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

Venkata K Yellepeddi; Raziye Mohammadpour; Siva P Kambhampati; Casey Sayre; Manoj K Mishra; Rangaramanujam M Kannan; Hamidreza Ghandehari

doi:10.1016/j.ijpharm.2018.04.040

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

Int J Pharm. 2018 Jul 10;545(1-2):113-116. doi: 10.1016/j.ijpharm.2018.04.040. Epub 2018 Apr 20.

Authors

Venkata K Yellepeddi¹, Raziye Mohammadpour², Siva P Kambhampati³, Casey Sayre⁴, Manoj K Mishra³, Rangaramanujam M Kannan⁵, Hamidreza Ghandehari⁶

Affiliations

¹ Division of Clinical Pharmacology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA; Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; College of Pharmacy, Roseman University of Health Sciences, South Jordan, UT, USA. Electronic address: venkata.yellepeddi@hsc.utah.edu.
² Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
³ Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ College of Pharmacy, Roseman University of Health Sciences, South Jordan, UT, USA.
⁵ Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
⁶ Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, UT, USA; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA; Department of Bioengineering, University of Utah, Salt Lake City, UT, USA.

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 (P_app) 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.

Keywords: Neuroinflammation; Oral bioavailability; PAMAM dendrimers; Pediatric formulations; Permeability; Pharmacokinetics.

Publication types

Comparative Study

MeSH terms

Acetylcysteine / administration & dosage*
Acetylcysteine / chemistry
Acetylcysteine / pharmacokinetics
Administration, Oral
Age Factors
Animals
Anti-Inflammatory Agents / administration & dosage*
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / pharmacology
Area Under Curve
Caco-2 Cells
Caprylates / chemistry
Dendrimers / chemistry*
Drug Carriers*
Drug Compounding
Drug Stability
Glycerides / chemistry
Humans
Intestinal Absorption
Intestinal Mucosa / metabolism
Male
Permeability
Rats, Sprague-Dawley
Technology, Pharmaceutical / methods

Substances

Anti-Inflammatory Agents
Caprylates
Dendrimers
Drug Carriers
Glycerides
PAMAM Starburst
monooctanoin
Acetylcysteine

Grants and funding

R01 HD076901/HD/NICHD NIH HHS/United States