الفهرس 
Introduction
Hyperlipidemia and atherogenesisOnly 14 pages are availabe for public view
 |  | from | 235 |  |  |
| | | from | 235 | | |
Abstract
The presented dissertation constitutes a literature survey on some antihyperlipidemics belonging to different monitoring groups of hypercholesterolemia, namely; atorvastatin, simvastatin, rosuvastatin, lovastatin fenofibrate, bezafibrate, niacin and ezetimibe. It introduces simultaneous determination of the investigated antihyperlipidemics together and with other cardiovascular and diabetic drugs by different techniques. In-vivo pharmacokinetic studies were applied on some of the developed analytical methods to detect safety and drug – drug interactions of some common drug combinations The dissertation comprises six chapters;
Chapter 1. Introduction.
It presents a general introduction on hypercholesterolemia and antihyperlipidemics
concerning their mechanism of action, medicinal importance, pharmacokinetics,
pharmacological and chemical classification, and chemical structures. Further, a
detailed literature survey on official and reported methods for their analysis by
different analytical techniques was discussed.
Chapter 2. Spectrodensitometric determination of some antihyperlipidemics in
pharmaceutical combinations and in plasma with a pharmacokinetic application.
A precise and sensitive spectrodensitometric method was developed for the
simultaneous determination of a quaternary mixture of antihyperlipidemics
containing; Niacin, ATOR, BEZA with either EZE or SIM. The densitometric
analysis was carried out using HPTLC silica gel G 60 F254 plates as stationary phase.
The plates were developed with benzene: ACN: n-butanol (7.00: 2.00: 1.00, v/v/v) +
1.50 %, v/v glacial HOAC in absorbance mode at 242 nm. The retention factors of
Niacin, ATOR, BEZA, EZE and SIM were 0.17, 0.38, 0.51, 0.65 and 0.66,
respectively. The method was validated according to USP 31 NF 26 and ICH
Summary
166
guidelines. Linearity ranges of all studied drugs were found to be in the range of 15.00
– 650.00 ng/band with correlation coefficient values of 0.9975 or more. Limits of
detection and quantitation were 5.00 – 50.00 and 15.00 – 150.00 ng/band,
respectively. Upon applying polynomial regression to the same concentration ranges
of standard solutions of all investigated drugs as well as spiked BEZA samples to
rabbit plasma, correlation coefficient values had greatly improved. The proposed
method was successfully applied for the simultaneous determination of the studied
antihyperlipidemic drugs in plasma and in their pharmaceutical formulations. The
developed method was utilized to study pharmacokinetic behavior of BEZA and its
drug-drug interaction with ATOR in rabbit males. This study has proven the increased
myotoxicity risk upon co-administration of ATOR with BEZA.
Chapter 3. A validated reversed phase liquid chromatographic method for
simultaneous determination of some antihyperlipidemic drugs.
A simple, sensitive, precise, fast and accurate reversed phase liquid
chromatographic method had been developed for the simultaneous estimation of six
antihyperlipidemic drugs. namely, ROS, BEZA, EZE, ATOR, FENO and SIM. The
method was developed using a reversed-phase C18 column with a mobile phase
consisting of water adjusted to pH 4.40 by orthophosphoric acid: ACN (30.00: 70.00,
v/v) at a flow rate of 1.00 mL/min and ultraviolet detection at 242 nm. Retention
times ranged from 3.1 to 20.5 min. The developed method was validated according to
USP 31 NF 26 and ICH guidelines. Under the optimum chromatographic conditions,
correlation coefficients were in the range of 0.9981 – 0.9996, linearity ranges were
from 0.06 to 20.00 μg/mL with detection limits from 0.02 to 0.11 μg/mL. The
proposed method could be applied efficiently for the estimation of the studied drugs in
their pure and combined dosage forms with excellent recoveries.
Summary
167
Chapter 4. Simultaneous HPLC determination of metformin hydrochloride,
amlodepine besylate, bezafibrate and valsartan in tablets and spiked rabbit
plasma with pharmacokinetic study.
A validated simple, rapid, selective reversed phase HPLC method had been
developed for simultaneous determination of some cardiovascular drugs; AMLO,
BEZA and VAL, in addition to MET in their tablets as well as spiked rabbit plasma.
The separation was performed on C18 column using a linear gradient mobile phase
system to achieve a complete separation of the four drugs in less than 15 min. Under
optimum conditions, the investigated drugs have exhibited linear relationship between
the concentration and the peak area in the range from 0.46 – 32.00 μg/mL with good
correlation coefficient values ≥ 0.9955. Detection and quantitation limits for the
studied drugs were 0.15 – 0.71 μg/mL and 0.46 – 2.15 μg/mL, respectively. The
proposed method has been applied successfully with excellent recoveries for analysis
of pure forms, tablets, and spiked rabbit plasma samples of the studied drugs.
Additionally, the developed method has been applied successfully to study the change
of pharmacokinetic behavior of BEZA upon co-administration of VAL in rabbit
males.
Chapter 5. MEKC determination of rosuvastatin in rabbit plasma and
evaluation of its pharmacokinetics and interaction with niacin.
A specific, accurate, precise and reproducible micellar electrokinetic
chromatographic method was developed for in-vitro and in-vivo estimation of ROS, a
synthetic and potent HMG-CoA inhibitor, in rabbit plasma. Additionally, the change
in its pharmacokinetics in the presence of Niacin which could be co-administered for
monitoring of severe hypercholestraemia has been studied. The assay procedures
involved simple liquid–liquid extraction of ROS and IS from small plasma volumes
directly into ACN. The organic layer was separated and evaporated under a gentle
stream of nitrogen. The residue was reconstituted in the mobile phase and injected
Summary
168
electrokinetically into electropherosis system. The background electrolyte is
consisting of borate buffer (25.00 mM, pH 9.50) mixed with 10.00 % organic
modifier (5.00 % MeOH + 5.00 % ACN) and 25.00 mM SDS at 20 kV applied
voltage and 215 nm detection wavelength for the effective separation of ROS, Niacin
and ATOR.
Chapter 6. Spectroscopic analysis.
Section a. Determination of binary mixtures of ezetimibe with atorvastatin or
simvastatin in pure forms and tablets by FTIR spectroscopy.
FTIR spectroscopy has been utilized for the simultaneous estimation of binary
mixtures of EZE – ATOR and EZE – SIM. The characteristic absorption bands at 514,
1651 and 868 cm-1 for EZE, ATOR and SIM, respectively has been chosen for their
selective simultaneous analysis. Beer’s law was obeyed in concentration ranges 0.08 –
0.40 and 0.03 – 0.30 % w/w for the investigated drugs alone and in synthetic binary
mixtures, respectively. Validation study was performed using USP 31 NF 26 and ICH
guidelines and good recoveries were obtained in the range of 85.30 – 103.32 % with
relative standard deviations less than 6.00 % depicting efficiency of the developed
method. Excellent recoveries were obtained upon application of the developed method
to their commercial tablets indicating the suitability of the proposed method for
routine analysis in the quality control laboratories.
Section b. FTIR spectroscopic study of two isostructural statins: Simvastatin and
Lovastatin.
A developed very simple analytical method has been developed for quantitation of
SIM in the presence of its isostructure LOVA without any interference. It was utilized
for easy and complete fine characterization of SIM FTIR spectrum from that of
LOVA. Simvastatin has been quantified efficiently by the developed method either
alone or in mixture with LOVA giving LOQ values of 0.009 and 0.02 % w/w,
Summary
169
respectively indicating good sensitivity. Correlation coefficients were 0.9975 and
0.9886 for SIM alone and in mixture with LOVA, respectively. The developed
spectroscopic method has provided simple and sensitive tool in quality control
laboratories for efficient quantitation SIM pharmaceutical tablets with good
recoveries.
The dissertation comprises 51 Tables, 44 Figures, 210 references and a summary
in English and in Arabic.
Conclusions