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D.P. DeVore, R.A. Eiferman, E.U. Keates, R. Nordquist; In situ Polymerizing, Collagen–Based Drug Delivery System . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5126.
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The purpose of this study was to develop and evaluate unique in situ polymerizing collagen–based compositions as drug delivery depots.
Soluble collagen for drug delivery formulations was prepared from porcine or bovine corium. Purified Type I collagen was dialyzed against 0.1N acetic acid to remove residual salts, and sterile filtered. Collagen was subsequently salt precipitated and the precipitate dialyzed against 0.1N HCl and then 0.035M EDTA as the pH of EDTA solution was slowly increased from 5.0 to 7.5. This slow increase in pH during EDTA dialysis resulted in a collagen preparation that remains "soluble" at neutral pH. The collagen solution rapidly undergoes gelation and fibril formation when exposed to physiological fluids. The final solution was analyzed for collagen purity and concentration. DSC was performed to determine the phase transition temperature. TEM was implemented to examine collagen fibrils formed after exposure to physiological fluid. Histological evaluation was performed on biopsies removed from human dermis and the application of the in situ polymerizing collagen was evaluated for sustained delivery of growth factors and drugs.
SDS–PAGE analysis showed protein bands corresponding to Type I collagen, with no lower molecular weight bands. Collagen concentration ranges from 25–35mg/mL. The kinetics of fibril formation was evaluated spectrophotometrically. Results demonstrated nearly instantaneous formation of fibrils when incubated with salt solution compared to "standard" acid soluble collagen. DSC analysis showed an increase in transition temperature from 39°C to more than 43°C. TEM analysis demonstrated the formation of well–banded collagen fibrils following incubation with physiological fluid. Histological analysis of biopsy specimens demonstrated the presence of a collagen bleb, integrated by host fibroblasts and absent of inflammatory cells. Applications–The collagen solution has been evaluated as a drug depot for sustained delivery of growth factors and active agents potentially useful for treating retinal disorders. Results showed sustained release for various time periods up to 2 months. There was no evidence of any adverse tissue reactions.
In situ polymerizing collagen is a unique collagen–based composition for sustained drug delivery. The composition polymerizes within 2 minutes, is not associated with any adverse tissue reactions, and appears to be a safe, efficacious composition for sustained drug release.
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