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

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.

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Department of Drug Science, University of Pavia, Pavia, Italy.
Department of Drug Science, University of Pavia, Pavia, Italy. Electronic address:
Department of Public Health, Experimental and Forensic Medicine, Histology and Embryology Unit, University of Pavia, Pavia, Italy.
Microbiology Unit, IRCCS-San Martino-IST, DISC, University of Genoa, Italy.


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.


Chitosan glutamate; DoE approach; Hyaluronic acid; Pectin; Wound healing

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