Agranulocytosis-Protective Olanzapine-Loaded Nanostructured Lipid Carriers Engineered for CNS Delivery: Optimization and Hematological Toxicity Studies

Gadhave, Dnyandev; Tagalpallewar, Amol; Kokare, Chandrakant

doi:10.1208/s12249-018-1213-y

Cited by 34 publications

(17 citation statements)

References 38 publications

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“…where Y is the measured response associated with each factor level combination; b0 is the intercept; b1 to b3 are the regression coefficients; and X1, X2, and X3 are the coded levels of independent variables (35).…”

Section: Optimization Of Tq Coconut Oil Nlcmentioning

confidence: 99%

RETRACTED ARTICLE: ArticleNoteOptimization of Thymoquinone-Loaded Coconut Oil Nanostructured Lipid Carriers for the Management of Ethanol-Induced Ulcer

et al. 2020

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In the global incidence of peptic ulcer, with the associated rates of hospitalizations and mortality are increasing, in the United States, peptic ulcer disease affects approximately 4.6 million people annually, with an estimated 10% of the US population having evidence of a duodenal ulcer. The present research aims to find a novel treatment for ethanol induced ulcer by loading thymoquinone (TQ) on a nanostructured lipid carrier (NLC), using Compritol® 888 and coconut oil. The TQ-loaded coconut oil NLC was formulated using melt emulsification combined with a sonication method using Poloxamer 188 as a surfactant. Finally, the optimization of the formulations was performed on a three-factor, three-level Box-Behnken statistical design, with 85.63% entrapment efficiency of TQ in the optimized formulation. A biphasic release pattern of the formulation was recorded in an in vitro drug release study, where the initial burst release of the drug was observed in the first 2 h, followed by a gradual release. Later, the TQ-loaded coconut oil NLC was found to protect the gastric mucous membrane more effectively (78.95% in.; p < 0.01) in an alcohol-induced ulcer model, whereas the TQ suspension showed 30.87% inhibition (p < 0.05) of the ulcerative index, when compared with the ulcer control group. The histopathological evaluations of the stomach in ulcer-induced animals demonstrated protection potential of TQ-loaded coconut oil NLC against an alcohol-induced gastric ulcer. In a nutshell, the entrapment of TQ within the NLC was found to deliver the entrapped drug more effectively when administered through an oral route to possess a gastroprotective effect.

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Section: Optimization Of Tq Coconut Oil Nlcmentioning

confidence: 99%

RETRACTED ARTICLE: ArticleNoteOptimization of Thymoquinone-Loaded Coconut Oil Nanostructured Lipid Carriers for the Management of Ethanol-Induced Ulcer

et al. 2020

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“…Precirol ® ATO5 and Tween ® 80 were used to prepare a NLC to improve the nose-to-brain transport of a glial cell-derived neurotrophic factor (GDNF) [ 69 ]. Tween 80 ® was used as surfactant olanzapine-loaded NLC [ 70 ] and in an asenapine-loaded NLC to promote brain delivery through intranasal administration [ 71 ].…”

Section: Methodsmentioning

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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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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“…where, Y represents measured responses such as droplet size, PDI, or surface charge, b0 is the intercept, whereas b1 to b3 represents the regression coefficients for the model term of A, B, C, respectively. 14,27,28…”

Section: Optimization (Post-run) Of Nanoemulsion Formulation Using Design Expertmentioning

confidence: 99%

Antipsychotic Potential and Safety Profile of TPGS-Based Mucoadhesive Aripiprazole Nanoemulsion: Development and Optimization for Nose-To-Brain Delivery

Kumbhar

Kokare

Shrivastava

et al. 2021

Journal of Pharmaceutical Sciences

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Delivering therapeutics to the brain using conventional dosage forms is always a challenge, thus the present study was aimed to formulate mucoadhesive nanoemulsion (MNE) of aripiprazole (ARP) for intranasal delivery to transport the drug directly to the brain. Therefore, a TPGS based ARP-MNE was formulated and optimized using the Box-Behnken statistical design. The improved in vitro release profile of the formulation was in agreement to enhanced ex vivo permeation through sheep mucous membranes with a maximum rate of permeation co-efficient (62.87 cm h À1 Â 10 3 ) and flux (31.43 mg cm À2 .h À1 ). The pharmacokinetic profile following single-dose administration showed the maximum concentration of drug in the brain (C max ) of 15.19 ± 2.51 mg mL À1 and T max of 1 h in animals with ARP-MNE as compared to 10.57 ± 1.88 mg mL À1 and 1 h, and 2.52 ± 0.38 mg mL À1 and 3 h upon intranasal and intravenous administration of ARP-NE, respectively. Further, higher values of % drug targeting efficiency (96.9%) and % drug targeting potential (89.73%) of ARP-MNE through intranasal administration were investigated. The studies in Wistar rats showed no existence of extrapyramidal symptoms through the catalepsy test and forelimb retraction results. No ex vivo ciliotoxicity on nasal mucosa reflects the safety of the components and delivery tool. Further, findings on locomotor activity and hind-limb retraction test in ARP-MNE treated animals established its antipsychotic efficacy. Thus, it can be inferred that the developed ARP-MNE could effectively be explored as brain delivery cargo in the effective treatment of schizophrenia without producing any toxic manifestation.

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Agranulocytosis-Protective Olanzapine-Loaded Nanostructured Lipid Carriers Engineered for CNS Delivery: Optimization and Hematological Toxicity Studies

Cited by 34 publications

References 38 publications

RETRACTED ARTICLE: ArticleNoteOptimization of Thymoquinone-Loaded Coconut Oil Nanostructured Lipid Carriers for the Management of Ethanol-Induced Ulcer

RETRACTED ARTICLE: ArticleNoteOptimization of Thymoquinone-Loaded Coconut Oil Nanostructured Lipid Carriers for the Management of Ethanol-Induced Ulcer

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

Antipsychotic Potential and Safety Profile of TPGS-Based Mucoadhesive Aripiprazole Nanoemulsion: Development and Optimization for Nose-To-Brain Delivery

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