Application of DoE approach in the development of mini-capsules, based on biopolymers and manuka honey polar fraction, as powder formulation for the treatment of skin ulcers

Int J Pharm. 2017 Jan 10;516(1-2):266-277. doi: 10.1016/j.ijpharm.2016.10.050. Epub 2016 Oct 24.


The aim of the present work was the development of a powder formulation for the delivery of manuka honey (MH) bioactive components in the treatment of chronic skin ulcers. In particular pectin (PEC)/chitosan glutamate (CS)/hyaluronic acid (HA) mini-capsules were obtained by inverse ionotropic gelation in presence of calcium chloride and subsequently freeze-dried. Optimization of unloaded (blank) formulation was performed using DoE approach. In a screening phase, the following three factors were investigated at two levels: CS (0.5-1% w/w), PEC (0.5-1% w/w) and HA (0.3-0.5% w/w) concentrations. For the optimization phase a "central composite design" was used. The response variables considered were: particle size, buffer (PBS) absorption and mechanical resistance. In a previously work two different MH fractions were investigated, in particular MH fraction 1 (Fr1), rich in polar substances (sugars, methylglyoxal (MGO), dicarbonyl compounds, …), was able to enhance human fibroblasts in vitro proliferation. In the present work, the loading of MH Fr1 into mini-capsules of optimized composition determined a significant increase in cell proliferation in comparison with the unloaded ones. Loaded particles showed antimicrobial activity against Staphylococcus aureus and Streptococcus pyogenes; they were also able to improve wound healing in vivo on a rat wound model.

Keywords: Chitosan glutamate; DoE approach; Hyaluronic acid; Pectin; Wound healing.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacology
  • Biopolymers / chemistry*
  • Capsules
  • Chemistry, Pharmaceutical / methods
  • Chitosan / chemistry
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Glutamic Acid / chemistry
  • Honey*
  • Humans
  • Hyaluronic Acid / chemistry
  • Male
  • Pectins / chemistry
  • Powders
  • Rats
  • Rats, Wistar
  • Skin Ulcer / drug therapy*
  • Skin Ulcer / pathology
  • Staphylococcal Infections / drug therapy
  • Staphylococcus aureus / drug effects
  • Streptococcal Infections / drug therapy
  • Streptococcus pyogenes / drug effects
  • Wound Healing / drug effects*


  • Anti-Bacterial Agents
  • Biopolymers
  • Capsules
  • Powders
  • Glutamic Acid
  • Pectins
  • Hyaluronic Acid
  • Chitosan