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Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): formulation design and optimization studies.

Pharmaceutical development and technology (2013-09-21)
Yu-Tsai Yang, Anthony J Di Pasqua, Yong Zhang, Katsuhiko Sueda, Michael Jay
ABSTRACT

The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit® RL PO and α-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit® RL PO and α-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Polyvinylpyrrolidone, K 30
Sigma-Aldrich
Poly(methyl methacrylate-co-methacrylic acid), average Mw ~34,000 by GPC, average Mn ~15,000 by GPC
Sigma-Aldrich
Polyvinylpyrrolidone, powder, average Mw ~29,000
Sigma-Aldrich
Polyvinylpyrrolidone, powder, average Mw ~55,000
Sigma-Aldrich
Polyvinylpyrrolidone, average Mw ~1,300,000 by LS
Sigma-Aldrich
Polyvinylpyrrolidone, K 90
Sigma-Aldrich
Polyvinylpyrrolidone solution, K 60, 45% in H2O
Sigma-Aldrich
Polyvinylpyrrolidone, K 25, tested according to Ph. Eur.
Sigma-Aldrich
(+)-α-Tocopherol, Type VI, from vegetable oil, liquid (≥0.88M based on potency, density and molecular wt.), BioReagent, suitable for insect cell culture, ≥1000 IU/g
Sigma-Aldrich
(+)-α-Tocopherol, from vegetable oil, Type V, ~1000 IU/g
Sigma-Aldrich
Polyvinylpyrrolidone, powder, BioXtra, suitable for mouse embryo cell culture
Sigma-Aldrich
Polyvinylpyrrolidone, suitable for plant cell culture, average mol wt 10,000
Sigma-Aldrich
Polyvinylpyrrolidone, for molecular biology, nucleic acid hybridization tested, mol wt 360,000
Sigma-Aldrich
Polyvinylpyrrolidone, average mol wt 40,000
Sigma-Aldrich
Polyvinylpyrrolidone, mol wt (number average molecular weight Mn 360)
Sigma-Aldrich
Polyvinylpyrrolidone, average mol wt 10,000
Sigma-Aldrich
Diethylenetriaminepentaacetic acid, ≥99% (titration)
Sigma-Aldrich
Diethylenetriaminepentaacetic acid, ≥98% (titration)
Sigma-Aldrich
Povidone, meets USP testing specifications
Sigma-Aldrich
Diethylenetriaminepentaacetic acid, for complexometry, ≥99.0%
Sigma-Aldrich
Kollidon® 25
Supelco
Poly(vinylpolypyrrolidone), ~110 μm particle size
Supelco
Povidone, Pharmaceutical Secondary Standard; Certified Reference Material
Crospovidone, European Pharmacopoeia (EP) Reference Standard
USP
Crospovidone, United States Pharmacopeia (USP) Reference Standard
USP
Povidone, United States Pharmacopeia (USP) Reference Standard
USP
Methacrylic acid copolymer type B, United States Pharmacopeia (USP) Reference Standard
USP
Methacrylic acid copolymer type C, United States Pharmacopeia (USP) Reference Standard
Povidone, European Pharmacopoeia (EP) Reference Standard