Adaptation of Quality by Design-Based Development of Isradipine Nanostructured–Lipid Carrier and Its Evaluation for In Vitro Gut Permeation and In Vivo Solubilization Fate

Alam, Tausif; Khan, Saba; Gaba, Bharti; Haider, Md. Faheem; Baboota, Sanjula; Ali, Javed

doi:10.1016/j.xphs.2018.07.021

Cited by 61 publications

(42 citation statements)

References 32 publications

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“…The selected lipids were compatible and miscible at the concentrations tested and a ratio of 70:30 (%, w / w ) was shown to be the best proportions of Precirol ® ATO5 and vitamin E for the preparation of the NLC formulation, as previously developed in our group [ 52 ]. Several studies have shown that a high concentration of liquid lipids increases drug retention, as drug solubility in liquid lipids is usually higher than in solid lipids, which decreases the particle size due to the decreased viscosity and surface tension of the NLC [ 46 , 79 , 88 ].…”

Section: Resultsmentioning

confidence: 99%

“…Smaller particle sizes have been observed when a higher surfactant/lipid ratio was used [ 31 , 62 , 63 ]. Accordingly, polysorbate 80 (Tween ® 80), a non-ionic surfactant containing a polyoxyethylene chain tetrahydrofuran ring that provides steric stabilization and a hydrophobic tail that prevents particle aggregation, was selected based on previous works that showed its compatibility with the lipids used [ 46 , 52 , 53 , 59 , 60 , 64 ]. The co-surfactant (Phospholipon ® 90G) was selected based on its emulsification capacity for the selected lipid mixture, its non-irritating effect on the nasal mucosa, and its ability to minimize the polymorphic state transitions of lipids.…”

Section: Methodsmentioning

confidence: 99%

“…The emulsification time and speed are important parameters in obtaining small nanoparticles with a narrow PDI [ 11 , 46 ]. Thus, the emulsification time was set to 5 min and the effect of increasing the rpm on CQAs was evaluated.…”

Section: Methodsmentioning

confidence: 99%

“…Generally, as the time and amplitude of sonication increase, particle size decreases [ 11 , 51 ]. However, it has been reported that a high amplitude of sonication increases the lipid nanoparticle size due to the formation of aggregates [ 11 , 46 ]. Therefore, the effect of increasing the amplitude of sonication on CQAs was evaluated.…”

Section: Methodsmentioning

confidence: 99%

“…Afterwards, the CPPs were selected, which corresponded to the production method (high-pressure homogenization—HPH; or ultrasound technique) to produce rivastigmine-loaded NLC formulations with the desired QTPP. A central composite design was used to optimize the CMAs to achieve high quality predictions for various factors at extreme levels [ 32 , 43 , 44 ], and a Box–Behnken design was used to optimize the CPPs, analyzing the effects of three variables and requiring less experiments [ 45 , 46 , 47 ]. Finally, the pH and osmolarity of the optimized NLC formulations were adjusted to the physiological values and in vitro release studies were performed.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 99%