Valproic Acid-Dextran Conjugate

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Material Information

Title:
Valproic Acid-Dextran Conjugate Synthesis, Characterization and in Vitro Hydrolysis Studies
Physical Description:
1 online resource (142 p.)
Language:
english
Creator:
Hassan, A. M. Mahbub
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Pharmaceutical Sciences, Pharmaceutics
Committee Chair:
Hochhaus, Guenther
Committee Co-Chair:
Hughes, Jeffrey
Committee Members:
Derendorf, Hartmut C
Batich, Christopher D

Subjects

Subjects / Keywords:
vpa
Pharmaceutics -- Dissertations, Academic -- UF
Genre:
Pharmaceutical Sciences thesis, Ph.D.
Electronic Thesis or Dissertation
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )

Notes

Abstract:
The objective of this study was to synthesize valproic acid-dextran conjugate which would be able to release the drug via chemical hydrolysis over an extended period and also to synthesize valproic acid-linker-dextran conjugate which would provide in situ activation to release the drug via enzymatic hydrolysis. Valproic acid (VPA) was conjugated directly to dextrans of molecular weights (Mw) 10,000 and 70,000 using carbonyldiimidazole. To synthesize valproic acid-linker-dextran conjugate, VPA was initially conjugated to linkers (triethylene glycol or pentaethylene glycol) using dicyclohexylcarbodiimide and subsequently, conjugated to dextran (Mw 1,000) using carbonyldiimidazole and dimethylaminopyridine. Syntheses of all the conjugates were confirmed by NMR analysis. The degree of substitution and solubility of the conjugates in water were studied. In vitro hydrolysis studies were conducted for valproic acid-dextran conjugates in phosphate buffered solution (pH 7.5) and in bicarbonate buffer (pH 10.22) at 37 °C and 47 °C. In vitro hydrolysis studies of VPA-linker-dextran conjugates were studied in phosphate buffered solution (pH 7.5) in presence of rat brain fraction (RBF) (S9 fraction) and porcine liver esterase (PLE) at 37 °C. Both pH and temperature were shown to affect the rates of hydrolysis of the VPA-dextran conjugates. Half-lives of hydrolysis in phosphate buffer for the conjugates VPA-dextran (Mw 10,000) and VPA-dextran (Mw 70,000) were 62 days and 57 days at 37 °C respectively. The VPA-linker-dextran conjugates were found to be hydrolyzed by RBF and PLE at a different rate. Modelling of the data of hydrolysis of VPA-linker-dextran conjugates was done and different rate constants for the hydrolysis were estimated from the best-fit model. The half-lives of hydrolysis in presence of RBF for the conjugates VPA-triethyleneglycol-dextran and VPA-pentaethyleneglycol-dextran were 28 hr and 44 hr respectively, whereas in presence of PLE these were 18 min and 21 min respectively. In conclusion, VPA-dextran conjugates were shown to release the drug in vitro for an extended period of time. The VPA-linker-dextran conjugates appeared to be very good substrates for PLE, whereas poor substrates for the enzymes in RBF. VPA-linker-dextran conjugates were shown to exhibit in situ activation to release the drug via enzymatic action. VPA-pentaethyleneglycol-dextran conjugate demonstrated a concentration-dependent cytotoxicity.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis:
Thesis (Ph.D.)--University of Florida, 2012.
Local:
Adviser: Hochhaus, Guenther.
Local:
Co-adviser: Hughes, Jeffrey.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2014-12-31
Statement of Responsibility:
by A. M. Mahbub Hassan.

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2012
System ID:
UFE0044944:00001