scholarly journals Development of Ritonavir Loaded Nanostructured Lipid Carriers Employing Quality By Design (QbD) As A Tool: Characterizations, Permeability, And Bioavailability Studies

2021 ◽  
Author(s):  
Vishal Gurumukhi ◽  
Sanjaykumar Bari
Keyword(s):  
Particle Size ◽  
Quality By Design ◽  
Physical Stability ◽  
Entrapment Efficiency ◽  
Nanostructured Lipid Carriers ◽  
Formulation Development ◽  
Enhanced Solubility ◽  
Formulation Variables

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.

scholarly journals Double Optimization of Rivastigmine-Loaded Nanostructured Lipid Carriers (NLC) for Nose-to-Brain Delivery Using the Quality by Design (QbD) Approach: Formulation Variables and Instrumental Parameters

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 599 ◽  
Author(s):  
Sara Cunha ◽  
Cláudia Pina Costa ◽  
Joana A. Loureiro ◽  
Jorge Alves ◽  
Andreia F. Peixoto ◽  
...  
Keyword(s):  
Particle Size ◽  
High Pressure ◽  
Drug Release ◽  
Quality By Design ◽  
Nanostructured Lipid Carriers ◽  
Brain Delivery ◽  
High Pressure Homogenization ◽  
Ultrasound Technique ◽  
Formulation Variables

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.

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
Keyword(s):  
Particle Size ◽  
Quality By Design ◽  
Fungal Infections ◽  
Ex Vivo ◽  
Entrapment Efficiency ◽  
Nanostructured Lipid Carriers ◽  
Fractional Factorial ◽  
Sonication Time ◽  
Drug Concentrations

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.

scholarly journals FORMULATION AND OPTIMIZATION OF NIFEDIPINE LOADED NANOCARRIERS

2021 ◽  
pp. 311-317
Author(s):  
ASHWINI JADHAV ◽  
BINOY VARGHESE CHERIYAN
Keyword(s):  
Particle Size ◽  
Zeta Potential ◽  
Physical Stability ◽  
Entrapment Efficiency ◽  
Tween 80 ◽  
Physicochemical Characteristics ◽  
Good Choice ◽  
The Stability

Objective: The main aim of this study to formulate a nifedipine-loaded nanocarrier for improving solubility and bioavailability. Methods: To improve the solubility of drug, nifedipine-loaded nanocarrier (lipotomes) were prepared by using the film lipid hydration technique. lipotomes were prepared by using tween 80, which is used for increasing solubility and cetyl alcohol for lipophilic environment. Drug excipients interaction determined by FTIR. lipotomes were characterized for particle size, Entrapment efficiency and zeta potential. lipotomes were optimized by using Design-Expert 12 software. Optimized formula further lyophilized by using different cyroproyectant to improve the stability and oral administration of the drug. Results: FTIR shows there was no interaction between formulation ingredients. Mean particle size, entrapment efficiency, zeta potential was determined and found to be 308.1 nm, 96.7%, 20.1mV, respectively. Surface morphology of lipotomes was observed by a scanning electron microscope (SEM). Optimized lipotomes was lyophilized with Mannitol (8% w/v) was the ideal cryoprotectant to retain the physicochemical characteristics of the OLT formulation after lyophilization. Conclusion: Nifedipine loaded nanocarrier was successfully prepared, using film hydration method. Which have good particle size, EE% and zeta potential. After lyophilization no significant changes was observed in particle size with good physical stability, so it could be a good choice for conventional drug delivery system by doing further investigation as in vitro and in vivo study

scholarly journals USE OF LACTIC ACID AND SPAN 80 IN THE FORMULATION OF LIPID BASED IMIQUIMOD VESICLES FOR GENITAL WARTS

2017 ◽  
Vol 9 (2) ◽  
pp. 292
Author(s):  
Saroj Jain ◽  
Anupama Diwan ◽  
Satish Sardana
Keyword(s):  
Particle Size ◽  
Lactic Acid ◽  
Zeta Potential ◽  
Spherical Shape ◽  
Entrapment Efficiency ◽  
Genital Warts ◽  
Formulation Development ◽  
Span 80

<p><strong>Objective: </strong>The objective of present study was formulation development of imiquimod using lactic acid and span 80 for topical delivery to cure genital warts.</p><p><strong>Methods: </strong>Lipid based vesicles (LBV) of 2% imiquimod were prepared with phospholipoin 90G, ethanol, lactic acid and span 80 using central composite design. The prepared vesicles were optimized statistically and characterized for particle size, zeta potential, percentage entrapment efficiency (% EE) and transmission electron microscopy (TEM). The optimized LBV were incorporated into gel formulation which was evaluated and compared with control gel and marketed formulation.</p><p><strong>Results: </strong>The optimized vesicles had particle size 394.8±9.6 nm, zeta potential-16.5±2.5 mV, % EE 88.27±0.45 and TEM study confirmed the formation of vesicular structure with spherical shape. The gel formulation of imiquimod vesicles showed positive results like spreadability 14.3±0.34 gcm/s, viscosity 13500±1.67 cp, consistency 6.1±0.14 mm and extrudability 16.47±0.11 g/cm<sup>2</sup>. <em>In vitro</em> permeation amount of drug was remarkably lower (10.13 %) than control (87.17 %) and marketed formulation (27.46 %). Results of retained drug for both <em>in vitro</em> as well as <em>in vivo</em> permeation study and local accumulation efficiency (4.021±0.2292) were considerably higher for LBV gel than control (0.1008±0.002513) and marketed formulation (0.8314±0.0300). To understand the mechanism of interaction between skin and vesicles, fourier transform infra-red spectroscopy studies were also done. Results of skin irritancy test and histological examination revealed biocompatible nature of formulation.</p><p><strong>Conclusion: </strong>Results of <em>in vitro </em>and <em>in vivo</em> studies indicated that this vesicle gel formulation provided efficient and site specific dermal delivery of imiquimod for cure of genital warts.</p>

scholarly journals Etodolac Containing Topical Niosomal Gel: Formulation Development and Evaluation

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Gyati Shilakari Asthana ◽  
Abhay Asthana ◽  
Davinder Singh ◽  
Parveen Kumar Sharma
Keyword(s):  
Particle Size ◽  
Ex Vivo ◽  
Skin Permeation ◽  
Entrapment Efficiency ◽  
Formulation Development ◽  
Topical Gel ◽  
Niosomal Gel ◽  
Span 60

The present study aimed to investigate the delivery potential of Etodolac (ETD) containing topical niosomal gel. Niosomal formulations were prepared by thin film hydration method at various ratios of cholesterol and Span 60 and were evaluated with respect to particle size, shape, entrapment efficiency, and in vitro characteristics. Dicetyl phosphate (DCP) was also added in the niosomal formulation. Mean particle size of niosomal formulation was found to be in the range of 2 μm to 4 μm. Niosomal formulation N2 (1 : 1) ratio of cholesterol and surfactant displayed good entrapment efficiency (96.72%). TEM analyses showed that niosomal formulation was spherical in shape. Niosomal formulation (N2) displayed high percentage of drug release after 24 h (94.91) at (1 : 1) ratio of cholesterol : surfactant. Further selected niosomal formulation was used to formulate topical gel and was characterized with respect to its various parameters such as pH, viscosity, spreadability, ex vivo study, and in vivo potential permeation. Ex vivo study showed that niosomal gel possessed better skin permeation study than the plain topical gel. Further in vivo study revealed good inhibition of inflammation in case of topical niosomal gel than plain gel and niosomal formulation. The present study suggested that topical niosomal gel formulations provide sustained and prolonged delivery of drug.

scholarly journals Development, Optimisation and Evaluation of Ketoprofen Lipospheres

2020 ◽  
Vol 11 (SPL4) ◽  
pp. 1853-1863
Author(s):  
Shubhra Rai ◽  
Gopal Rai ◽  
Ashish Budhrani
Keyword(s):  
Drug Delivery ◽  
Particle Size ◽  
Research Work ◽  
Extended Period ◽  
Entrapment Efficiency ◽  
Inflammatory Activity ◽  
Scanning Calorimetry ◽  
Anti Inflammatory

Lipospheres represent a novel type of fat-based encapsulation system produced for the topical drug delivery of bioactive compounds. The goal of this research work was to develop lipospheres, including ketoprofen applied for topical skin drug delivery. Ketoprofen lipospheres were formulated by melt emulsification method using stearic acid and Phospholipon® 90G. The lipospheres were analysed in terms of particle size and morphology, entrapment efficiency, Differential scanning calorimetry, In-vitro drug release, In-vivo (Anti-inflammatory activity). Outcomes of research revealed that particle size was found to be 9.66 µm and entrapment efficiency 86.21 ± 5.79 %. In-vivo, the study of ketoprofen loaded lipospheres formulation shows a higher plain formulation concentration in plasma (5.61 mg/mL). For dermis, ketoprofen retention was 27.02 ± 5.4 mg/mL for the lipospheres formulation, in contrast to that of the plain formulation group (10.05 ± 2.8 mg/mL). The anti-inflammatory effect of liposphere drug delivery systems was assessed by the xylene induced ear oedema technique and compared with marketed products. Finally, it seems that the liposphere drug delivery system possesses superior anti-inflammatory activity as compared to the marketed product gel consistencies. Liposphere may be capable of entrapping the medicament at very high levels and controlling its release over an extended period. Liposphere furnishes a proper size for topical delivery as well as is based on non-irritating and non-toxic lipids; it’s a better option for application on damaged or inflamed skin.

scholarly journals Formulation, Development and Evaluation of Ibuprofen Loaded Nano-transferosomal Gel for the Treatment of Psoriasis

2019 ◽  
pp. 1-8
Author(s):  
Marwa H. Abdallah ◽  
Amr S. Abu Lila ◽  
Md. Khalid Anwer ◽  
El-Sayed Khafagy ◽  
Muqtader Mohammad ◽  
...  
Keyword(s):  
Drug Release ◽  
Zeta Potential ◽  
Drug Loading ◽  
Entrapment Efficiency ◽  
Tween 80 ◽  
Formulation Development ◽  
In Vitro Drug Release ◽  
Vesicle Size

The present work was aimed to develop a transferosomal gel of ibuprofen (IBU) for the amelioration of psoriasis like inflammation. Three formulation of IBU loaded transferosomes (TFs1-TFs3) were prepared using different proportions of lipid (phospholipon 90H) and surfactant (tween 80) and further evaluated for vesicle size, zeta potential (ZP), entrapment efficiency and in vitro drug release. The IBU loaded transferosomes (TFs2) was optimized with vesicle size (217±8.4 nm), PDI (0.102), ZP (-31.5±4.3 mV), entrapment efficiency (88.4±6.9%) and drug loading (44.2±2.9%). Further, the optimized IBU loaded transferosomes (TFs2) was incorporated into 1% carbopol 934 gel base and characterized for homogeneity, extrudability, viscosity and drug content. The in vivo pharmacodynamic study of gel exhibited reduction in psoriasis like inflammation in mice. The ibuprofen loaded transferosomal gel was successfully developed and has shown the potential to be a new therapy against psoriasis like inflammation.

scholarly journals DEVELOPMENT OF RITONAVIR LOADED NANOPARTICLES: IN VITRO AND IN VIVO CHARACTERIZATION

2018 ◽  
Vol 11 (3) ◽  
pp. 284
Author(s):  
Pravin S Patil ◽  
Shashikant C Dhawale
Keyword(s):  
Particle Size ◽  
Drug Release ◽  
Dissolution Rate ◽  
Drug Carrier ◽  
Entrapment Efficiency ◽  
Significant Rise ◽  
Scanning Calorimetry ◽  
In Vitro Drug Release

 Objective: The purpose of the present investigation was to develop a nanosuspension to improve dissolution rate and oral bioavailability of ritonavir.Methods: Extended-release ritonavir loaded nanoparticles were prepared using the polymeric system by nanoprecipitation technique. Further, the effect of Eudragit RL100 (polymeric matrix) and polyvinyl alcohol (surfactant) was investigated on particle size and distribution, drug content, entrapment efficiency, and in vitro drug release from nanosuspension where a strong influence of polymeric contents was observed. Drug-excipient compatibility and amorphous nature of drug in prepared nanoparticles were confirmed by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction studies, respectively.Results: Hydrophobic portions of Eudragit RL100 could result in enhanced encapsulation efficiency. However, increase in polymer and surfactant contents lead to enlarged particle size proportionately as confirmed by transmission electron microscopy. Nanosuspension showed a significant rise in dissolution rate with complete in vitro drug release as well as higher bioavailability in rats compared to the pure drug.Conclusion: The nanoprecipitation technique used in present research could be further explored for the development of different antiretroviral drug carrier therapeutics.

In Vitro and In Vivo Evaluation of Olmesartan Medoxomil Microcrystals and Nanocrystals: Preparation, Characterization, and Pharmacokinetic Comparison in Beagle Dogs

2019 ◽  
Vol 16 (6) ◽  
pp. 500-510
Author(s):  
Rong Chai ◽  
Hailing Gao ◽  
Zhihui Ma ◽  
Meng Guo ◽  
Qiang Fu ◽  
...  
Keyword(s):  
Particle Size ◽  
Oral Bioavailability ◽  
Olmesartan Medoxomil ◽  
Water Soluble ◽  
Size Reduction ◽  
Drug Dissolution ◽  
Beagle Dogs ◽  
Enhanced Solubility

Background: Olmesartan medoxomil (OLM) is a promising prodrug hydrolyzed to olmesartan (OL) during absorption from the gastrointestinal tract. OL is a selective angiotensin II receptor antagonist, with high drug resistance and low drug interaction. However, OLM has low solubility and low bioavailability. Therefore, it is extremely urgent to reduce the drug particle size to improve its biological bioavailability. Objective: The aim of the study was to improve the oral bioavailability of poorly water-soluble olmesartan medoxomil (OLM) by using different particle size-reduction strategies. Method: Raw drug material was micronized or nanosized by either jet or wet milling processes, respectively. The particle sizes of the prepared nanocrystals (100-300 nm) and microcrystals (0.5-16 μm) were characterized by DLS, SEM, and TEM techniques. Solid state characterization by XPRD and DSC was used to confirm the crystalline state of OLM after the milling processes. Results: We demonstrated that OLM nanocrystals enhanced solubility and dissolution in the non-sink condition in which high sensitivity was found in purified water. After 1 h, 65.4% of OLM was dissolved from nanocrystals, while microcrystals and OLMETEC® only showed 37.8% and 31.9% of drug dissolution, respectively. In the pharmacokinetic study using Beagle dogs, an increase in Cmax (～2 fold) and AUC (～1.6 fold) was observed after oral administration of OLM nanocrystals when compared to microcrystals and reference tablets, OLMETEC®. In contrast, OLM microcrystals failed to improve the oral bioavailability of the drugs. Conclusion: Particles size reduction to nano-scale by means of nanocrystals technology significantly increased in vitro dissolution rate and in vivo oral bioavailability of OLM.

scholarly journals Quality by design (QbD) based fabrication of atazanavir loaded nanostructured lipid carriers for lymph targeting: Bioavailability enhancement using chylomicron flow block model and toxicity study

2021 ◽  
Author(s):  
Vishal Gurumukhi ◽  
Sanjaykumar Bari
Keyword(s):  
High Pressure ◽  
Quality By Design ◽  
Aqueous Solubility ◽  
Relative Bioavailability ◽  
Nanostructured Lipid Carriers ◽  
Block Model ◽  
Critical Material ◽  
Bioavailability Enhancement

Abstract Atazanavir (ATV) is widely used as anti-HIV agent with poor aqueous solubility which requires fabrication of novel drug delivery system to enhance therapeutic activity and safety. For this purpose, the quality by design (QbD) based ATV loaded nanostructured lipid carriers (NLCs) to address the challenges of bioavailability and its safety on oral administration. Herein, the main objective was to identify the influencing variables for the production of quality product. 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, PXRD, 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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