Background:
Recombinant human keratinocyte growth factor (rHuKGF) has gained
considerable attention by researchers as epithelial cells proliferating agent. Moreover, intravenous
truncated rHuKGF (palifermin) has been approved by Food and Drug Administration (FDA) to treat
and prevent chemotherapy-induced oral mucositis and small intestine ulceration. The labile structure
and short circulation time of rHuKGF in-vivo are the main obstacles that reduce the oral bioactivity
and dosage of such proteins at the target site.
Objective:
Formulation of methacrylic acid-methyl methacrylate copolymer-coated capsules filled
with chitosan nanoparticles loaded with rHuKGF for oral delivery.
Methods:
We report on chitosan nanoparticles (CNPs) with diameter < 200 nm, prepared by ionic
gelation, loaded with rHuKGF and filled in methacrylic acid-methyl methacrylate copolymercoated
capsules for oral delivery. The pharmacokinetic parameters were determined based on the
serum levels of rHuKGF, following a single intravenous (IV) or oral dosages using a rabbit model.
Furthermore, fluorescent microscope imaging was conducted to investigate the cellular uptake of
the rhodamine-labelled rHuKGF-loaded nanoparticles. The proliferation effect of the formulation
on FHs 74 Int cells was studied as well by MTT assay.
Results:
The mucoadhesive and absorption enhancement properties of chitosan and the protective
effect of methacrylic acid-methyl methacrylate copolymer against rHuKGF release at the stomach,
low pH, were combined to promote and ensure rHuKGF intestinal delivery and increase serum
levels of rHuKGF. In addition, in-vitro studies revealed the protein bioactivity since rHuKGFloaded
CNPs significantly increased the proliferation of FHs 74 Int cells.
Conclusion:
The study revealed that oral administration of rHuKGF–loaded CNPs in methacrylic
acid-methyl methacrylate copolymer-coated capsules is practically alternative to the IV administration
since the absolute bioavailability of the orally administered rHuKGF–loaded CNPs, using the
rabbit as animal model, was 69%. Fluorescent microscope imaging revealed that rhodaminelabelled
rHuKGF-loaded CNPs were taken up by FHs 74 Int cells, after 6 hours’ incubation time,
followed by increase in the proliferation rate.
pH‐Sensitive methacrylic acid–methyl methacrylate copolymer Eudragit L100 and dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate tri‐copolymer Eudragit E100
