DMP 504, a potential bile acid sequestrant for the treatment of hypercholesterolemia, is a highly insoluble, cross-linked polymer which does not lend itself to ordinary means of characterization used for drug substances in the pharmaceutical industry. Therefore, alternative characterization techniques have been sought. As part of an effort into extensive characterization of DMP 504 drug substance, nuclear magnetic resonance (NMR) was employed to provide insight into details of the DMP 504 polymer structure. The primary motivation for determining the structure of the polymer chain is to relate the DMP 504 structure to its performance properties as a bile acid sequestrant. Characterization of the polymer chain and understanding of the structural basis of its properties is essential in optimizing and controlling the manufacture of reproducible drug substance. NMR has proven a versatile tool for the description of polymer structure and dynamics because of the wide range of nuclear interactions affecting the NMR signal. This allows the design of experiments to elicit information about specific polymer interactions or properties. The methods of sample preparation utilized to obtain NMR spectra of the insoluble polymer, as well as a discussion and comparison of results for the characterization of DMP 504 obtained using several different NMR techniques will be presented.
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DMP-504 (DuPont Pharmaceuticals Co).
IDrugs
October 2000
Mylan Pharmaceutical Inc, PO Box 4310, Morgantown, WV 26504-4310, USA.
DMP-504 is a novel hydrogel bile acid sequestrant being developed by DuPont for the potential treatment of primary moderate hypercholesterolemia. It is in phase III trials. Equilibrium binding studies coupled with computer simulation of human bile flow predict that DMP-504 could be 3- to 4-fold more potent than cholestyramine in a clinical setting.
View Article and Find Full Text PDFEvaluation of the in vivo disintegration of solid dosage forms of a bile acid sequestrant in dogs using gamma-scintigraphy and correlation to in vitro disintegration.
Pharm Res
March 2003
Bristol-Myers Squibb Company, Pharmaceutics R&D, New Brunswick, New Jersey 08903-0191, USA.
Purpose: [corrected] To evaluate the in vivo disintegration behavior of tablets and capsules of a bile acid sequestrant, DMP 504, in beagle dogs and to assess the significance of the in vitro disintegration of the dosage forms on subsequent in vivo behavior in order to draw possible in vitro-in vivo correlations.
Methods: Tablet and capsule formulations of a bile acid sequestrant, DMP 504, were formulated with samarium oxide and neutron activated to produce radioactive 53Sm to noninvasively evaluate their in vivo behavior in beagle dogs by gamma-scintigraphy. A four-way crossover design was completed (n = 4) in which (a) tablets from two different batches were administered under the fasted condition and manufactured using different lots of drug substance where one batch exhibited relatively faster in vitro disintegration time (30 min) than the other tablet batch, which resulted in slower disintegration (45 min), (b) a capsule formulation was administered to fasted beagles, and (c) the tablet having slower in vitro disintegration was also administered in the fed state, and its in vivo disintegration was compared to that observed in the fasted state.
Development and validation of a cholate binding capacity method for DMP 504, a bile acid sequestrant.
J Pharm Biomed Anal
June 2001
DuPont Pharmaceuticals Company, PO Box 80353, Wilmington, DE 19880-0353, USA.
DMP 504, a highly cross-linked insoluble polymer, is a bile acid sequestrant developed by the DuPont Pharmaceuticals Company for serum cholesterol reduction. Since DMP 504 is insoluble, it was necessary to develop unique specific analytical methods to measure and control the quality of different lots of the drug. Since the mechanism of action of DMP 504 is believed to be by sequestration of bile acids, the in-vitro binding capacity of the polymer for cholic acid was chosen as a surrogate of in-vivo performance and used to assess potency of the compound.
View Article and Find Full Text PDFNMR characterization of a novel bile acid sequestrant, DMP 504.
J Pharm Biomed Anal
February 2001
The DuPont Pharmaceuticals Company, Wilmington, DE 19880-0353, USA.
DMP 504, a potential bile acid sequestrant for the treatment of hypercholesterolemia, is a highly insoluble, cross-linked polymer which does not lend itself to ordinary means of characterization used for drug substances in the pharmaceutical industry. Therefore, alternative characterization techniques have been sought. As part of an effort into extensive characterization of DMP 504 drug substance, nuclear magnetic resonance (NMR) was employed to provide insight into details of the DMP 504 polymer structure.
View Article and Find Full Text PDFDetermination of a novel bile acid sequestrant in rodent diet by near-infrared spectroscopy.
J Pharm Biomed Anal
May 1999
DuPont Merck Pharmaceuticals Company, Analytical R&D, Wilmington, DE 19880, USA.
DMP 504 is a high molecular weight polymer currently under development by The DuPont Merck Pharmaceutical Company as a novel bile acid sequestrant to lower serum cholesterol. To assess its safety, DMP 504 is incorporated into rodent diet for oral administration to rats and mice. An analytical method was developed to determine the accuracy and homogeneity of the blends.
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