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Pharmaceutical Research

, Volume 33, Issue 8, pp 1936–1944 | Cite as

Rapid Absorption of Dry-Powder Intranasal Oxytocin

  • Mikolaj Milewski
  • Adrian Goodey
  • Dinah Lee
  • Eric Rimmer
  • Robert Saklatvala
  • Shuzo Koyama
  • Mic Iwashima
  • Shunji Haruta
Research Paper

Abstract

Purpose

To probe the suitability of a dry-powder oxytocin formulation containing a carrier (μco™; SNBL, Ltd.) for intranasal (IN) administration to treat post-partum hemorrhage in the developing world. Specifically, to investigate (1) whether IN administration can achieve rapid systemic absorption in cynomolgus monkeys, and (2) whether the formulation exhibits sufficient physical and chemical stability. This study was conducted to support Merck for Mothers, Merck’s 10-year global initiative to end preventable maternal deaths.

Methods

A partial-crossover pharmacokinetic (PK) study in cynomolgus monkeys (n = 6) was utilized to compare in vivo absorption of dry-powder IN oxytocin at three dose levels against an IM injection of an aqueous oxytocin formulation. Particle size distribution, delivered dose and chemical assay were monitored over a 12 month stability study.

Results

IN administration of oxytocin resulted in short (5 min) Tmax and good dose linearity in AUC and Cmax over the dose range tested (10–80 IU per animal). The relative bioavailability (BA) of IN oxytocin to IM injection was approximately 12%. The 80 IU formulation exhibited good physical stability and consistent dosing. After 12 months at 30°C/65%RH, pouched samples retained 86.0% of their original assay value.

Conclusions

The PK and stability data suggests that IN administration of oxytocin formulated in the μco™ carrier may represent a viable option for rapid systemic absorption in humans and a product compatible with resource-scarce regions.

KEY WORDS

intranasal absorption peptide pharmacokinetics preclinical stability 

Abbreviations

AUC

Area under the curve

BA

Bioavailability

Cmax

Maximum plasma concentration of drug

Dv10

The diameter of particles where 10% of the population by volume lies below this value

Dv50

The diameter of particles where half of the population by volume lies below this value

Dv90

The diameter of particles where 90% of the population by volume lies below this value

IM

Intramuscular

IN

Intranasal

IU

International units

PK

Pharmacokinetic

PPH

Postpartum hemorrhage

RH

Relative humidity

SD

Standard deviation

Tmax

Time to maximum plasma concentration of drug

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank Pastorus Pharma, LLC owner of the license for the dry-powder oxytocin formulation for making it available for Merck-for-Mothers study and sharing pharmacokinetic data of an independent study involving intranasal oxytocin. This research was supported by funding from Merck & Co., Inc., Kenilworth, NJ through its Merck for Mothers program, a $500 Million, 10-year initiative to reducing maternal mortality.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Mikolaj Milewski
    • 1
  • Adrian Goodey
    • 1
  • Dinah Lee
    • 1
  • Eric Rimmer
    • 1
  • Robert Saklatvala
    • 1
  • Shuzo Koyama
    • 2
  • Mic Iwashima
    • 2
  • Shunji Haruta
    • 2
  1. 1.Merck Research Laboratories, Merck & Co., Inc.KenilworthUSA
  2. 2.TR DivisionShin Nippon Biomedical Laboratories, Ltd.KagoshimaJapan

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