A zuranolone nanocrystal formulation enables solubility-independent in vivo study of pentylenetetrazol-induced seizures in a rat model

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F24%3A00585365" target="_blank" >RIV/67985823:_____/24:00585365 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61388963:_____/24:00585365 RIV/60461373:22340/24:43930873

Výsledek na webu

<a href="https://doi.org/10.1039/D3PM00043E" target="_blank" >https://doi.org/10.1039/D3PM00043E</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1039/D3PM00043E" target="_blank" >10.1039/D3PM00043E</a>

Jazyk výsledku

angličtina

Název v původním jazyce

A zuranolone nanocrystal formulation enables solubility-independent in vivo study of pentylenetetrazol-induced seizures in a rat model

Popis výsledku v původním jazyce

Neuroactive steroids are a promising class of substances with many potential therapeutic applications, but their preclinical evaluation is challenging due to very low aqueous solubility. A common practice is to “solubilise” such drugs using water-miscible solvents, but this approach has drawbacks: the drug can precipitate uncontrollably after injection, the solvent can artificially increase membrane permeability, and such formulations are not directly transferrable to humans. It would be beneficial to use the same physical form of the drug during preclinical and clinical studies. This work reports an approach based on an aqueous suspension of phospholipid-coated nanocrystals of zuranolone, chosen as a representative of poorly soluble neuroactive steroid drugs. The wet stirred media milling method was used for creating a nanosuspension with a mean particle size of d1,0 = 114 ± 39 nm, colloidally stable in PBS over 24 months at a concentration up to 100 mg mL−1. The applicability of the nanosuspension was demonstrated in a study of pentylenetetrazol-induced seizures in developing rats as a model of human generalized tonic–clonic seizures. The incidence and severity of seizures were assessed for the zuranolone nanosuspension and compared to an established dosage as a cyclodextrin complex. The incidence of generalized seizures with or without the tonic phase was found to be lower in P12 rats receiving zuranolone in doses of 0.5 and 1 mg kg−1 in the nanocrystal formulation than in those receiving the cyclodextrin solution. In contrast, both formulations significantly decreased seizure severity in P25 rats at a dose of 1 mg kg−1. Crucially, the nanocrystal formulation enabled the creation of a concentration series independent of the thermodynamic solubility of the drug. A constant volume appropriate to the body size of the young rats could therefore be injected during the in vivo study.

Název v anglickém jazyce

A zuranolone nanocrystal formulation enables solubility-independent in vivo study of pentylenetetrazol-induced seizures in a rat model

Popis výsledku anglicky

Neuroactive steroids are a promising class of substances with many potential therapeutic applications, but their preclinical evaluation is challenging due to very low aqueous solubility. A common practice is to “solubilise” such drugs using water-miscible solvents, but this approach has drawbacks: the drug can precipitate uncontrollably after injection, the solvent can artificially increase membrane permeability, and such formulations are not directly transferrable to humans. It would be beneficial to use the same physical form of the drug during preclinical and clinical studies. This work reports an approach based on an aqueous suspension of phospholipid-coated nanocrystals of zuranolone, chosen as a representative of poorly soluble neuroactive steroid drugs. The wet stirred media milling method was used for creating a nanosuspension with a mean particle size of d1,0 = 114 ± 39 nm, colloidally stable in PBS over 24 months at a concentration up to 100 mg mL−1. The applicability of the nanosuspension was demonstrated in a study of pentylenetetrazol-induced seizures in developing rats as a model of human generalized tonic–clonic seizures. The incidence and severity of seizures were assessed for the zuranolone nanosuspension and compared to an established dosage as a cyclodextrin complex. The incidence of generalized seizures with or without the tonic phase was found to be lower in P12 rats receiving zuranolone in doses of 0.5 and 1 mg kg−1 in the nanocrystal formulation than in those receiving the cyclodextrin solution. In contrast, both formulations significantly decreased seizure severity in P25 rats at a dose of 1 mg kg−1. Crucially, the nanocrystal formulation enabled the creation of a concentration series independent of the thermodynamic solubility of the drug. A constant volume appropriate to the body size of the young rats could therefore be injected during the in vivo study.

Druh

J_ost - Ostatní články v recenzovaných periodicích

CEP obor

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OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

RSC Pharmaceutics

ISSN

2976-8713

e-ISSN

2976-8713

Svazek periodika

1

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

10

Strana od-do

37-46

Kód UT WoS článku

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EID výsledku v databázi Scopus

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