Development and optimization of Luliconazole Nanostructured lipid carriers based gel by Quality by Design its skin distribution studies, dermatokinetic modeling & In-vitro and Ex-vivo correlation

2020 ◽  
Vol 18 ◽  
Author(s):  
Eranti Bhargav ◽  
Yiragamreddy Padmanabha Reddy ◽  
Koteshwara Kunnatur B

Objective : 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 27-27-2 fractional factorial design and optimization by Box Behnken design. Cholesterol: Cetyl Palmitate, PEG 200 and probe sonication time were identified as factors, Particle size (<200 nm), PDI (0.4), % Entrapment efficiency (% EE, >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 that 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 highly significant amount of LZ was permeated, distributed and transported through the skin layers. The better linear correlations were obtained by LZ permeation through 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.

Author(s):  
Pooja Shettigar ◽  
Marina Koland ◽  
S. M. Sindhoor ◽  
Ananth Prabhu

Background: Clarithromycin is a macrolide antibiotic used in acne treatment, but it has poor solubility, which decreases its permeability through lipid barriers such as skin. Nanostructured lipid carriers can enhance the permeability of clarithromycin through the skin, thus improving its potential for controlling acne. Aim: To formulate and evaluate Nanostructured lipid carriers of clarithromycin for topical delivery in acne treatment Methods: Nanostructured lipid carriers were prepared by emulsification and ultrasonication methods using lipids such as glycerol monostearate and oleic with poloxamer 188 as stabilizer. These nano-carriers were optimized with the help of the Quality by Design (QbD) approach employing Design-Expert® software. The nanoparticles were characterized for particle size analysis, zeta potential, drug-excipient compatibility, entrapment efficiency, and surface morphology by Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). The nano-carriers were also investigated for in vitro drug release and ex vivo permeation through excised goat skin. The optimized formulation was incorporated into topical carbopol gel base, formulated and examined for pH, viscosity, spreadability, in vitro drug release, ex vivo permeation, and stability under accelerated conditions. Results: The average particle size of the optimized nanoparticles was 164.8 nm, and zeta potential was -39.2 mV. FTIR studies showed that drug and lipids are compatible with each other. The morphology study by SEM and TEM showed spherical shaped particles. The entrapment efficiency of the optimized formulation was found to be 88.16%. In vitro drug release studies indicated sustained release from the formulation due to diffusion through the lipid matrix of the particles. The ex vivo permeation study using goat skin produced greater permeation from the NLC gel (89.5%) than marketed gel (65%) due to the lipid solubility of the nanoparticles in the skin. The formulation was stable under accelerated conditions. Conclusion: The optimized formulation can be considered as promising nano-carriers suitable for the sustained release of clarithromycin into the skin for effective control of acne.


Coatings ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 158
Author(s):  
Sadaf Jamal Gilani ◽  
May Bin-Jumah ◽  
Md. Rizwanullah ◽  
Syed Sarim Imam ◽  
Khalid Imtiyaz ◽  
...  

In the present study, luteolin (LTN)-encapsulated chitosan (CS) coated nanostructured lipid carriers (NLCs) were formulated using the melt emulsification ultrasonication technique. NLCs were optimized by using the 33-QbD approach for improved in vitro efficacy against breast cancer cell lines. The optimized LTN-CS-NLCs were successfully characterized by different in vitro and ex vivo experiments as well as evaluated for cytotoxicity in MDA-MB-231 and MCF-7 cell lines. The prepared LTN-CS-NLCs showed particle size (PS), polydispersity index (PDI), and entrapment efficiency (%EE) in the range between 101.25 nm and 158.04 nm, 0.11 and 0.20, and 65.55% and 95.37%, respectively. Coating of NLCs with CS significantly increased the particle size, encapsulation efficiency, and zeta potential changes positively. Moreover, slow-release rate of LTN was achieved during 24 h of study for LTN-CS-NLCs. In addition, optimized LTN-CS-NLCs showed significantly higher mucoadhesion, gastrointestinal stability, and intestinal permeation compared to non-coated LTN-NLCs and LTN suspension. Furthermore, LTN-CS-NLCs showed statistically enhanced antioxidant potential as well as dose and time-dependent cytotoxicity against MDA-MB-231 and MCF-7 cells compared to uncoated LTN-NLCs and pure LTN. On the basis of the above findings, it may be stated that chitosan-coated LTN-NLCs represents a great potential for breast cancer management.


2021 ◽  
Author(s):  
Vishal Gurumukhi ◽  
Sanjaykumar Bari

Abstract The objective of the present work was to optimize ritonavir (RTV) loaded nanostructured lipid carriers (NLCs) to improve bioavailability using quality by design (QbD) based technique. Risk assessment was studied using ‘cause and effect’ diagram followed by failure mode effect analysis (FMEA) to identify the effective high-risk variables for the formulation development. Quality target product profile (QTPP) and critical quality attributes (CQAs) were initially assigned for the proposed product. Central composite rotatable design (CCRD) was used to identify the individual and combined interactions of formulation variables. RTV loaded NLC (RTV-NLC) was prepared using emulsification-ultrasonication method. The effect of formulation variables like ultrasound amplitude, lipid concentration, surfactant concentration on their responses like particle size, polydispersity index (PDI), and entrapment efficiency (EE) were studied by CCRD. The optimized formulation was subjected to lyophilization to obtain dry NLCs for solid-state analysis. DSC and PXRD investigations showed RTV was molecularly dispersed in lipid matrix indicating amorphous form present in the formulation. FESEM and AFM depicted the spherical and uniform particles. The enhanced solubility and dissolution may be attributed due to the reduced particle size. The optimized NLCs showed good physical stability during storage for six months. RTV-NLC was further subjected to in vitro studies and found a successful sustained release rate of 92.37±1.03 %. The parallel artificial membrane permeability assay (PAMPA) and everted gut sac model have demonstrated the permeation enhancement of RTV. In vivo study observed the enhanced bioavailability with 2.86 fold suggesting optimized NLC successfully overcome the issue of solubility.


Author(s):  
Anjali Pandya ◽  
Rajani Athawale ◽  
Durga Puro ◽  
Geeta Bhagwat

Background: The research work involves development of PLGA biodegradable microspheres loaded with dexamethasome for intraocular delivery. Objective: To design and evaluate long acting PLGA microspheres for ocular delivery of dexamethasone. Method: Present formulation involves the development of long acting dexamethasone loaded microspheres composed of a biodegradable controlled release polymer, Poly(D, L- lactide-co-glycolide) (PLGA), for the treatment of posterior segment eye disorders intravitreally. PLGA with monomer ratio of 50:50 of lactic acid to glycolic acid was used to achieve a drug release up to 45 days. Quality by Design approach was utilized for designing the experiments. Single emulsion solvent evaporation technique along with high pressure homogenization was used to facilitate formation of microspheres. Results: Particle size evaluation, drug content and drug entrapment efficiency were determined for the microspheres. Particle size and morphology was observed using Field Emission Gun-Scanning Electron Microscopy (FEG-SEM) and microspheres were in the size range of 1-5 μm. Assessment of drug release was done using in vitro studies and transretinal permeation was observed by ex vivo studies using goat retinal tissues. Conclusion: Considering the dire need for prolonged therapeutic effect in diseases of the posterior eye, an intravitreal long acting formulation was designed. Use of biodegradable polymer with biocompatible degradation products was a rational approach to achieve this aim. Outcome from present research shows that developed microspheres would provide a long acting drug profile and reduce the frequency of administration thereby improving patient compliance.


Coatings ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 6
Author(s):  
Sultan Alshehri ◽  
Syed Sarim Imam ◽  
Md Rizwanullah ◽  
Khalid Umar Fakhri ◽  
Mohd Moshahid Alam Rizvi ◽  
...  

In the present study, thymoquinone (TQ)-encapsulated chitosan- (CS)-coated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) were formulated using the emulsion evaporation method. NPs were optimized by using 33-QbD approach for improved efficacy against breast cancer. The optimized thymoquinone loaded chitosan coated Poly (d,l-lactide-co-glycolide) nanoparticles (TQ-CS-PLGA-NPs) were successfully characterized by different in vitro and ex vivo experiments as well as evaluated for cytotoxicity in MDA-MB-231 and MCF-7 cell lines. The surface coating of PLGA-NPs was completed by CS coating and there were no significant changes in particle size and entrapment efficiency (EE) observed. The developed TQ-CS-PLGA-NPs showed particle size, polydispersibility index (PDI), and %EE in the range between 126.03–196.71 nm, 0.118–0.205, and 62.75%–92.17%. The high and prolonged TQ release rate was achieved from TQ-PLGA-NPs and TQ-CS-PLGA-NPs. The optimized TQ-CS-PLGA-NPs showed significantly higher mucoadhesion and intestinal permeation compared to uncoated TQ-PLGA-NPs and TQ suspension. Furthermore, TQ-CS-PLGA-NPs showed statistically enhanced antioxidant potential and cytotoxicity against MDA-MB-231 and MCF-7 cells compared to uncoated TQ-PLGA-NPs and pure TQ. On the basis of the above findings, it may be stated that chitosan-coated TQ-PLGA-NPs represent a great potential for breast cancer management.


2021 ◽  
Vol 18 ◽  
Author(s):  
Sonia S. Pandey ◽  
Farhinbanu I. Shaikh ◽  
Arti R. Gupta ◽  
Rutvi J. Vaidya

Background: Despite significant biological effects, the clinical use of chrysin has been restricted because of its poor oral bioavailability. Objective: The purpose of the present research was to investigate the targeting potential of Mannose decorated chrysin (5,7- dihydroxyflavone) loaded solid lipid nanocarrier (MC-SLNs) for gastric cancer. Methods: The Chrysin loaded SLNs (C-SLNs) were developed optimized, characterized and further mannosylated. The C-SLNs were developed with high shear homogenizer, optimized with 32 full factorial designs and characterized by Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD) and Scanning Electron Microscope (SEM) and evaluated for particle size/polydispersity index, zeta-potential, entrapment efficiency, % release and haemolytic toxicity. The ex-vivo cytotoxicity study was performed on gastric cancer (ACG) and normal cell lines. Results: DSC and XRD data predict the chrysin encapsulation in lipid core and FTIR results confirm the mannosylation of C-SLNs. The optimized C-SLNs exhibited a narrow size distribution with a particle size of 285.65 nm. The % Entrapment Efficiency (%EE) and % controlled release were found to be 74.43% and 64.83%. Once C-SLNs were coated with mannose, profound change was observed in dependent variable - increase in the particle size of MC-SLNs (307.1 nm) was observed with 62.87% release and 70.8% entrapment efficiency. Further, the in vitro studies depicted MC- SLNs to be least hemolytic than pure chrysin and C-SLNs. MC-SLNs were most cytotoxic and were preferably taken up ACG tumor cells as evaluated against C-SLNs. Conclusion: These data suggested that the MC-SLNs demonstrated better biocompatibility and targeting efficiency to treat the gastric cancer.


Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 599 ◽  
Author(s):  
Sara Cunha ◽  
Cláudia Pina Costa ◽  
Joana A. Loureiro ◽  
Jorge Alves ◽  
Andreia F. Peixoto ◽  
...  

Rivastigmine is a drug commonly used in the management of Alzheimer’s disease that shows bioavailability problems. To overcome this, the use of nanosystems, such as nanostructured lipid carriers (NLC), administered through alternative routes seems promising. In this work, we performed a double optimization of a rivastigmine-loaded NLC formulation for direct drug delivery from the nose to the brain using the quality by design (QbD) approach, whereby the quality target product profile (QTPP) was the requisite for nose to brain delivery. The experiments started with the optimization of the formulation variables (or critical material attributes—CMAs) using a central composite design. The rivastigmine-loaded NLC formulations with the best critical quality attributes (CQAs) of particle size, polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE) were selected for the second optimization, which was related to the production methods (ultrasound technique and high-pressure homogenization). The most suitable instrumental parameters for the production of NLC were analyzed through a Box–Behnken design, with the same CQAs being evaluated for the first optimization. For the second part of the optimization studies, were selected two rivastigmine-loaded NLC formulations: one produced by ultrasound technique and the other by the high-pressure homogenization (HPH) method. Afterwards, the pH and osmolarity of these formulations were adjusted to the physiological nasal mucosa values and in vitro drug release studies were performed. The results of the first part of the optimization showed that the most adequate ratios of lipids and surfactants were 7.49:1.94 and 4.5:0.5 (%, w/w), respectively. From the second part of the optimization, the results for the particle size, PDI, ZP, and EE of the rivastigmine-loaded NLC formulations produced by ultrasound technique and HPH method were, respectively, 114.0 ± 1.9 nm and 109.0 ± 0.9 nm; 0.221 ± 0.003 and 0.196 ± 0.007; −30.6 ± 0.3 mV and −30.5 ± 0.3 mV; 97.0 ± 0.5% and 97.2 ± 0.3%. Herein, the HPH was selected as the most suitable production method, although the ultrasound technique has also shown effectiveness. In addition, no significant changes in CQAs were observed after 90 days of storage of the formulations at different temperatures. In vitro studies showed that the release of rivastigmine followed a non-Fickian mechanism, with an initial fast drug release followed by a prolonged release over 48 h. This study has optimized a rivastigmine-loaded NLC formulation produced by the HPH method for nose-to-brain delivery of rivastigmine. The next step is for in vitro and in vivo experiments to demonstrate preclinical efficacy and safety. QbD was demonstrated to be a useful approach for the optimization of NLC formulations for which specific physicochemical requisites can be identified.


Author(s):  
Shereen Ahmed Sabry

Objective: The fundamental objective of this research investigation was to develop intravaginal diazepam (DZ)-loaded alginate beads for the management of acute pelvic floor dysfunction (PFD) pain with minimal sedative effect.Methods: DZ loaded beads were prepared by an ionotropic gelation method using SA (sodium alginate) alone, or in combination with either poloxamer 407 (PL), pectin (PC), or xanthan gum (XG) at different ratios in the presence of different concentrations of calcium chloride as a cross-linking agent. The successfully developed beads were evaluated for the particle size, pH, yield percentage, entrapment efficiency, in vitro bioadhesion, swelling percentage, and in vitro drug release. The stability, ex vivo drug permeation, and sedative action of the optimized beads formulations were studied.Results: The particle size of the formulated beads was from 395±3.3 to 515±2.8 μm, yield percentage was from 68.2±1.7 to 87.5±2.1, entrapment efficiency was from 65.6±1.6 to 87.5±2.1. pH ranged from 6.1±0.2 to 6.8±0.6, bioadhesion strength was from 71.5±1.3 to 87.6±3.1, and swelling percentage was in the range from 53.4±3.1 to 85.2±3.7. Approximately 92.4–72.6% of the loaded dose was released from the prepared beads. The optimized beads showed a good stability under the selected storage conditions. About 74.8%, 71.1%, 68.6%, and 63.4% of the loaded dose permeated through the rabbit vaginal mucosa from F7, F9, F3, and F11, respectively. The formulated beads decreased the sedative action associated with orally or parenterally administered DZ.Conclusion: The developed beads were considered a promising candidate to formulate DZ into a new dosage form for the treatment of PFD with a minimum central nervous system sedation.


Author(s):  
Kavee Srichaivatana ◽  
Anan Ounaroon ◽  
Waree Tiyaboonchai

Objective: To develop and characterize Piper retrofractum extract loaded nanostructured lipid carriers (PRE loaded NLCs) for topical oral cavity administration to enhance bioavailability and stability of piperine.Methods: PRE loaded NLCs were prepared with a hot high-pressure homogenization technique followed by coating the particle surface with mucoadhesive polymers; polyethene glycol 400 (PEG) and polyvinyl alcohol (PVA). The physicochemical properties in terms of particle size, polydispersity index, zeta potential, drug entrapment efficiency, in vitro drug release profile and antimicrobial activities were examined. In vitro, mucoadhesion studies were assessed by the wash-off test. The physicochemical stabilities of mouth spray containing PRE loaded NLCs were investigated by kept at room temperature and 4 °C for 6 mo.Results: The PRE loaded NLCs showed spherical shape with a mean particle size of ~100-120 nm and zeta potential of ~-24 mV. Up to 90% drug entrapment efficiency was achieved. PEG-NLCs and PVA-NLCs showed a strong interaction with porcine buccal mucosa than uncoated-NLCs. All PRE loaded NLCs formulations revealed fast release characteristics and effective against Streptococcus mutans and S. sanguinis. The mouth spray containing PRE loaded NLCs showed good physical stability without particle aggregation. In addition, the chemical stability of piperine in NLCs was significantly improved during storage at both storage conditions compared to its solution form.Conclusion: The developed PRE loaded polymer coated-NLCs showed high potential to use as a local drug delivery system for reducing the bacterial growth in the oral cavity.


2020 ◽  
Vol 10 (3) ◽  
pp. 408-417
Author(s):  
Jyotsana R. Madan ◽  
Izharahemad N. Ansari ◽  
Kamal Dua ◽  
Rajendra Awasthi

Purpose : The objective of this work was to formulate casein (CAS) nanocarriers for the dissolution enhancement of poorly water soluble drug celecoxib (CLXB). Methods: The CLXB loaded CAS nanocarriers viz., nanoparticles, reassembled CAS micelles and nanocapsules were prepared using sodium caseinate (SOD-CAS) as a carrier to enhance the solubility of CLXB. The prepared formulations were characterized for particle size, polydispersity index, zeta potential, percentage entrapment efficiency, and surface morphology for the selection of best formulation. Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray powder diffraction study was used to for the confirmation of encapsulation of CLXB. Further, in vitro drug dissolution, ex-vivo permeation studies on chicken ileum and stability studies were carried out. Results: The CLXB loaded casein nanoparticles (CNP) (batch A2) showed a particle size diameter 216.1 nm, polydispersity index 0.422 with percentage entrapment efficiency of 90.71% and zeta potential of -24.6 mV. Scanning electron microscopy of suspension confirmed globular shape of CNP. The in vitro release data of optimized batch followed non Fickian diffusion mechanism. The ex vivo permeation studies on chicken ileum of CLXB loaded CNP showed permeation through mucous membrane as compared to pure CLXB. The apparent permeability of best selected freeze dried CLXB loaded CNP (batch A2) was higher and gradually increased from 0.90 mg/cm2 after 10 min to a maximum of 1.95 mg/cm2 over the subsequent 90 min. A higher permeation was recorded at each time point than that of the pure CLXB. Conclusion: The study explored the potential of CAS as a carrier for solubility enhancement of poorly water soluble drugs.


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