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Journal ArticleDOI: 10.1080/02726351.2020.1750515

Development of mebendazole loaded nanostructured lipid carriers for lymphatic targeting: Optimization, characterization, in-vitro and in-vivo evaluation

04 Mar 2021-Particulate Science and Technology (Taylor & Francis)-Vol. 39, Iss: 3, pp 380-390
Abstract: The basic objective of research work was to develop, optimize and evaluate MBZ loaded NLCs to overcome the issues of poor solubility and bioavailability of the drug. The nanoformulation was prepare...

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9 results found


Open access
01 Jan 2014-
Abstract: The lymphatic system has an important defensive role in the human body. The metastasis of most tumors initially spreads through the surrounding lymphatic tissue and eventually forms lymphatic metastatic tumors; the tumor cells may even transfer to other organs to form other types of tumors. Clinically, lymphatic metastatic tumors develop rapidly. Given the limitations of surgical resection and the low effectiveness of radiotherapy and chemotherapy, the treatment of lymphatic metastatic tumors remains a great challenge. Lymph node metastasis may lead to the further spread of tumors and may be predictive of the endpoint event. Under these circumstances, novel and effective lymphatic targeted drug delivery systems have been explored to improve the specificity of anticancer drugs to tumor cells in lymph nodes. In this review, we summarize the principles of lymphatic targeted drug delivery and discuss recent advances in the development of lymphatic targeted carriers.

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47 Citations


Open accessJournal ArticleDOI: 10.3390/PHARMACEUTICS12100978
Ji-Hun Jang1, Seung-Hyun Jeong1, Yong-Bok Lee1Institutions (1)
16 Oct 2020-Pharmaceutics
Abstract: Methotrexate, which is widely used in the treatment of cancer and immune-related diseases, has limitations in use because of its low bioavailability, short half-life, and tissue toxicity. Thus, in this study, a nano-sized water-in-oil-in-water (W/O/W) double emulsion containing methotrexate was prepared to enhance its lymphatic delivery and bioavailability. Based on the results from solubility testing and a pseudo-ternary diagram study, olive oil as the oil, Labrasol as a surfactant, and ethanol as a co-surfactant, were selected as the optimal components for the nanoemulsion. The prepared nanoemulsion was evaluated for size, zeta potential, encapsulation efficiency, pH, morphology, and in vitro release profiles. Furthermore, pharmacokinetics and lymphatic targeting efficiency were assessed after oral and intravenous administration of methotrexate-loaded nanoemulsion to rats. Mean droplet size, zeta potential, encapsulation efficiency, and pH of formulated nanoemulsion were 173.77 ± 5.76 nm, -35.63 ± 0.78 mV, 90.37 ± 0.96%, and 4.07 ± 0.03, respectively. In vitro release profile of the formulation indicated a higher dissolution and faster rate of methotrexate than that of free drug. The prepared nanoemulsion showed significant increases in maximum plasma concentration, area under the plasma concentration-time curve, half-life, oral bioavailability, and lymphatic targeting efficiency in both oral and intravenous administration. Therefore, our research proposes a methotrexate-loaded nanoemulsion as a good candidate for enhancing targeted lymphatic delivery of methotrexate.

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Topics: Bioavailability (53%)

7 Citations


Journal ArticleDOI: 10.1016/J.JDDST.2021.102585
Abstract: In dosage form design, drug delivery technology facing a major problem due to degradation of the drug through the first-pass metabolism upon oral delivery. We can overcome this bioavailability-related problem by adopting the intestinal lymphatic pathway for drug delivery. Nanocarriers like lipid nanoparticles, polymeric nanoparticles, liposomes, emulsions, etc. can be used to enhance the lymphatic uptake of drugs. In the lymphatic pathway absorption of drugs takes place by endocytosis via Peyer's patches and the chylomicron uptake. Peyer's patches exhibit M-cells which represent many receptors like mannose receptors, folate receptors, claudins, integrins, transferrin receptors, biotin receptors etc. Targeting these receptors through nanocarriers can improve the lymphatic absorption of drugs and thus improve bioavailability. Targeting drugs through the lymphatic system can treat many diseases including cancer, AIDS, tuberculosis, lymphodema, diabetes, schizophrenia, etc. Thus, by using lymphatic drug delivery systems we can improve the treatment efficacy, survival, and life expectancy of the patient. In this article, we discussed various strategies to enhance drug bioavailability through lymphatic targeting.

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Topics: Nanocarriers (60%), Targeted drug delivery (59%), Drug delivery (54%)

2 Citations


Journal ArticleDOI: 10.1007/S13346-021-01014-4
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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2 Citations


Journal ArticleDOI: 10.1007/S12247-021-09567-0
Abstract: The objective of this work was to develop a new nanostructured lipid carrier (NLC) formulation for the oral delivery of quetiapine fumarate (QTF) and assess the drug’s in vitro release mechanism through gastric and intestinal conditions. A preformulation study was conducted to select the most suitable components and solid-to-liquid lipid ratio for the formulation of nanoparticles. Then, a central composite design was employed to optimize the development of NLC and to study the effect of lipid and surfactant percentages on the physical characteristics of the preparation. The optimal formulation was subjected to physicochemical characterization and stability study. An in vitro release assay using simulated gastrointestinal fluids was performed to study the QTF release mechanism. The optimal formulation showed good particle size, PDI, and zeta potential of 179.2 ± 2.6 nm, 0.220 ± 0.020, and −33.63 ± 0.23 mV, respectively. The encapsulation efficiency and the loading capacity were 84.49 ± 1.25% and 2.6 ± 0.03%, respectively. DSC and FTIR analysis showed compatibility between QTF and other components of the formulation and successful encapsulation of the drug within lipid nanoparticles. The optimal formulation also showed good long-term stability at 4 °C storage temperature. The in vitro release of QTF followed the Korsmeyer-Peppas model. The study demonstrated that QTF was mainly released by diffusion mechanism in the gastric medium, and by erosion and anomalous transport in the intestinal medium. NLC represents a suitable formulation for the oral delivery of QTF. Further studies should investigate the oral absorption and lymphatic transport potential of the optimized formulation.

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References
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23 results found


Journal ArticleDOI: 10.1016/J.EJPS.2010.10.002
M.R. Aji Alex1, A.J. Chacko1, S. Jose1, Eliana B. Souto2  +1 moreInstitutions (3)
Abstract: The poor orally available lopinavir was successfully encapsulated in glyceryl behenate based solid lipid nanoparticles (Lo-SLN) for its ultimate use to target intestinal lymphatic vessels in combined chemotherapy-the so-called Highly Active Anti-Retroviral Therapy (HAART). SLN with mean particle size of 230 nm (polydispersity index, PDI<0.27) and surface electrical charge of approx. -27mV, were produced by hot homogenization process followed by ultrasonication. Particles were characterized using differential scanning calorimetry (DSC), wide angle X-ray scattering (WAXS) and atomic force microscopy (AFM) to confirm their solid character and the homogeneous distribution of drug within the lipid matrix. In vitro release studies at pH 6.8 phosphate buffer (PBS) and at pH 1.2 HCl 0.1N showed a slow release in both media. From the intestinal lymphatic transport study it became evident that SLN increased the cumulative percentage dose of lopinavir secreted into the lymph, which was 4.91-fold higher when compared with a conventional drug solution in methyl cellulose 0.5% (w/v) as suspending agent (Lo-MC). The percentage bioavailability was significantly enhanced. The AUC for the Lo-SLN was 2.13-fold higher than that obtained for the Lo-MC of similar concentration. The accelerated stability studies showed that there was no significant change in the mean particle size and PDI after storage at 25±2°C/60±5% RH. The shelf life of optimized formulation was assessed based on the remained drug content in the stabilized formulation and was shown to be 21.46 months.

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192 Citations


Journal ArticleDOI: 10.1016/J.IJPHARM.2009.10.014
Guopei Luo1, Xianjun Yu1, Chen Jin1, Feng Yang1  +5 moreInstitutions (1)
Abstract: Active tumor targeting by biodegradable nanoparticles has been widely studied for cancer diagnosis and therapy. However, target-specific nanoparticles for drug delivery to lymphatic metastases have not been reported yet due to the lack of specific markers in the tumor lymphatics. Recently, peptide LyP-1 has been recognized for its specific home to tumors and their lymphatics. In this study, we tested the possibility of LyP-1 serving as a target-specific peptide of PEG-PLGA nanoparticles to tumor lymph metastases. LyP-1 was synthesized by using Boc-protected amino acids. The copolymers of maleimide-PEG-PLGA were formed by the conjugation of maleimide-PEG-NH(2) to PLGA-COOH, which were applied to prepare pegylated nanoparticles with mPEG-PLGA by means of double emulsion/solvent evaporation technique. LyP-1 with sulfhydryl group was conjugated to the maleimide function located at the distal end of PEG surrounding the nanoparticle surface. LyP-1-conjugated PEG-PLGA nanoparticle (LyP-1-NPs) had a round and regular shape with a diameter around 90 nm. In vitro, cellular uptake of LyP-1-NPs was about four times of that of PEG-PLGA nanoparticles without LyP-1 (NPs). In vivo, the uptake of LyP-1-NPs in metastasis lymph nodes was about eight times of that of NPs. This study indicates that LyP-1-NP is a promising carrier for target-specific drug delivery to lymphatic metastatic tumors.

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Topics: Drug delivery (54%), Drug carrier (54%)

136 Citations


Journal ArticleDOI: 10.1016/J.IJPHARM.2015.09.014
Abstract: The aim of the present work was to develop a lymph targeted SLN formulation of antiretroviral (ARV) drug and to have an understanding of its underlying mechanism of uptake by the lymphatics. The lymphatics are the inaccessible reservoirs of HIV in human body. Efavirenz (EFV) is a BCS class II, ARV drug that undergoes extensive first pass metabolism. The EFV SLN formulation was prepared using Gelucire 44/14, Compritol 888 ATO, Lipoid S 75 and Poloxamer 188 by hot homogenization technique followed by ultrasonication method, with mean particle size of 168 nm, polydispersity index (PDI) <0.220, and mean zeta potential of -35.55 mV. DSC and XRPD studies revealed change in crystallinity index of drug when incorporated into SLN. In vitro drug release was found to be prolonged and biphasic in PBS pH 6.8. There was no significant change in the mean particle size, PDI, zeta potential and entrapment efficiency of EFV SLN after storage at 30 ± 2°C/60 ± 5%RH for two months. The results from lymphatic transport and tissue distribution study indicate that a significant part of the EFV had by-passed portal system and was recovered in the lymph via chylomicron uptake mechanism. Reduction in the amount (44.70%) of the EFV reaching to liver indicates that major amount of EFV bypasses the liver and thereby, enhances the oral bioavailability of the EFV. A significant amount of EFV was found in spleen, a major lymphatic organ. EFV SLN seems to have potential to target the ARV to lymphatics for the better management of HIV.

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101 Citations


Journal ArticleDOI: 10.1016/J.EJPS.2015.03.024
Abstract: The current study was aimed to investigate the potential of solid self-nanoemulsifying drug delivery system (S-SNEDDS) composed of Capmul MCM C8 (oil), Tween 80 (surfactant) and Transcutol P (co-surfactant) in improving the dissolution and oral bioavailability of darunavir. Liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) were developed by using rational blends of components with good solubilizing ability for darunavir which were selected based on solubility studies, further ternary phase diagram was constructed to determine the self-emulsifying region. The prepared L-SNEDDS formulations were evaluated to determine the effect of composition on physicochemical parameters like rate of emulsification, clarity, phase separation, thermodynamic stability, cloud point temperature, globule size and zeta potential. In vitro drug release studies showed initial rapid release of about 13.3 ± 1.4% within 30 min from L-SNEDDS followed by slow continuous release of entrapped drug and reached a maximum of 62.6 ± 3.5% release at the end of 24h. The globule size analysis revealed the formation of nanoemulsion (144 ± 2.3 nm) from the optimized L-SNEDDS formulation and was physically adsorbed onto neusilin US2. In vitro dissolution studies indicated faster dissolution of darunavir from the developed S-SNEDDS with 3 times greater mean dissolution rate (MDR) compared to pure darunavir. Solid state studies concluded the presence of drug in non-crystalline amorphous state without any significant interaction of drug with the components of S-SNEDDS. Furthermore, in vivo pharmacokinetic studies in Wistar rats resulted in enhanced values of peak drug concentration (Cmax) for L-SNEDDS (2.98 ± 0.19 μg/mL) and S-SNEDDS (3.7 ± 0.28 μg/mL) compared to pure darunavir (1.57 ± 0.17 μg/mL).

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Topics: Darunavir (59%), Drug delivery (51%), Bioavailability (51%)

92 Citations


Journal ArticleDOI: 10.1080/10611860802475688
Abstract: The present investigation was aimed at lymphatic targeting of zidovudine (ZDV)-loaded surface-engineered liposomes (SE liposomes). Surface of liposomes was engineered by incorporation of charges (positive or negative) and site-specific ligand (mannose) in order to enhance localization to lymphatics, specifically to lymph node and spleen. Positively and negatively charged nanosized SE liposomes (120 +/- 10 nm) were prepared using stearylamine (SA) and dicetyl phosphate (DCP), respectively, while ligand-coated SE liposomes were prepared using mannose-terminated SA (mannose conjugate). The SE liposomes were characterized for shape and surface morphology, size, entrapment efficiency, and in vitro drug release. All the SE liposomes formulations showed biphasic ZDV release, whereas mannose-coated liposomes (MAN-Lip) significantly reduced (p negatively charged > positively charged > Lip. Thus, the SE liposomes appeared to be promising novel vesicular system for enhanced targeting of ZDV to lymphatics, in AIDS chemotherapy.

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Topics: Liposome (55%)

92 Citations


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