Rheumatoid arthritis (RA) is a chronic inflammatory joint disease associated with high levels of
tumour necrosis factor-alpha (TNF-a) in synovial fluid and synovial tissue (Saxne et al., 1989).
Thalidomide is a proven inhibitor of the biological synthesis of TNF-a (Sampaio et al., 1991)
and is believed to rely on this action for its suppression of the wasting of tissue which
accompanies RA. Oral administration of thalidomide has proven to be effective in RA, but
unacceptable side effects are easily provoked (Gutierrez-Rodriguez, 1984). Administration of
thalidomide via the dermal route can down-regulate TNF-a production in and around the
affected joint, and this without raising the systemic blood level to a problematical level.
Based on thalidomide's physicochemical properties, it is unlikely that it can be delivered
percutaneously at a dose required for RA. Therefore, we have embraced the idea of using
N-alkyl analogues of thalidomide. The most important feature that an analogue of this
compound might contribute is decreased crystallinity and increased lipophilicity. Ordinarily both
these parameters should favour percutaneous delivery. The current study was primarily aimed
at exploring the feasibility of percutaneous delivery of thalidomide and subsequently, three of its
odd chain IV-alkyl analogues (methyl, propyl and pentyl) via physicochemical characterization
and assessment of their innate abilities to diffuse through skin as an initial step towards
developing a topical dosage form for the best compound. The biological activities, more
specifically their potential to inhibit the production of TNF-a was determined for thalidomide and
its N-alkyl analogues.
In order to achieve the objectives, the study was undertaken by synthesizing and determining
the physicochemical parameters of thalidomide and its N-alkyl analogues. A high level of
crystallinity is expressed in the form of a high melting point and heat of fusion.
This limits solubility itself, and thus also sets a limit on mass transfer across the skin. Generally,
the greater a drug's innate tendency to dissolve, the more likely it is that the drug can be
delivered at an appropriate rate across the skin (Ostrenga et al., 1971). Therefore, the melting
points and heats of fusion were determined by differential scanning calorimetry. Aqueous
solubility and the partition coefficient (relative solubility) are major determinants of a drug's
dissolution, distribution and availability. N-octanollwater partition coefficients were determined
at pH 6.4. Solubilities in water, a series of n-alcohols and mixed solvents were obtained, as well
as the solubility parameters of the compounds in study. Secondly, in vitro permeation studies
were performed from these solvents and vehicles using vertical Franz diffusion cells with human
epidermal membranes. Thirdly, tumour necrosis factor-alpha (TNF-a) inhibition activities were
assessed for thalidomide and its N-alkyl analogues.
By adding a methyl group to the thalidomide structure, the melting point drops by over 100°C
and, in this particular instance upon increasing the alkyl chain length to five -CH2- units the
melting points decrease linearly. Heats of fusion decreased dramatically upon thalidomide's
alkylation as well. Methylation of the thalidomide molecule enhanced the aqueous solubility
6-fold, but as the alkyl chain length is further extended from methyl to pentyl, the aqueous
solubility decreased exponentially. The destabilization of the crystalline structure with
increasing alkyl chain length led to an increase in lipophilicity and consequently an increase in
solubility in nonpolar media. Log partition coefficients increased linearly with increasing alkyl
chain length. Solubilities in a series of n-alcohols, methanol through dodecanol, were found to
be in the order of pentyl > propyl > methyl > thalidomide. The N-alkyl analogues have more
favourable physicochemical properties than thalidomide to be delivered percutaneously. The in
vitro skin permeation data proved that the analogues can be delivered far easier than
thalidomide itself. N-methyl thalidomide showed the highest steady-state flux through human
skin from water, n-alcohols and combination vehicles. Thalidomide and its N-alkyl analogues
were all active as TNF-a inhibitors.
Finally, active as a TNF-a inhibitor, N-methyl thalidomide is the most promising candidate to be
delivered percutaneously for treatment of rheumatoid arthritis, of those studied. / Thesis (PhD (Pharmaceutics))--PU for CHE, 1999.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/1598 |
| Date | January 1998 |
| Creators | Goosen, Colleen |
| Publisher | Potchefstroom University for Christian Higher Education |
| Source Sets | South African National ETD Portal |
| Detected Language | English |
| Type | Thesis |
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