Optimization of Nanostructured Lipid Carriers of Lurasidone Hydrochloride Using Box-Behnken Design for Brain Targeting: In Vitro and In Vivo Studies

Jazuli, Imrana; Annu, .; Nabi, Bushra; Moolakkadath, Thasleem; Alam, Tausif; Baboota, Sanjula; Ali, Javed

doi:10.1016/j.xphs.2019.05.001

Cited by 75 publications

(27 citation statements)

References 25 publications

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“…This phenomenon can be explained by the rapid solidification of the solid lipids during the formation of the NLC, which results in nanoparticles with an internal core containing a low amount of liquid lipids, which in turn accumulate in the outermost layers. As rivastigmine is an oil, it also tends to accumulate on the surface of the NLC, meaning it is released more quickly [ 33 , 99 , 101 ].…”

Section: Resultsmentioning

confidence: 99%

“…For instance, the release of teriflunomide from a NLC intranasal formulation in simulated nasal electrolyte solution followed a biphasic behavior, with 75.11% of the drug being released after 8 h. Similar values were observed for the optimized rivastigmine-loaded NLC produced by ultrasound technique (75.89%) after the same period of time and using the same dissolution media ( Figure 5 ) [ 31 ]. Jazuli et al conducted drug release studies with lurasidone-loaded NLCs for nose-to-brain delivery and observed fast drug release after 12 h followed by sustained drug release, with a maximum release of 92.12% after 24 h [ 101 ]. This biphasic behavior was also observed with both optimized rivastigmine-loaded NLC formulations ( Figure 4 and Figure 5 ), although the maximum drug release was observed after 48 h. Alam et al observed sustained in vitro release of isradipine from a NLC, with a maximum value of 92.89% after 24 h [ 46 ], which was also observed for the rivastigmine release from the optimized NLC produced by HPH (93.55%) after 24 h ( Figure 5 ).…”

Section: Resultsmentioning

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%

Section: Resultsmentioning

confidence: 99%

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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“…17,19,23 Recently, NLCs have been widely employed as a promising delivery system for brain targeting of versatile drugs via the nasal route. 8,24,25 In this work, the potential of employing nanostructured lipid carriers loaded in situ gel for enhancing nose-to-brain delivery of FLB has been explored. Box-Behnken design was applied for optimization of FLB-NLCs.…”

Section: Introductionmentioning

confidence: 99%

<p>Optimized Nanostructured Lipid Carriers Integrated into In Situ Nasal Gel for Enhancing Brain Delivery of Flibanserin</p>

Fahmy¹,

Ahmed²,

Badr-Eldin³

et al. 2020

IJN

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Background and Aim: Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug's first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery. Methods: Box-Behnken design was applied to explore the impact of solid lipid % (SL%, X 1), liquid lipid % (LL%, X 2), and sonication time (ST, X 3) on particle size. The optimized NLC formulation was characterized and incorporated into gellan gum in situ gel. The prepared gel was subjected to in vitro drug release, in vivo pharmacokinetic performance, and histopathological assessment in rats. Results: Statistical analysis revealed a significant negative effect for both SL% and ST on NLCs size. In contrast, a significant positive effect was observed for the LL%. The optimized formulation showed spherical shape with vesicular size of 114.63 nm. The optimized FLB-NLC in situ gel exhibited adequate stability and enhanced in vitro release compared to raw FLB control gel. The plasma and brain concentrations of the drug after nasal administration in rats increased by more than 3-6-fold, respectively, compared to raw FLB in situ gel. In addition, the histopathological studies revealed the absence of any pathological signs. Conclusion: The aforementioned results highlight the safety of FLB-NLC in situ nasal gel and its potential to improve the drug bioavailability and brain delivery.

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“…Furthermore, the insignicant lack of t value (p if > 0.05) highlights the adequacy of all response surfaces. [18][19][20] 3.1.2 Effect of independent variables on particle size and encapsulation efficiency. The effect of each independent variable on particle size is described by eqn (6) and shown in the corresponding 3D response surface plots (Fig.…”

Section: Resultsmentioning

confidence: 99%

Preparing, optimising, and evaluating chitosan nanocapsules to improve the stability of anthocyanins from Aronia melanocarpa

Wang

Wan

et al. 2021

RSC Adv.

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Optimization of Nanostructured Lipid Carriers of Lurasidone Hydrochloride Using Box-Behnken Design for Brain Targeting: In Vitro and In Vivo Studies

Cited by 75 publications

References 25 publications

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

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

<p>Optimized Nanostructured Lipid Carriers Integrated into In Situ Nasal Gel for Enhancing Brain Delivery of Flibanserin</p>

Preparing, optimising, and evaluating chitosan nanocapsules to improve the stability of anthocyanins from Aronia melanocarpa

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