Percutaneous delivery of drugs promises many advantages over oral or intravenous
administration, such as a better control of blood levels, a reduced incidence of systemic
toxicity, an absence of hepatic first-pass metabolism, better patient compliance, etc.
However, the dermal drug transport is limited by the unsuitable physicochemical
properties of most drugs and the efficient barrier function of the skin. Thus, numerous
attempts have been reported to improve topical absorption of drugs, concentrating
mainly on the barrier function of the stratum corneum by use of penetration enhancers
and/or skin warming. An alternative and interesting possibility for improved dermal
permeability is the synthesis of derivatives or analogues with the aim of changing the
physicochemical properties in favour of skin permeation, efficacy and therapeutic value.
Cyclizine (I) is an anti-emetic drug primarily indicated for the prophylaxis and treatment
of nausea and vomiting associated with motion sickness, post operation and Meniere's
disease. It acts both on the emetic trigger zone and by damping the labyrinthine
sensitivity. Pharmacologically it has anti-histaminic, antiserotonergic, local anaesthetic
and vagolytic actions. It is widely used and also suitable for children from six year of
age. Percutaneous absorption of (I) can, among others, avoid the "first-pass" effect and
the discomfort of injection.
The main objective of this study was to explore the feasibility of percutaneous
absorption of (I) and its alkyl analogues via physicochemical characterization and
assessment of their permeation parameters. The intent was also to establish a
correlation between the physicochemical properties of these compounds and their
percutaneous rate of absorption. To achieve these objectives, the study was undertaken
by synthesizing the alkyl analogues and determining the physicochemical parameters
relevant to skin transport. Identification and level of purity for the prepared analogues
were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR)
spectrometry and infrared (IR) spectrometry. Experimental aqueous solubility (25 °c &
32 °C) and partition coefficient for each compound were determined. In vitro permeation
studies were performed at pH 7.4, using Franz diffusion cells with human epidermal
membranes. Diffusion experiments were conducted over a period of 24 hours
maintaining a constant temperature (37 DC) by means of water bath. All samples were
analysed by high pressure liquid chromatography (HPLC).
Cyclizine (I) has a methyl group at N-4. Increasing the alkyl chain length on N-4 of the
piperazine ring resulted' in compounds with lower melting points and higher water
solubility than (I). (II) exhibited 3-fold increase in water solubility, followed by (IV) with
about 2.5 fold increase. The water solubility of (III) was almost the same as that of (I).
Log partition coefficients increased linearly with increasing alkyl chain length. The
analogues therefore, possessed more favourable physicochemical properties to be
delivered percutaneously. Indeed, the in vitro skin permeation data proved that these
analogues could be delivered more easily than (I) itself. The flux of (I) was 0.132
ug/cm2/h in a saturated aqueous solution. Compound (II) resulted in a 53-fold (6.952
ug/cm2/h) increase in permeation compared to (I). (III) and (IV) resulted in a 2- and 5fold
enhancement of permeation respectively.
Based on the results of the study, it seems that increased aqueous solubility and low
level of crystallinity play a vital role in optimizing percutaneous absorption of (I) and its
alkyl analogues. But the importance of the effect of increased lipophilicity cannot be
ignored. The low percutaneous• absorption of (I) might be attributed to its low aqueous
solubility and increased crystallinity, as is evident from the higher melting point than the
analogues. From all the permeability data using aqueous solutions, it is clear that
compound (II) is the best permeant of this series and in addition it is known that this
compound antagonizes the effects of histamine. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/328 |
| Date | January 2003 |
| Creators | Monene, Lesibana Mishack |
| Publisher | North-West University |
| Source Sets | South African National ETD Portal |
| Detected Language | English |
| Type | Thesis |
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