1 |
Percutaneous absorption of cyclizine and its alkyl analogues / Lesibana Mishack MoneneMonene, Lesibana Mishack January 2003 (has links)
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.
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2 |
Percutaneous absorption of cyclizine and its alkyl analogues / Lesibana Mishack MoneneMonene, Lesibana Mishack January 2003 (has links)
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.
|
3 |
Percutaneous delivery of thalidomide and its N-alkyl analogues for treatment of rheumatoid arthritis / Colleen GoosenGoosen, Colleen January 1998 (has links)
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.
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4 |
Percutaneous delivery of thalidomide and its N-alkyl analogues for treatment of rheumatoid arthritis / Colleen GoosenGoosen, Colleen January 1998 (has links)
Thesis (PhD (Pharmaceutics))--PU for CHE, 1999.
|
5 |
Percutaneous delivery of thalidomide and its N-alkyl analogues for treatment of rheumatoid arthritis / Colleen GoosenGoosen, Colleen January 1998 (has links)
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.
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