99.95 ± 0.015% and drug-loading capacity was 3.76 ± 0.005%. Morphological studies were carried out by transmission electron microscopy (TEM) indicating spherical morphology of the NPs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay measurements on cell viability proved that the synthesized CUR-NLC-SPIONs possess a better cytotoxic activity against human breast cancer cells compared with free curcumin. This new drug delivery system, which benefits from superparamagnetic properties may serve as a suitable platform for developing new biocompatible drug carriers and with a potential to use in targeted cancer therapy.

Here, polyethylene glycol (PEG)-stabilized solid lipid nanoparticles (SLNs) containing Pt(IV) prodrugs derived from kiteplatin were designed and proposed as novel nanoformulations potentially useful for the treatment of glioblastoma multiforme. Four different Pt(IV) prodrugs were synthesized, starting from kiteplatin by the addition of two carboxylate ligands with different length of the alkyl chains and lipophilicity degree, and embedded in the core of PEG-stabilized SLNs composed of cetyl palmitate. The SLNs were extensively characterized by complementary optical and morphological techniques. The results proved the formation of SLNs characterized by average size under 100 nm and dependence of drug encapsulation efficiency on the lipophilicity degree of the tested Pt(IV) prodrugs. A monolayer of immortalized human cerebral microvascular endothelial cells (hCMEC/D3) was used as in vitro model of blood–brain barrier (BBB) to evaluate the ability of the SLNs to penetrate the BBB. For this purpose, optical traceable SLNs were achieved by co-incorporation of Pt(IV) prodrugs and luminescent carbon dots (C-Dots) in the SLNs. Finally, an in vitro study was performed by using a human glioblastoma cell line (U87), to investigate on the antitumor efficiency of the SLNs and on their improved ability to be cell internalized respect to the free Pt(IV) prodrugs.

Superparamagnetic iron oxide nanoparticles (SPIONs) can be used for the delivery of the anticancer drug Sorafenib, which possesses multikinase inhibitor activity, to specific locations in the body through the application of an external magnetic field. In order to increase the biocompatible and protect the drug, solid lipid NPs (SLN) have been used to contain sorafenib and SPIONs by means of hot homogenization technique using cetyl palmitate as lipid matrix and polyethylene glycol-modified phospholipids (PEG lipids), in order to achieve a PEG-based anti-fouling coating on SLN surface.

The aim of this work was to study the physicochemical characterization of lipid matrices composed of cetyl palmitate (CP)/perillyl alcohol (PA) and develop preliminary studies of SLN for potential application in cancer treatment. The pre-formulation was submitted to recrystallization process (heatingcooling) in a concentration of CP/AP (F1 1:0; F2 1:9; F3 1:3; and F4 1:1). The characterization showed TG presents a single stage of thermal decomposition for AP, F1, F2 and F3 and two stages for F4. DSC decrease of the onset temperature of CP before and after thermal decomposition in all samples indicates a reduction in crystallinity, and WAXD data confirmed DSC results, showing a reduction in the intensity of main diffraction peaks of the lipid mixtures and a presence of the amorphous portion in 2 angles of 21.51° and 23.62°. Results showed the binary mixtures presented a amorphous portion facilitates AP incorporation in SLN satisfactory size, polydispersity index, zeta potential and morphology was obtained., The authors acknowledge the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil), Fundação de AmAPro a Pesquisa do Estado de Sergipe (FAPITEC, EDITAL CAPES/FAPITEC/SE N° 01/2016—Programa de apoio a pós-doutorado no estado de Sergipe (PPDOC-SE): atração e qualifcação de pesquisadores) e do Conselho Nacional de Pesquisas (CNPq) for supporting funds., info:eu-repo/semantics/publishedVersion

The essential oil from Croton argyrophyllus Kunth is known for its antiproliferative, anti-inflammatory, antinociceptive, and anticancer activities, and is recognized as a source of phytochemicals for potential use in pharmaceutic and food sectors. Solid lipid nanoparticles (SLN) have been produced to load Croton argyrophyllus (CA) Kunth essential oil (CAEO) and its antioxidant properties evaluated in vitro as a new approach for the treatment of neurodegenerative diseases. Cetyl palmitate SLN loading CAEO (CAEO-SLN) with a mean particle size of 201.4 &plusmn, 2.3 nm (polydispersity index 0.211) have been produced by hot high-pressure homogenisation. The release of the oil followed the Korsmeyers-Peppas model. The risk of lipid peroxidation has been determined by applying the production of thiobarbituric acid-reactive substances (TBARS) standard assay. The antioxidant activity was determined by the capacity of the antioxidants existing in CAEO to scavenge the stable radical DPPH&bull, The cytotoxicity of CA Kunth essential oil-loaded SLN (CAEO-SLN) was evaluated in a human cell line SH-SY5Y (derived from human neuroblastoma) by determining the reduction of the yellow dye 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). Both free essential oil (fEO) and loaded essential oil (CAEO-SLN) were demonstrated to inhibit the Fenton reaction. CAEO-SLN showed DPPH&bull, radical scavenging capacity. The loading of the oil into cetyl palmitate SLN reduced the risk of cytotoxicity.

5-Aminosalicylic acid (5-ASA), the active moiety of sulphasalazine, is the most commonly used drug for treating patients with inflammatory bowel disease (IBD). Its bioavailability is low, i.e. 20--30\% upon oral administration and 10--35\\% by rectal administration. As the extent of 5-ASA absorption is very much dependent on the time-length, the drug is retained in the colon, a way to increase drug retention is the use of orally administered sustained released formulations. Solid lipid microparticles (SLM) are a viable option for site-specific targeted delivery in compressed tablets produced by direct compaction. In this study, we describe the development and characterization of 5-ASA-loaded SLM for sustained release. The solubility of 5-ASA in different types of solid lipids (e.g. cetyl palmitate, cetyl alcohol, and cetearyl alcohol) was evaluated to select the best lipid as the inert matrix-forming agent to control the release of the drug. SLM dispersions were prepared using the hot emulsification method employing the selected solid lipid, lecithin (Lipoid®) as surfactant, dimethyl sulphoxide, and acetone stabilized with Arlacel®. The characterization was performed by differential scanning calorimetry, thermogravimetric analysis, wide-angle x-ray diffraction, Fourier transform infrared spectroscopy measurements, optical microscopy, and scanning electron microscopy. Results show that the best lipid for dissolving the 5-ASA was cetyl palmitate and that the melting process did not affect the chemical stability of the materials. The thermal analysis suggests that 5-ASA was successfully encapsulated with the microparticles, of spherical shape and uniform size distribution., The authors wish to thank Conselho Nacional de Desenvolvimento Científico e Tecnológico –CNPq (Processes #443238/2014-6 and #470388/2014-5) for their financial support. This work was also financed through the project M-ERA-NET/0004/2015 from the Portuguese Science and Technology Foundation, Ministry of Science and Education (FCT/MEC) from national funds, and co-financed by FEDER, under the Partnership Agreement PT2020., info:eu-repo/semantics/publishedVersion

Cetyl palmitate was synthetized by esterification the cetyl alcohol with palmitic acid in a solvent-free system. Reactions were performed in batch mode using commercial lipase Lipozyme RM IM as catalyst. Stirring speed (180, 480 and 720 rpm), temperature (60, 70, 80 and 87 °C), amount of catalyst (0.5, 1.0 and 1.5% wt% related to the mass of substrates) and alcohol:acid molar ratio (0.5:1, 1:1 and 2:1) were evaluated and best reaction conditions obtained were 480 rpm, 70 °C, 1.0% of enzyme and 1:1 M ratio. A novel kinetic model based on random-sequential bi-bi mechanism was proposed and showed a good agreement with experimental data. Furthermore, this model was proved to be suitable for kinetics predictions with a small uncertainty. The catalyst was recycled and showed good stability since reaction conversion decreased only 6.8% after 15 reuses.

Nanostructured lipid carriers (NLC) have been studied for over 20 years, constituting the second generation of lipid nanoparticles. These nanosystems were introduced to overcome the drawbacks of solid lipid nanoparticles (SLN). Passion fruit seeds oil have a high antioxidant potential and also skin whitening properties. The objectives of this work were to prepare NLC by two methods (ultrasonication and High pressure homogenization) using different solid lipids (Glyceryl Distearate, Glyceryl Dibehenate and Cetyl Palmitate) and passion fruit seeds oil as liquid lipid. The nanoparticles prepared with glyceryl distearate, using the ultrasonication method showed better characteristics, since these nanosystems presented smaller particle sizes and polydispersity index, and higher zeta potential. Besides that, these nanoparticles showed a high occlusion factor and non-irritant potential in HET-CAM assay. Based on the results obtained, it may be suggested that the prepared NLCs can be applied to the face, since they did not cause any irritation, and represent a potential strategy for further use in topical formulations with antioxidant activity.

In this work, we aimed at developing an improved topical SLN formulation combining itraconazole delivery with a coating layer of didodecyldimethylammonium bromide, thus repurposing the drug effectiveness by synergistic skin anticancer effectiveness. In order to obtain a stable SLN formulation with small homogeneously dispersed particles, a deep formulative study was developed screening three different solid lipids (Suppocire NB, Cetyl Palmitate and Dynasan 114) for the SLN preparation by the phase inversion temperature. A bluishcolored shade formulation, with homogeneous small particles size (50 nm) was obtained only using Suppocire NB. The cytotoxicity of all SLN was tested after 24 h exposure against three adherent skin cell lines (A431, HaCaT and SK-MEL-5). Results demonstrate that both unloaded and drugloaded SLN did not significantly affect the cell viability of the non-tumoral HaCaT cell line, thus confirming the safe potential topical application of these formulations. A dose-dependent decrease in cell viability was observed for the tumoral cell lines, A431 and SK-MEL-5, with a significant reduction of the A431 cancer cell line viability. The drug molecule addition to the uncoated nanoparticles was able to increase of almost 20% the reduction of the viability of the cancer cells treated. Ours results demonstrate the potentiality of repurposing itraconazole activity by using the combined nanoencapsulation strategy with the positively charged coating layer on SLN, which can be further investigated as a promising stable and safe approach to significantly reduce the viability of skin cancer cells.

BACKGROUND Bupivacaine is the most used local anesthetic in surgical procedures, producing prolonged anesthesia. The major limiting factor for the clinical use of bupivacaine comes from its systemic toxicity. Nanostructured lipid carriers (NLC) are vehicles for sustained drug delivery that are able to minimize the toxicity and to increase the action time of lipophilic drugs. METHODS This work reports a 22 factorial design, which elucidates the role of the lipids mixture in the NLC, towards an optimized formulation. It also provides a new method for bupivacaine S75:R25 (BVCS75) quantification in NLC. Moreover, physicochemical stability studies on the prepared NLC formulations were carried out by monitoring particle size, polydispersity, Zeta potential and BVCS75 encapsulation efficiency for 90 days, at 25°C. RESULTS The factorial design showed that the liquid lipid Capryol 90® has a negative effect over particle size and PDI values while cetyl palmitate presented a positive effect in size. The analytical method was accurate, reproducible, specific and linear over the concentration range of 0.16-54.00 µg.mL-1 BVCS75 with limits of quantification and detection of 0.10 and 0.03 µg.mL-1, respectively. The validated method was used to quantify the BVCS75 encapsulation (55.5 ±2.8 %). Encapsulation did not affect the nanoparticles morphology (confirmed by Transmission Electron Microscopy), but increased their Zeta potential (from -15.7 to -37.0 mV). The NLC physical stability was maintained (particles: size < 170 nm, polydispersity

Epilepsy is the second most common chronic central nervous system disorder. Oxcarbazepine (OXC) is an antiepileptic drug with low solubility in aqueous media but is used for the treatment of both focal and generalized seizures. Studies of OXC encapsulation in nanostructured lipid carriers (NLCs) composed of cetyl palmitate and oleic acid coated with polyvinyl alcohol (PVA) or chitosan (Ch) to obtain nanoparticles with negative and positive surface charge, respectively, are reported. All NLCs displayed 97%–98% OXC encapsulation efficiency, 14.5%–14.6% drug loading, 121.8–212.3 nm size range, and polydispersity indexes between 0.248 and 0.282 nm, depending on their composition. The homogeneity of the NLCs was confirmed by electron microscopy. The OXC release from the NLCs was analyzed by Higuchi, Baker-Londsdale, and Korsmeyer-Peppas structured models. The Korsmeyer-Peppas model provides the best data fit (R2 > 0.98), and n > 0.58, suggesting a mechanism driven by non-Fickian molecular release. In vitro permeability studies using MDCK-MDR1 cells revealed enhanced permeability of the encapsulated drug compared with free OXC. Surface plasmon resonance tested in the presence of BSA, IgG, and IgM, commonly found in human plasma, revealed no interaction with naked and PVA-coated NLCs. These promising results allow considering further in vivo studies for efficient delivery of OXC.

Wax esters, which are esters of fatty alcohols and fatty acids (FAs), are one of the main classes of reserve lipids in all coral species. The chemical structures and the content of wax ester molecular species were determined for the first time in nine coral species from three taxonomic groups: symbiotic reef-building corals, (Hexacorallia subclasses), symbiotic soft coral alcyonarians, and asymbiotic soft coral gorgonians (Octocorallia subclasses) collected in the South China Sea (Vietnam). Our comparison of these groups showed that the absence of symbiotic microalgae (zooxanthellae) and the exoskeleton affects the profile of molecular species of wax esters considerably. The main components of wax esters of all corals were cetyl palmitate (16:0-16:0) and other saturated wax esters containing 30, 34, and 36 carbon atoms. The content of unsaturated molecular species 6:0–16:1, 16:0–18:1, and 16:0–20:1 in wax esters of symbiotic soft corals (alcyonarians) was greater than that in wax esters of reef-building corals. In contrast to symbiotic coral species, wax esters of asymbiotic soft corals, namely azooxanthellate gorgonians, contained a considerable amount of long-chain molecular species (C37-C41) with an odd number of carbon atoms. The presence of such molecular species indicates that asymbiotic gorgonians may use bacterial FAs in biosynthesis of their own wax esters. This observation confirms our hypothesis that bacterial community is important for maintaining the energy balance of azooxanthellate corals.

Effect of different surfactants (nonionic, anionic, cationic and zwitterionic) as stabilizer on the physicochemical properties of the nanostructured lipid carriers (NLC) comprising cetyl palmitate, triolein and palmitic acid were explored in the absence and presence of a potent antifungal drug, itraconazole. The blank and drug loaded NLC formulations were prepared by way of hot homogenization and ultrasonication technique. Combined dynamic light scattering, electron microscopy, atomic force microscopy, differential scanning calorimetry, UV–vis absorption spectroscopy and method of dialysis were adopted in characterizing the formulations. NLCs were stable up to 100 days irrespective of the surfactant. While the ionic surfactant comprising NLCs were electrostatically stable, the nonionic surfactants imparted better steric stabilization as revealed from the decreased size and polydispersity index values. Up shift in the phase transition temperature, changes in enthalpy and heat capacity in case of nonionic surfactant comprising systems substantiated its superior stabilization effect over the ionic surfactants. NLC formulations, stabilized by nonionic surfactants, exhibited superior drug incorporation, loading capacity and sustained release for itraconazole. Itraconazole loaded NLC formulations exhibited substantial antifungal activity against the fungal strain Aspergillusniger MTCC 3323. Such a comprehensive set of studies could assess the NLC formulation as potential drug delivery system for itraconazole.

One of the most favored features of using nanoparticulate delivery systems such as solid lipid nanoparticles (SLNs) is their capability to encapsulate multi-agents of different chemical structures to achieve simultaneous delivery to the site of action. The present work has been carried out to elaborate a convenient methodology for the loading of the drug combination efficiently and with high drug content. Thus, two representatives of the naturally occurring flavonoids (FLs) with a broad spectrum of biological functions, i.e., fisetin (FIS) or myricetin (MYR), along with the indocyanine-type photosensitizer IR-780 were co-loaded in the cetyl palmitate (CP) matrix of the phosphatidylcholine-based solid lipid nanoparticles (SLNs) by means of the high pressure homogenization method (HPH). The HPH process – optimized in regard to different ratios of combination drugs, particle components content as well as variable parameters as pressure and number of homogenization cycles – provided physically stable and fairly monodisperse FL + IR-780-loaded SLN dispersions (with polydispersity indices below 0.3). The sizes of the studied nanosystems along with the size distribution were determined by dynamic light scattering (DLS), while shape and morphology – by atomic force microscopy (AFM). The physical state of the studied co-loaded SLNs was characterized by Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analysis (TG-DTA). Both FLs and IR-780 preserved their structural state and were thoroughly dispersed in the CP-matrix during the HPH procedure. Our synthetic methodology enabled to perform remote loading of two drugs (FIS or MYR and IR-780) in the SLN – type nanocarriers having desirable chemical and colloidal stability, making them useful for therapeutic and diagnostic applications or combination therapies.

This research is aimed at the preparation of biopolymeric skimmed milk powder (SMP) and pectin coated dual layer solid lipid nanoparticles loaded with soluble curcumin (CMN) to enhance the cytotoxicity of the drug delivered to the colon for colorectal cancer (CRC). The curcumin (C‐) and curcumin solid dispersion (C‐SD) (soluble curcumin) loaded solid lipid nanoparticle (SLN) (C‐SD‐SLN) are prepared by hot homogenization method and characterized its physicochemical properties. The surface of the C‐SD‐SLNs was coated with natural biopolymers of pectin and skimmed milk powder (SMP), called cetyl palmitate (CP)‐SD‐SLN. The resultant nanoparticles showed significantly high drug loading, better stability, and slower release profile (92.1%) in various GI conditions up to 72 H. zebra fish toxicity studies of CP‐SD‐SLN confirm its in vivo safety, and the result from in vitro cytotoxicity showed that 50% inhibition (26 μM/ml) is achieved with an amount of CP‐SD‐SLN, which was considerably lesser than free CMN. The result from flow cytometry analysis confirmed the cell cycle arrest in the G2/M phase (49.11%), and western blot analysis was performed to understand its molecular level apoptosis in Caco‐2 cells. The profound efficiency of SMP and pectin coated CP‐SD‐SLN is a promising preparation that indicated its potential application for CRC treatment without toxicity. PRACTICAL APPLICATION: The pharma and biotech industry is seeking techniques to increase potential and reduce the toxicity of chemotherapeutic agents. The solid lipid nanoparticle (SLN) has fascinated significant attention in anticancer drug delivery generally because of the targeted delivery to the particular site and devoid of other tissues. The present investigation provides the efficiency of skimmed milk powder (SMP)‐coated lipid shell contains soluble curcumin to release the drug at colon and improve the metabolism and therefore increase the potential activity several fold than native curcumin. The results show that SMP and pectin coated SLN is a potential carrier for delivery to the colon and thus improve anticancer potential of human adenocarcinoma (Caco‐2) cells of curcumin. These results will contribute in designing SLN techniques for optimizing the wide‐ranging quality of natural curcumin.

In this work, we report the development and optimization of solid lipid nanoparticles (SLN) production by a simple, fast, and cost-effective high shear homogenization process. A screening of several solid lipids (Compritol 888 ATO, Precirol ATO 5, Cetyl Palmitate, Dynasan 118, Imwitor 900K, Stearic acid) has been carried out in combination with Poloxamer 188 as the selected surfactant, based on the mean particle size and polydispersity index. The improvement of the physical stability of the SLN dispersions was achieved by the use of a cationic lipid (cetyl trimethylammonium bromide) reaching zeta potential values above +60 mV. Combining the optimized speed and time of shear, monodispersed SLN (PdI < 0.25) under the nanometer range could be produced., The authors also wish to acknowledge Fundação para a Ciência e Tecnologia (FCT, Portugal) under the reference SFRH/BD/60552/2009. This work was also financed through the projects M-ERA-NET-0004/2015-PAIRED and UID/AGR/04033/2019, receiving support from the Portuguese Science and Technology Foundation, Ministry of Science and Education (FCT/MEC) through national funds, and co-financed by FEDER, under the Partnership Agreement PT2020., info:eu-repo/semantics/publishedVersion

Mupirocin is a promising broad-spectrum antibiotic that is effective in treating MRSA infections. However, due to its rapid elimination and hydrolysis following injection and high protein binding, current therapeutic use is limited to topical administration. Nanotechnology-driven innovations provide hope for patients and practitioners in overcoming the problem of drug degradation by encapsulation. The objective of this research is to develop and characterize Mupirocin-Loaded Nanostructured Lipid Carriers (M-NLC) for intravascular administration. The MNLC was produced by a combination of high shear homogenization and high pressure homogenization of solid (cetyl palmitate) and liquid (caprylic/caprylic acid) biocompatible lipids in 5 different ratios. The mean particle size, polydispersity index (PDI) and the zeta potential (ZP) of the MNLC formulations were between 99.8 and 235 nm, PDI lower than 0.164, ZP from −25.96 to −19.53 and pH ranging from 6.28–6.49. The MNLC formulation also enhances the anti-bacterial activity of mupirocin. All formulation showed sustained drug release and good physical characteristics for three months storage under 25 °C. It also revealed that the MNLC 1 is safe at 250 mg/kg dose in rats. The MNLC 1 also showed a significant increase in plasma concentration in rabbits following IV administration thus, demonstrating an enhancement on its pharmacokinetic profile as compared to free mupirocin.

Perorale Nanopartikel gelangten in den letzten Jahren vermehrt in den Fokus der Wissenschaft. Die Untersuchung des gastrointestinalen Verhaltens und der Einfluss intestinaler Verdausäfte auf diese Partikel sind daher essentiell. In dieser Dissertation wurden Lipidnanopartikel aus Cetylpalmitat und Polymernanopartikel aus PLGA mit der pH-stat Methode sowie Referenzmethoden, wie HPTLC, untersucht und das Ausmaß des enzymatischen Abbaus durch die pankreatische Lipase bestimmt. Im Weiteren wurde der Einfluss von diversen Stabilisatoren auf den Verdau sowie der Verdau der Stabilisatoren selbst untersucht. Zur Beobachtung des in vivo Verhaltens der peroral applizierten Partikel wurde die nicht invasive Fluoreszenzbildgebung im Mausmodell angewendet. Hierbei konnten für die fluoreszenzmarkierten Partikelformulierungen Transit-Zeit-Profile erstellt sowie Aussagen zum Verdau, zur Aufnahme und den Interaktionen mit der Schleimhaut im Gastrointestinaltrakt getroffen werden., In the last decade peroral nanoparticles get more in the focus of research. The knowledge about behavior and fate of nanoparticle formulations in the gastro intestinal tract is of central concern for the rational design of peroral drug delivery systems. In this thesis lipid nanoparticles of cetyl palmitate and polymer nanoparticles of PLGA were investigated in vitro by the pH-stat method and different reference methods like HPTLC. The impact of pancreatic lipase on the particle digestion was determined as well as the influence of various stabilizers. A mouse model for the in vivo monitoring of fluorescence-marked particles was developed by using non-invasive multispectral fluorescence imaging. Thereby transit-time-profiles were recorded and the digestion, the uptake and interaction with mucus of these particles were analyzed in more detail.

To take advantage of solid-state properties, the nano spray-drying (NSD) technique was investigated as an innovative one-step method to produce solid lipid nanoparticles (SLN) in the form of a dry powder starting from a lipid/leucine O/W emulsion. Compritol was chosen as wall-forming lipid. Rapamycin (Rp) was employed as a model drug to be loaded into SLN. Based on an initial screening, Lutrol F68 was chosen as surfactant and high-shear homogenization as an emulsification method. A two-level fractional factorial design and an extended factorial design were employed to determine critical factors and best preparation conditions. Compritol concentration, L-leucine/lipid ratio, and Lutrol F68 concentration resulted critical. Best conditions granted 51% yield, 3.2 μm L-leucine/SLN particle size, and a SLN population around 150 nm. All samples showed the presence of lipid aggregates. Material loss in the emulsification step was found responsible for SLN aggregation and low yield. The almost quantitative Rp loading increased SLN population span. Replacing compritol with cetyl palmitate produced aggregation of dry powders and SLN. Overall, NSD was found a fast method to produce SLN dry powders. More insightful assessment of the emulsification step and lipid property effects will be critical to the optimization of the NSD process. Hypotheses account for direct coupling of high-pressure homogenization with NSD for future successful development of this promising manufacturing method.

The present work reports the development, optimization and characterization of novel lipid based nanoformulations viz., Liquid crystalline nanoparticles (LCNP), solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and liposomes loaded with Tacrolimus (Tac) for topical delivery. Different nanoformulations were developed after screening lipids and suitable surfactants depending upon emulsification ability. The various nanoformulations were then optimized (to achieve higher entrapment efficacy, lower particle size, PDI and zeta potential), characterized and loaded into gel. The gels loaded with nanoformulations were also characterized depending upon rheology and viscosity. The gels were analyzed for in vitro drug release, HaCaT cell lines studies and skin permeation studies. The in vivo efficacy studies were carried out using mouse tail model and skin irritation studies using Draize patch test and measurement of TEWL. The developed nanoformulations showed optimum particle size (200 nm), polydispersity index (PDI 0.3), zeta potential (≥-10 mV) and higher entrapment efficiency (85%). The nanoformulations showed higher penetration of Tac into skin. Tac-LCNP, Tac-SLN, Tac-NLC and Tac-liposomes loaded gels showed 14, 11.5, 12.5 and 3.7 folds increment in dermal bioavailability respectively, in comparison to free Tac loaded gel and 2.5, 2 and ∼2 folds augmentation in dermal bioavailability respectively as compared to Tacroz™ Forte. In case of Tac-liposomes, the dermal bioavailability was lower as compared with the marketed formulation, Tacroz™ Forte. Despite, the increased bioavailability into the skin, the developed nanoformulations showed no significant skin irritation. The above mentioned nanoformulations were able to achieve greater penetration of Tac into the skin as compared to marketed ointment of Tac, Tacroz™ Forte.

In dental practice, local anesthesia causes pain, fear, and stress, and is frequently the reason that patients abandon treatment. Topical anesthetics are applied in order to minimize the discomfort caused by needle insertion and injection, and to reduce the symptoms of superficial trauma at the oral mucosa, but there are still no efficient commercially available formulations. Factorial design is a multivariate data analysis procedure that can be used to optimize the manufacturing processes of lipid nanocarriers, providing valuable information and minimizing development time. This work describes the use of factorial design to optimize a process for the preparation of nanostructured lipid carriers (NLC) based on cetyl palmitate and capric/caprylic triglycerides as structural lipids and Pluronic 68 as the colloidal stabilizer, for delivery of the local anesthetics lidocaine and prilocaine (both at 2.5%). The factors selected were the excipient concentrations, and three different responses were followed: particle size, polydispersity index and zeta potential. The encapsulation efficiency of the most effective formulations (NLC 2, 4, and 6) was evaluated by the ultrafiltration/centrifugation method. The formulations that showed the highest levels of encapsulation were tested using in vitro release kinetics experiments with Franz diffusion cells. The NLC6 formulation exhibited the best sustained release profile, with 59% LDC and 66% PLC released after 20h. This formulation was then characterized using different techniques (IR-ATR, DSC, DRX, TEM, and NTA) to obtain information about its molecular organization and its physicochemical stability, followed during 14months of storage at 25°C. This thorough pre-formulation study represents an important advance towards the development of an efficient pre-anesthetic for use in dentistry.

The long-term use of topical hydroquinone as an anti-hyperpigmentation treatment has well-known, unwanted effects. Deoxyarbutin (4-[(tetrahydro-2H-pyran-2-yl)oxy]phenol) is a relatively new tyrosinase inhibitor, with stronger inhibitory potency than hydroquinone, that exhibited decreased cytotoxicity against melanocytes and other cells. This study developed novel nanostructured lipid carriers (NLCs) for improved topical delivery of deoxyarbutin (dArb), leading to improved depigmenting efficacy. dArb is a hydrophobic substance, but it easily degrades in aqueous medium and is thermolabile. Screening and optimisation of the solid lipid, liquid lipid, surfactant, co-surfactant and production methods were performed to choose the optimum particle size and stability for NLCs. One percent dArb NLCs were obtained from a combination of cetyl palmitate (CP) and caprylic/capric tryglicerides (Myr) in 12% total lipids using poloxamer 188 (P-188) and polyethylene glycol (PEG) 400 as a surfactant and co-surfactant, respectively, with a particle diameter of approximately 500 nm and a polydispersity index (PI) &lt, 0.4. These NLCs were produced using the simple method of high-shear homogenisation (10,000 rpm, 5 minutes) and ultrasonication (3.5 min). The compatibility between the substances in the formula was evaluated using Fourier Transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The morphology of the NLCs was observed using transmission electron microscopy (TEM). In vitro penetration of dArb NLCs was evaluated and compared to the nanoemulsion (NE) and conventional emulsion (CR) delivery methods across Spangler’s membrane (SS). Delivery improvement was clearly observed, and after 8 h of application, dArb gel-NLCs showed the highest dArb penetration, followed by liquid NLCs, NE, and CR.

Loading of hydrophobic α-tocopherol into nanostructured lipid carrier (NLC) was performed for improving its oxidative stability. First, various NLCs with different constituents and mixing ratios were prepared and their characteristics were investigated. While the stable NLCs were made when cetyl palmitate (CP) or glyceryl monosterate (GMS) was used as a solid lipid, the phase separation occurred in the NLCs consisting of stearic acid. Particle sizes of the NLCs were several hundreds of nanometers and the size decreased with increasing the ratio of solvent to lipid. It was examined from DSC thermogram and anisotropy test that the degree of crystallinity of the lipid phase decreased and the lipid matrix became less ordered when octyldodecanol, a long chain fatty alcohol, was added into the solid lipid. The oxidative stability of α -tocopherol in NLC was remarkably improved compared to that in solution or emulsion under high temperature (45 °C) and UV radiation, which was verified through DPPH test and peroxide value measurement.

Pre-formulation studies are conducted each time new nanoparticulate formulations are in development to the selection of a satisfactory drug delivery system. We hypothesized that laser diffraction technique could be used as an initial screening, being an excellent tool to save time and reduce the number of necessary tests to select formulations. We built radar charts based on laser diffraction data as a new approach to determine the fingerprints of nanocarrier formulations in order to select promising drug delivery systems. To validate our approach different lipophilic dispersions of poly(epsilon-caprolactone) and polysorbate 80, combined with 4 solid materials: sorbitan monostearate (I), cetyl palmitate (II), stearic acid (III) or cholesterol (IV), and 4 oils: capric/caprylic triglycerides (A), mineral oil (B), octyl methoxycinnamate (C) or oleic acid (D), were prepared. Formulations were analyzed by laser diffraction, as well as considering the visual appearance, pH, organic phase viscosity, hydrodynamic diameter, polydispersity index, zeta potential and in vitro drug release. Specific fingerprints were determined for formulations having unimodal particle size distributions with low polydispersity. On the other hand, formulations showing multimodal particle size distributions were rapidly identified in the radar charts and classified as noncompliance products.

The interfacial behavior of curcumin, a model anti-inflammatory drug was studied upon interaction with cetyl palmitate and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine. Cetyl palmitate finds applications for topical delivery in nanostructured lipid carriers, while the phosphatidylcholine was used both as a component of the carrier and as a model membrane lipid. Here, surface pressure, thermodynamics, Brewster angle microscopy, molecular dynamics and polarization modulation infrared reflection-absorption spectroscopy were used to better our understanding of the interaction between the components of the delivery systems and, on the other hand, of their interaction with biological membranes. Moreover, thermodynamics was used to analyze the effect of curcumin on the lipid systems and, in particular, on the model membranes. The results obtained indicate that mixtures of curcumin and cetyl palmitate form Langmuir films, while none of the two pure components does. This effect was interpreted in terms of formation of a complex between curcumin and the hydrophobic, water insoluble cetyl palmitate. The hydrophilic-hydrophobic balance of the complex allows its penetration into the monolayer and mixing with the phospholipid phase. This finding may be of interest for further design of phytolipids for drug delivery applications.

Cetyl palmitate (CP) was thermally synthesized using binary 1-hexadecanol (HD) and palmitic acid (PA) mixture as the starting materials in nitrogen with the absence of any catalyst. The molecule structure, thermal property, thermal stability and reliability of as-prepared cetyl palmitate was studied by 1H nuclear magnetic resonance (1H NMR), Fourier transformation infrared (FT-IR) spectrometer, differential scanning calorimetry (DSC) and thermogravimetric analyzer (TGA), respectively. 1HNMR and FT-IR confirmed the as-prepared product under 350 °C for 30 min was CP with high purity. According to the DSC measurements, the onset melting temperature and latent heat of fusion for the as-prepared CP was 52.3 °C and 180.9 J/g, respectively. Results showed that the synthesized cetyl palmitate was favorable used as phase change material (PCM) owing to its desirable thermal properties, excellent thermal stability and reliability. Due to the low thermal conductivity of CP, it was impregnating into nickel (Ni) foams with different pore sizes to make CP/Ni foam composite PCMs (CPCMs). Compared with pure CP, thermal conductivity of CP/Ni foam (70, 90, and 110PPI) CPCMs were increased by 1.88, 2.02 and 4.86 times, respectively. The CP/Ni foam CPCMs displayed appropriate thermal properties for latent heat energy storage applications.

Docetaxel (DTX), a widely prescribed anticancer agent, is now associated with increased instances of multidrug resistance. Also, being a problematic BCS class IV drug, it poses challenges for the formulators. Henceforth, it was envisioned to synthesize an analogue of DTX with a biocompatible lipid, i.e., palmitic acid. The in-silico studies (molecular docking and simulation) inferred lesser binding of docetaxel palmitate (DTX-PL) with P-gp vis-a-vis DTX and paclitaxel, indicating it to be a poor substrate for P-gp efflux. Solid lipid nanoparticles (SLNs) of the conjugate were prepared using various lipids, viz. palmitic acid, stearic acid, cetyl palmitate and glyceryl monostearate. The characterization studies for the nanocarrier were performed for the surface charge, drug payload, micromeritics, release pattern of drug and surface morphology. From the cytotoxicity assays on resistant MCF-7 cells, it was established that the new analogue offered substantially decreased IC50 to that of DTX. Further, apoptosis assay also corroborated the results obtained in IC50 determination wherein, SA-SLNs showed the highest apoptotic index than free DTX. The conjugate not only enhanced the solubility but also offered lower plasma protein binding and improved pharmacokinetic and pharmacodynamic effect for DTX loaded SA-SLNs in apt animal models, and lower affinity to P-gp efflux. The studies provide preliminary evidence and a ray of hope for a better candidate in its nano version for safer and effective cancer chemotherapy.

The purpose of this research is to determine the optimum composition of solid lipid and liquid lipid in order to increase the penetration and effectiveness of Q10 as antioxidant in anti-aging cosmetics. Solid lipid and liquid lipid used in this study were cetyl palmitate and caprylic, which were combined to four (4) different ratios, namely 10:0; 9:1; 7:3 and 5:5. NLC Q10 in this study was produced by high shear homogenization method at 3400 rpm for 5 cycles and at 24000 for 1 cycle. The fourth formula was evaluated in term of characteristics, penetration and effectiveness. From the pH test , it was known that all formulas met the skin pH range (4.0-6.0). For the particle size test , all formulas (NLC 1 - NLC 4) were in the range from 269.13 to 354.77 nm with NLC 3 (7: 3) had the smallest particle size. The results of viscosity and surface tension test were also consistent with the theory, where the addition of liquid lipid reduced viscosity and surface tension of the system. The entrapment efficiency (EE) demonstrated the EE of NLC 1: 22.24%; NLC 2: 24.71%; NLC 3: 58.21% and NLC 4:36.94%. The penetration test showed all systems were able to penetrate the dermis layer at the 5th hour. NLC 3 (7:3) had more rapid onset, while the NLC Q10 with the ratio of lipid 9:1, had slower onset of action but can penetrate farther than the other NLC Q10 system. The result of Q10 effectiveness test showed NLC 2 (9:1) has lowest total macrophage (23.33) and very dense collagen observation (score : 4). From this research, it can be concluded that NLC 2 (9:1) had the most optimal lipid composition to increase the penetration and effectiveness of Q10 as an antioxidant in anti-aging cosmetics.