Experimental design in formulation of diazepam nanoemulsions: physicochemical and pharmacokinetic performances

J Pharm Sci. 2013 Nov;102(11):4159-72. doi: 10.1002/jps.23734. Epub 2013 Sep 23.

Abstract

With the aid of experimental design, we developed and characterized nanoemulsions for parenteral drug delivery. Formulations containing a mixture of medium-chain triglycerides and soybean oil as oil phase, lecithin (soybean/egg) and polysorbate 80 as emulsifiers, and 0.1 M phosphate buffer solution (pH 8) as aqueous phase were prepared by cold high-pressure homogenization. To study the effects of the oil content, lecithin type, and the presence of diazepam as a model drug and their interactions on physicochemical characteristics of nanoemulsions, a three factor two-level full factorial design was applied. The nanoemulsions were evaluated concerning droplet size and size distribution, surface charge, viscosity, morphology, drug-excipient interactions, and physical stability. The characterization revealed the small spherical droplets in the range 195 -220 nm with polydispersity index below 0.15 and zeta potential between -30 and - 60 mV. Interactions among the investigated factors, rather than factors alone, were shown to more profoundly affect nanoemulsion characteristics. In vivo pharmacokinetic study of selected diazepam nanoemulsions with different oil content (20%, 30%, and 40%, w/w) demonstrated fast and intense initial distribution into rat brain of diazepam from nanoemulsions with 20% and 30% (w/w) oil content, suggesting their applicability in urgent situations.

Keywords: FTIR; atomic force microscopy; diazepam; drug-excipient interaction; full factorial design; nanoemulsion; particle size; pharmacokinetics; stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Anesthesia / administration & dosage*
  • Adjuvants, Anesthesia / chemistry
  • Adjuvants, Anesthesia / pharmacokinetics*
  • Animals
  • Brain / metabolism*
  • Diazepam / administration & dosage*
  • Diazepam / chemistry
  • Diazepam / pharmacokinetics*
  • Emulsifying Agents / chemistry
  • Emulsions / chemistry*
  • Lecithins / chemistry
  • Male
  • Pharmaceutical Vehicles / chemistry*
  • Polysorbates / chemistry
  • Rats
  • Rats, Wistar
  • Solubility
  • Soybean Oil / chemistry
  • Triglycerides / chemistry

Substances

  • Adjuvants, Anesthesia
  • Emulsifying Agents
  • Emulsions
  • Lecithins
  • Pharmaceutical Vehicles
  • Polysorbates
  • Triglycerides
  • Soybean Oil
  • Diazepam