Nose to brain delivery of tailored clozapine nanosuspension stabilized using (+)-alpha-tocopherol polyethylene glycol 1000 succinate: Optimization and in vivo pharmacokinetic studies

Patel, Hetal; Chaudhari, Priyanka S.; Gandhi, Priyanshi A.; Desai, Bhargavi V.; Desai, Ditixa T.; Dedhiya, Praful P.; Vyas, Bhavin; Maulvi, Furqan A.

doi:10.1016/j.ijpharm.2021.120474

Cited by 34 publications

(15 citation statements)

References 49 publications

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“…Clozapine is an atypical antipsychotic drug frequently used to treat schizophrenia symptoms and acts by blocking dopamine D2 and serotonin 5-HT2 receptors, having few extrapyramidal side effects [ 56 ]. Nevertheless, its water solubility is only 0.186 mg/mL [ 57 ], which makes strategies to increase its strength in formulation highly relevant.…”

Section: Nanometric Dispersionsmentioning

confidence: 99%

“…Nevertheless, its water solubility is only 0.186 mg/mL [ 57 ], which makes strategies to increase its strength in formulation highly relevant. Additionally, its poor dissolution rate, high gastrointestinal degradation and high hepatic first-pass metabolism in oral forms makes it difficult for the drug to reach the brain, and its severe adverse drug reactions (such as agranulocytosis, hepatotoxicity, and cardiotoxicity) lead many patients to discontinue the treatment [ 56 ]. Therefore, Patel et al [ 56 ] suggested that exploring a non-invasive route other than oral administration, such as intranasal administration, could be beneficial.…”

Section: Nanometric Dispersionsmentioning

confidence: 99%

“…Additionally, its poor dissolution rate, high gastrointestinal degradation and high hepatic first-pass metabolism in oral forms makes it difficult for the drug to reach the brain, and its severe adverse drug reactions (such as agranulocytosis, hepatotoxicity, and cardiotoxicity) lead many patients to discontinue the treatment [ 56 ]. Therefore, Patel et al [ 56 ] suggested that exploring a non-invasive route other than oral administration, such as intranasal administration, could be beneficial. Moreover, to tackle clozapine’s solubility problem, a nanosuspension was developed using a combination of (+)-alpha-tocopherol polyethylene glycol 1000 succinate, a surfactant, stabilizer, and permeation enhancer, and polyvinylpyrrolidone K-30, a suspending agent.…”

Section: Nanometric Dispersionsmentioning

confidence: 99%

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Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

et al. 2022

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Intranasal administration is a promising route for brain drug delivery. However, it can be difficult to formulate drugs that have low water solubility into high strength intranasal solutions. Hence, the purpose of this work was to review the strategies that have been used to increase drug strength in intranasal liquid formulations. Three main groups of strategies are: the use of solubilizers (change in pH, complexation and the use cosolvents/surfactants); incorporation of the drugs into a carrier nanosystem; modifications of the molecules themselves (use of salts or hydrophilic prodrugs). The use of high amounts of cosolvents and/or surfactants and pH decrease below 4 usually lead to local adverse effects, such as nasal and upper respiratory tract irritation. Cyclodextrins and (many) different carrier nanosystems, on the other hand, could be safer for intranasal administration at reasonably high concentrations, depending on selected excipients and their dose. While added attributes such as enhanced permeation, sustained delivery, or increased direct brain transport could be achieved, a great effort of optimization will be required. On the other hand, hydrophilic prodrugs, whether co-administered with a converting enzyme or not, can be used at very high concentrations, and have resulted in a fast prodrug to parent drug conversion and led to high brain drug levels. Nevertheless, the choice of which strategy to use will always depend on the characteristics of the drug and must be a case-by-case approach.

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Section: Nanometric Dispersionsmentioning

confidence: 99%

Section: Nanometric Dispersionsmentioning

confidence: 99%

Section: Nanometric Dispersionsmentioning

confidence: 99%

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Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

et al. 2022

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“…Various dosage forms (solutions [ 21 , 22 ], suspensions [ 23 ], microemulsions [ 24 , 25 ], gels [ 26 ]) have been prepared for nose-to-brain delivery. Conventional forms usually do not provide a controlled release of drug molecules and are not capable of targeted delivery [ 27 ].…”

Section: Desired Features Of Micro- and Nanoparticles For Successful ...mentioning

confidence: 99%

Micro- and Nanosized Carriers for Nose-to-Brain Drug Delivery in Neurodegenerative Disorders

Boyuklieva

Pilicheva

2022

Biomedicines

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Neurodegenerative disorders (NDs) have become a serious health problem worldwide due to the rapid increase in the number of people that are affected and the constantly aging population. Among all NDs, Alzheimer’s and Parkinson’s disease are the most common, and many efforts have been made in the development of effective and reliable therapeutic strategies. The intranasal route of drug administration offers numerous advantages, such as bypassing the blood–brain barrier and providing a direct entrance to the brain through the olfactory and trigeminal neurons. The present review summarizes the available information on recent advances in micro- and nanoscale nose-to-brain drug-delivery systems as a novel strategy for the treatment of Alzheimer’s and Parkinson’s disease. Specifically, polymer- and lipid-base micro- and nanoparticles have been studied as a feasible approach to increase the brain bioavailability of certain drugs. Furthermore, nanocomposites are discussed as a suitable formulation for administration into the nasal cavity.

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“…Different CLZ nanoformulations were performed such as intranasal (IN) nanosuspension using (+)-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) and polyvinylpyrrolidone K-30 (PVP K-30), which improved its poor pharmacokinetic parameters (Patel et al, 2021 a,b). Another approach for enhancing its pharmacokinetics parameters was achieved through formulation of CLZ loaded nanostructured lipid carriers as nose to brain delivery system (Patel et al, 2021a,b ).…”

Section: Introductionmentioning

confidence: 99%

Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m

Sayed

Elsharkawy²,

Amin

et al. 2021

Drug Delivery

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The research objective is to design intranasal (IN) brain targeted CLZ-loaded polymeric nanomicellar systems (PNMS) aiming to improve central systemic CLZ bioavailability. Direct equilibrium method was used to prepare CLZ-PNMS using two hydrophobic poloxamines; Tetronic V R 904 (T904) and Tetronic V R 701 (T701) and one hydrophilic poloxamer; Synperonic V R PE/F127 (F127). Optimization is based on higher percent transmittance, solubilizing efficiency, and in vitro release after 24 h with smaller particle size was achieved using Design-Expert V R software. The optimized formula was further evaluated via TEM, ex vivo nasal permeation in addition to in vivo biodistribution using radiolabeling technique of the optimized formula by Technetium-99m ( 99m Tc). The optimized formula M5 has small size (217 nm) with relative high percentage of transmittance (97.72%) and high solubilization efficacy of 60.15-fold following 92.79% of CLZ released after 24 h. Ex vivo nasal permeation showed higher flux of 36.62 lg/ cm 2 .h compared to 7.324 lg/cm 2 .h for CLZ suspension with no histological irritation. In vivo biodistribution results showed higher values of radioactivity percentage of the labeled optimized formula ( 99m Tc-M5) in brain and brain/blood ratio following IN administration of 99m Tc-M5 complex which were greater than their corresponding values following intravenous route. It is obvious that nasal delivery of CLZ-PNMS could be a promising way to improve central systemic CLZ bioavailability.

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Nose to brain delivery of tailored clozapine nanosuspension stabilized using (+)-alpha-tocopherol polyethylene glycol 1000 succinate: Optimization and in vivo pharmacokinetic studies

Cited by 34 publications

References 49 publications

Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs

Micro- and Nanosized Carriers for Nose-to-Brain Drug Delivery in Neurodegenerative Disorders

Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m

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