Pediatric oral formulation of dendrimer-N-acetyl-L-cysteine conjugates for the treatment of neuroinflammation

Venkata K. Yellepeddi, Raziye Mohammadpour, Siva Pramodh Kambhampati, Casey Sayre, Manoj K. Mishra, Kannan Rangaramanujam, Hamidreza Ghandehari

Research output: Contribution to journalArticle

Abstract

N-Acetyl-L-cysteine (NAC) commonly used as an antidote in acetaminophen poisoning has shown promise in the treatment of neurological disorders such as cerebral palsy (CP). However, NAC suffers from drawbacks such as poor oral bioavailability and suboptimal blood-brain-barrier (BBB) permeability limiting its clinical success. It was previously demonstrated that intravenous administration of dendrimer-NAC (D-NAC) conjugates have shown significant promise in the targeted treatment of neuroinflammation, in multiple preclinical models. Development of an oral formulation of D-NAC may open new administrative routes for this compound. Here, we report the gastrointestinal stability, in vitro transepithelial permeability, and in vivo oral absorption and pharmacokinetics in rats of a pediatric formulation of D-NAC containing Capmul MCM (glycerol monocaprylate) as a penetration enhancer. D-NAC was stable for 6 h in all five simulated gastrointestinal fluids with no signs of chemical degradation. The apparent permeability (Papp) of D-NAC increased 9-fold in the formulation containing Capmul. The area under the curve [AUC]0-∞ of D-NAC with Capmul increased by 47% when compared to D-NAC alone. These results indicate that an oral pediatric formulation containing D-NAC and Capmul can be an effective option for the treatment of neuroinflammation.

Original languageEnglish (US)
Pages (from-to)113-116
Number of pages4
JournalInternational Journal of Pharmaceutics
Volume545
Issue number1-2
DOIs
StatePublished - Jul 10 2018

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Keywords

  • Neuroinflammation
  • Oral bioavailability
  • PAMAM dendrimers
  • Pediatric formulations
  • Permeability
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmaceutical Science

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