Development and In Vitro-In Vivo Evaluation of Polymeric Implants for Continuous Systemic Delivery of Curcumin
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The introduction of curcumin into clinics is hindered by its low water solubility and poor bioavailability. To overcome these limitations, we developed curcumin implants using poly (ε-caprolactone) as the polymeric matrix.
Implants were prepared by melt-extrusion method; in vitro drug release was optimized for effects of polymer composition, drug load, surface area and water-soluble additives. Implants were also tested under in vivo conditions for cumulative curcumin release, and liver concentration was correlated with its efficacy to modulate selected xenobiotic-metabolizing enzymes (CYP1A1 and GSTM).
Drug release from implants followed biphasic release pattern with Higuchi kinetics and was proportional to the surface area of implants. Drug release increased proportionately from 2 to 10% (w/w) drug load, and incorporation of 10% (w/w) of water-soluble additives (F-68, PEG 8000 and cyclodextrin) did not significantly alter the drug release. In vivo drug release was found to be ∼1.8 times higher than in vitro release. Curcumin was detected at 60 ± 20 ng/g in the liver after four days of implantation and was almost constant (8–15 ng/g) for up to 35 days. This time-dependent drop in curcumin level was found to be due to induction of CYP1A1 and GSTM (μ) enzymes which led to increased metabolism of curcumin.
Our data showed that these implants were able to release curcumin for long duration and to modulate liver phase I and phase II enzymes, demonstrating curcumin’s biological efficacy delivered via this delivery system.
KEY WORDSbioavailability chemoprevention controlled release curcumin implants
bovine calf serum
- CYP 1A1
cytochrome P450 1A1
differential scanning calorimetry
Fourier transform infrared spectroscopy
glutathione S-transferase (μ)
2-hydroxyl propyl β-cyclodextrin
- PEG 8K
polyethylene glycol (molecular weight 8,000)
powder X-ray diffraction
scanning electron microscopy
This research work was supported from USPHS grants CA-118114, CA-125152, CA-90892, and from Agnes Brown Duggan Endowment. R.C.G. is Agnes Brown Duggan Chair in Oncological Research. Dr. Hina Kausar is acknowledged for her assistance in the western blot studies.
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