title: Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): formulation design and optimization studies.
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.
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill , Chapel Hill, NC , USA.
authors.forename: Yu-Tsai
authors.initials: YT
authors.lastname: Yang
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Di Pasqua
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Sueda
authors.forename: Michael
authors.initials: M
authors.lastname: Jay
mesh_terms: D000284:Administration, Oral; D000931:Antidotes / Q000008:administration & dosage* / Q000737:chemistry; D002614:Chelating Agents / Q000008:administration & dosage* / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000737:chemistry*; D004369:Pentetic Acid / Q000008:administration & dosage* / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry; D011205:Povidone / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D012995:Solubility; D024502:alpha-Tocopherol / Q000737:chemistry
chemical_list: D000931:Antidotes; D002614:Chelating Agents; D003692:Delayed-Action Preparations; D011109:Polymethacrylic Acids; D011355:Prodrugs; C038300:methylmethacrylate-methacrylic acid copolymer; D004369:Pentetic Acid; D011205:Povidone; D024502:alpha-Tocopherol
references.citation: Water Res. 2001 Jun;35(8):1877-86
references.pmid: 11337832
references.citation: Skin Therapy Lett. 2009 Jan;14(1):3-5
references.pmid: 19214355
references.citation: J Control Release. 2007 Mar 12;118(1):78-86
references.pmid: 17241685
references.citation: Drug Dev Ind Pharm. 2008 Jul;34(7):668-75
references.pmid: 18608461
references.citation: AAPS PharmSciTech. 2009;10(1):27-33
references.pmid: 19145487
references.citation: Eur J Pharm Biopharm. 2000 Jul;50(1):47-60
references.pmid: 10840192
references.citation: Int J Pharm. 2004 Mar 19;272(1-2):1-10
references.pmid: 15019063
references.citation: Science. 1974 Feb 22;183(4126):715-22
references.pmid: 4595239
references.citation: Radiat Prot Dosimetry. 2009 Feb;134(1):38-48
references.pmid: 19351653
references.citation: Int J Pharm. 2003 Nov 28;267(1-2):79-91
references.pmid: 14602386
references.citation: AAPS PharmSciTech. 2006 Jan 03;7(1):E1
references.pmid: 16584139
references.citation: Drug Dev Ind Pharm. 2006 Oct;32(9):1025-32
references.pmid: 17012115
references.citation: Radiat Prot Dosimetry. 2007;127(1-4):472-6
references.pmid: 17562654
references.citation: J Control Release. 2003 Sep 4;91(3):477-88
references.pmid: 12932724
references.citation: AAPS PharmSciTech. 2006 Aug 18;7(3):68
references.pmid: 17025249
references.citation: Health Phys. 2010 Sep;99(3):285
references.pmid: 20699687
references.citation: J Pharm Sci. 2012 Aug;101(8):2844-53
references.pmid: 22644947
references.citation: AAPS J. 2013 Apr;15(2):523-32
references.pmid: 23389812
references.citation: Health Phys. 2010 Oct;99(4):553-9
references.pmid: 20838098
references.citation: J Pharm Sci. 1971 Jan;60(1):125-7
references.pmid: 5548221
references.citation: Drug Dev Ind Pharm. 1998 Mar;24(3):295-300
references.pmid: 9876588
references.citation: Radiat Res. 2008 Oct;170(4):540-8
references.pmid: 19024661