International Journal of Pharmaceutics, May 1, 2008
Lyophilised wafers are being developed as topical drug delivery systems for the treatment of chro... more Lyophilised wafers are being developed as topical drug delivery systems for the treatment of chronic wounds. This study describes the formulation of xanthan wafers containing a selective, insoluble MMP-3 inhibitor (UK-370,106) and a non-ionic surfactant, designed to release accurate doses of UK-370,106 directly to a suppurating wound bed. Stability of UK-370,106 in the wafer compared to a non-lyophilised gel suspension was investigated using a combination of light scattering, thermal and microscopic techniques. Particle size distributions in UK-370,106-loaded wafers were constant throughout an accelerated stability study (12 weeks, 40 degrees C) while the mean particle size in a non-lyophilised suspension increased by 15 microm in the same period. Thermal analysis of UK-370,106-loaded wafers highlighted an unexpected interaction between the drug and the surfactant that was further investigated using simple mixtures of each component. It was concluded that an in situ solvate of UK-370,106 and the non-ionic surfactant can form and that this may have implications towards the stability of UK-370,106 during the formulation process. Further concerns regarding high water contents (14%) in the wafer and its effect on product stability were unfounded and it was concluded that these novel delivery systems provided a viable alternative to gel suspensions.
Liquid paraffin-in-water emulsions prepared with cetomacrogol 1000 and alcohols cetostearyl (A), ... more Liquid paraffin-in-water emulsions prepared with cetomacrogol 1000 and alcohols cetostearyl (A), cetyl (B), stearyl (C) and myristyl (D) were examined by microscopical, particle size analytical and rheological (continuous shear, small strain creep and oscillation) techniques at 25° as they aged over 30 days. The particle sizes of the emulsions were similar and did not increase significantly with age. Thus the rheological stabilities were not correlated with particle size distributions, but rather with viscoelastic networks formed in the continuous phases when the non-ionic mixed emulsifiers interacted with water. The rheological properties of emulsions B and D differed from those of emulsion C. Emulsion A, of mixed homologue composition, showed some properties similar to each of the pure alcohol emulsions. Emulsions B and D were semi-solid immediately after preparation whereas emulsion C was so mobile initially that small strain data were not derived. On ageing, the consistencies of B and D changed slightly initially, and then remained essentially constant. In contrast, the consistency of emulsion C increased on ageing, especially over the first few days when there was a change from mobile liquid to semisolid. Emulsion A was a semisolid initially but like emulsion C increased in consistency especially over the first 24 h. Continuous shear data indicated that this emulsion was the most resistant to structure breakdown. Microscopical examinations supported the view that the networks formed in emulsion A were the most extensive and that stearyl alcohol networks in C formed comparatively slowly. Although the cetomacrogol/pure alcohol networks were diffuse and sometimes crystallized, they did not rapidly disintegrate on storage as did the ionic surfactant/pure alcohol networks examined previously.
International Journal of Pharmaceutics, Feb 1, 2007
This work reports investigations into the interaction and adsorption of the hydrophilic polymer h... more This work reports investigations into the interaction and adsorption of the hydrophilic polymer hyaluronic acid (HA) onto the surface of the hydrophobic corticosteroid drug fluticasone propionate (FP). The eventual aim is to formulate a bioadhesive pulmonary drug delivery system with prolonged action that avoids rapid clearance from the lungs by the mucociliary escalator. Adsorption isotherms detailing the adsorption of HA from aqueous HA solution concentrations ranging from 0.14 to 0.0008% (w/v) to a fixed FP particle concentration of 0.1% (w/v) were investigated. The method of preparing FP particles with HA molecules adsorbed on their surfaces (FP/HA particles) involved suspension of the FP either in hydrated HA solution or in water followed by addition of solid HA, centrifugation of the solids to form a pellet, washing the pellet several times with water until no HA was found in the supernatant and then freeze drying the suspension obtained by dispersing the final pellet. The freeze dried powder was then analysed for adsorbed HA using a Stains-all assay. The influence of order of addition of HA to FP, time for the adsorption process, and temperature of preparation on the adsorption isotherms was investigated. The non-equilibrium adsorption isotherms produced generally followed the same trend, in that as the HA solution concentration increased, the amount of HA adsorbed increased to a maximum at a solution concentration of approximately 0.1% (w/v) and then decreased. The maxima in the adsorption isotherms were close to the change from secondary to tertiary conformation in the HA solutions. Below the maxima, adsorption occurred via interaction of FP with the hydrophobic patches along the HA chains in the secondary structures. Above the maxima, secondary HA molecules aggregate in solution to form tertiary network structures. Adsorption from tertiary structure was reduced because strong interactions between the HA molecules limited the availability of hydrophobic patches for adsorption of HA onto FP. The influence of preparation variables on adsorption was also related to the availability of hydrophobic patches for adsorption.
Previous studies (Eccleston, 1976) showed that the homologue composition of fatty alcohols can ma... more Previous studies (Eccleston, 1976) showed that the homologue composition of fatty alcohols can markedly affect the consistencies and stabilities of ( O / W ) creams prepared with ionic surfactants. Similar results were obtained when the nonionic surfactant cetomacrogol 1000 was used, although the effect was not as marked (Eccleston, 1 9 7 7 ) . ionic surfactants including polyethylene glycol 1000 monostearate (PEG 1000 monostearate, Cithrol 10 MS, Croda). alcohol to form a commercial non-ionic emulsifying wax.
International Journal of Cosmetic Science, Aug 1, 1982
Synopsis Liquid paraffin in water emulsions stabilized by PEG 1000 monostearate and alcohols ceto... more Synopsis Liquid paraffin in water emulsions stabilized by PEG 1000 monostearate and alcohols cetostearyl (c/s) myristyl (C(14)), cetyl (C(16)) or stearyl (C(18)) and ternary systems prepared by dispersing each fatty alcohol and surfactant in water were examined during 30 days using a Ferranti-Shirley cone and plate viscometer. Microscopical diffusion experiments investigated interaction between PEG 1000 monostearate solution and each alcohol at high and low temperature. The rheological properties of each ternary system and corresponding emulsion were similar. Formulations prepared from pure C(14), C(16) or c/s alcohols were semisolid immediately after preparation. Flow curves were in the form of anticlockwise hysteresis loops with spur points. On ageing for 24 h, structure built-up over a time scale similar to that observed in diffusion experiments, so that apparent viscosities increased. However, on further ageing the pure C(14) and C(16) alcohol systems were not as stable as those prepared with c/s alcohol. In contrast, the pure C(18) systems were mobile liquids and the emulsion cracked within days. This correlated with diffusion experiments where little interaction was observed between stearyl alcohol and PEG 1000 monostearate.
The rheological profiles of commercial corticosteroid nasal spray suspensions (Beconase, Nasacort... more The rheological profiles of commercial corticosteroid nasal spray suspensions (Beconase, Nasacort, Flixonase, and Nasonex) were compared using shear and extensional techniques. Thixotropy/shear thinning was investigated (Carri-Med CSL100, concentric cylinder geometry) by (a) the generation of flow curves at low (100 sec-1) and high (1200 sec-1) maximum shear rates and (b) determination of equilibrium shear viscosities at constant shear rates of 10 sec-1, 100 sec-1, or 1200 sec-1. Extensional properties, on which droplet breakup and size depend, were examined using digital camera photography of droplet evolution and the length any trailing filament formed when the suspension was extruded from a 10-ml syringe at 500 microliters/min. All the nasal suspensions were shear thinning and were also thixotropic to varying degrees. The absence of significant thixotropic recovery at short times (5 min) for all the sprays implies that thixotropy is not necessarily the controlling factor for prolonged residence of the spray in the nasal cavity, but rather that it is the high viscosities present in all four sprays, even after structure breakdown. Preliminary extensional flow data identified differences among the four sprays, with extensional filament lengths increasing in the same rank order as the lowest shear rate (10 sec-1) equilibrium viscosities.
Unneutralized Carbopol 940 and 941. Flow curves were similar but showed a marked decrease in cons... more Unneutralized Carbopol 940 and 941. Flow curves were similar but showed a marked decrease in consistency compared with neutralised systems. Carbopol 941 gels increased in hysteresis with increase in concentration. The creep curves approached Hookean behaviour and calculated parameters were of the same order as those derived from neutralized gels. This indicates that in their rheological ground state the neutralized and unneutralized systems are similar, but when tested at high shear rates differences in structure become apparent (i.e. strong electrostatic repulsion between ionized carboxy groups and weak hydrogen bonding between undissociated carboxy groups). Subjective differences at tertiary level (Sherman, 1971)-940 gels were creamy and viscous, 941 preparations were sticky and elastic.
Journal of Pharmaceutical and Biomedical Analysis, Mar 1, 2006
Batch variation in Tween 60 has shown to influence the rheological properties of semisolid emulsi... more Batch variation in Tween 60 has shown to influence the rheological properties of semisolid emulsions. MS (LC-MS, GC-MS, MS(n)) and NMR ((13)C, (1)H, (1)H COSY and HMBC) techniques were used to analyze and compare the composition of two batches of Tween 60 with particular emphasis on the number of POE groups and their distribution within the molecule. Acid and saponification values were also determined. The batches contained different proportions of components (sorbitan polyethoxylates, sorbitan monoester-diester-polyethoxylates and isosorbide monoester-diester-polyethoxylates). The number of POE groups were averaged over the four sites in sorbitan and the two sites in isosorbide molecules. The batches differed from each other in terms of (i) the POE sorbitan stearate/POE sorbitan palmitate ratios (batch 1, 3:2 and batch 2, 4:5), (ii) the ratio of sorbitans to isosorbides (batch 1, 2:3; batch 2, 7:13); and (iii) the acid values (batch 1, 3.1; batch 2, 0). It is concluded that liquid chromatography combined with electrospray mass spectrometry and ion trap separation is a useful tool for establishing the compositional profile of different batches of Tweens. (1)H NMR could provide a simple and rapid pharmacopoeial test for the ratio of sorbitan to isosorbide in Tweens.
International Journal of Pharmaceutics, May 1, 2008
Lyophilised wafers are being developed as topical drug delivery systems for the treatment of chro... more Lyophilised wafers are being developed as topical drug delivery systems for the treatment of chronic wounds. This study describes the formulation of xanthan wafers containing a selective, insoluble MMP-3 inhibitor (UK-370,106) and a non-ionic surfactant, designed to release accurate doses of UK-370,106 directly to a suppurating wound bed. Stability of UK-370,106 in the wafer compared to a non-lyophilised gel suspension was investigated using a combination of light scattering, thermal and microscopic techniques. Particle size distributions in UK-370,106-loaded wafers were constant throughout an accelerated stability study (12 weeks, 40 degrees C) while the mean particle size in a non-lyophilised suspension increased by 15 microm in the same period. Thermal analysis of UK-370,106-loaded wafers highlighted an unexpected interaction between the drug and the surfactant that was further investigated using simple mixtures of each component. It was concluded that an in situ solvate of UK-370,106 and the non-ionic surfactant can form and that this may have implications towards the stability of UK-370,106 during the formulation process. Further concerns regarding high water contents (14%) in the wafer and its effect on product stability were unfounded and it was concluded that these novel delivery systems provided a viable alternative to gel suspensions.
Liquid paraffin-in-water emulsions prepared with cetomacrogol 1000 and alcohols cetostearyl (A), ... more Liquid paraffin-in-water emulsions prepared with cetomacrogol 1000 and alcohols cetostearyl (A), cetyl (B), stearyl (C) and myristyl (D) were examined by microscopical, particle size analytical and rheological (continuous shear, small strain creep and oscillation) techniques at 25° as they aged over 30 days. The particle sizes of the emulsions were similar and did not increase significantly with age. Thus the rheological stabilities were not correlated with particle size distributions, but rather with viscoelastic networks formed in the continuous phases when the non-ionic mixed emulsifiers interacted with water. The rheological properties of emulsions B and D differed from those of emulsion C. Emulsion A, of mixed homologue composition, showed some properties similar to each of the pure alcohol emulsions. Emulsions B and D were semi-solid immediately after preparation whereas emulsion C was so mobile initially that small strain data were not derived. On ageing, the consistencies of B and D changed slightly initially, and then remained essentially constant. In contrast, the consistency of emulsion C increased on ageing, especially over the first few days when there was a change from mobile liquid to semisolid. Emulsion A was a semisolid initially but like emulsion C increased in consistency especially over the first 24 h. Continuous shear data indicated that this emulsion was the most resistant to structure breakdown. Microscopical examinations supported the view that the networks formed in emulsion A were the most extensive and that stearyl alcohol networks in C formed comparatively slowly. Although the cetomacrogol/pure alcohol networks were diffuse and sometimes crystallized, they did not rapidly disintegrate on storage as did the ionic surfactant/pure alcohol networks examined previously.
International Journal of Pharmaceutics, Feb 1, 2007
This work reports investigations into the interaction and adsorption of the hydrophilic polymer h... more This work reports investigations into the interaction and adsorption of the hydrophilic polymer hyaluronic acid (HA) onto the surface of the hydrophobic corticosteroid drug fluticasone propionate (FP). The eventual aim is to formulate a bioadhesive pulmonary drug delivery system with prolonged action that avoids rapid clearance from the lungs by the mucociliary escalator. Adsorption isotherms detailing the adsorption of HA from aqueous HA solution concentrations ranging from 0.14 to 0.0008% (w/v) to a fixed FP particle concentration of 0.1% (w/v) were investigated. The method of preparing FP particles with HA molecules adsorbed on their surfaces (FP/HA particles) involved suspension of the FP either in hydrated HA solution or in water followed by addition of solid HA, centrifugation of the solids to form a pellet, washing the pellet several times with water until no HA was found in the supernatant and then freeze drying the suspension obtained by dispersing the final pellet. The freeze dried powder was then analysed for adsorbed HA using a Stains-all assay. The influence of order of addition of HA to FP, time for the adsorption process, and temperature of preparation on the adsorption isotherms was investigated. The non-equilibrium adsorption isotherms produced generally followed the same trend, in that as the HA solution concentration increased, the amount of HA adsorbed increased to a maximum at a solution concentration of approximately 0.1% (w/v) and then decreased. The maxima in the adsorption isotherms were close to the change from secondary to tertiary conformation in the HA solutions. Below the maxima, adsorption occurred via interaction of FP with the hydrophobic patches along the HA chains in the secondary structures. Above the maxima, secondary HA molecules aggregate in solution to form tertiary network structures. Adsorption from tertiary structure was reduced because strong interactions between the HA molecules limited the availability of hydrophobic patches for adsorption of HA onto FP. The influence of preparation variables on adsorption was also related to the availability of hydrophobic patches for adsorption.
Previous studies (Eccleston, 1976) showed that the homologue composition of fatty alcohols can ma... more Previous studies (Eccleston, 1976) showed that the homologue composition of fatty alcohols can markedly affect the consistencies and stabilities of ( O / W ) creams prepared with ionic surfactants. Similar results were obtained when the nonionic surfactant cetomacrogol 1000 was used, although the effect was not as marked (Eccleston, 1 9 7 7 ) . ionic surfactants including polyethylene glycol 1000 monostearate (PEG 1000 monostearate, Cithrol 10 MS, Croda). alcohol to form a commercial non-ionic emulsifying wax.
International Journal of Cosmetic Science, Aug 1, 1982
Synopsis Liquid paraffin in water emulsions stabilized by PEG 1000 monostearate and alcohols ceto... more Synopsis Liquid paraffin in water emulsions stabilized by PEG 1000 monostearate and alcohols cetostearyl (c/s) myristyl (C(14)), cetyl (C(16)) or stearyl (C(18)) and ternary systems prepared by dispersing each fatty alcohol and surfactant in water were examined during 30 days using a Ferranti-Shirley cone and plate viscometer. Microscopical diffusion experiments investigated interaction between PEG 1000 monostearate solution and each alcohol at high and low temperature. The rheological properties of each ternary system and corresponding emulsion were similar. Formulations prepared from pure C(14), C(16) or c/s alcohols were semisolid immediately after preparation. Flow curves were in the form of anticlockwise hysteresis loops with spur points. On ageing for 24 h, structure built-up over a time scale similar to that observed in diffusion experiments, so that apparent viscosities increased. However, on further ageing the pure C(14) and C(16) alcohol systems were not as stable as those prepared with c/s alcohol. In contrast, the pure C(18) systems were mobile liquids and the emulsion cracked within days. This correlated with diffusion experiments where little interaction was observed between stearyl alcohol and PEG 1000 monostearate.
The rheological profiles of commercial corticosteroid nasal spray suspensions (Beconase, Nasacort... more The rheological profiles of commercial corticosteroid nasal spray suspensions (Beconase, Nasacort, Flixonase, and Nasonex) were compared using shear and extensional techniques. Thixotropy/shear thinning was investigated (Carri-Med CSL100, concentric cylinder geometry) by (a) the generation of flow curves at low (100 sec-1) and high (1200 sec-1) maximum shear rates and (b) determination of equilibrium shear viscosities at constant shear rates of 10 sec-1, 100 sec-1, or 1200 sec-1. Extensional properties, on which droplet breakup and size depend, were examined using digital camera photography of droplet evolution and the length any trailing filament formed when the suspension was extruded from a 10-ml syringe at 500 microliters/min. All the nasal suspensions were shear thinning and were also thixotropic to varying degrees. The absence of significant thixotropic recovery at short times (5 min) for all the sprays implies that thixotropy is not necessarily the controlling factor for prolonged residence of the spray in the nasal cavity, but rather that it is the high viscosities present in all four sprays, even after structure breakdown. Preliminary extensional flow data identified differences among the four sprays, with extensional filament lengths increasing in the same rank order as the lowest shear rate (10 sec-1) equilibrium viscosities.
Unneutralized Carbopol 940 and 941. Flow curves were similar but showed a marked decrease in cons... more Unneutralized Carbopol 940 and 941. Flow curves were similar but showed a marked decrease in consistency compared with neutralised systems. Carbopol 941 gels increased in hysteresis with increase in concentration. The creep curves approached Hookean behaviour and calculated parameters were of the same order as those derived from neutralized gels. This indicates that in their rheological ground state the neutralized and unneutralized systems are similar, but when tested at high shear rates differences in structure become apparent (i.e. strong electrostatic repulsion between ionized carboxy groups and weak hydrogen bonding between undissociated carboxy groups). Subjective differences at tertiary level (Sherman, 1971)-940 gels were creamy and viscous, 941 preparations were sticky and elastic.
Journal of Pharmaceutical and Biomedical Analysis, Mar 1, 2006
Batch variation in Tween 60 has shown to influence the rheological properties of semisolid emulsi... more Batch variation in Tween 60 has shown to influence the rheological properties of semisolid emulsions. MS (LC-MS, GC-MS, MS(n)) and NMR ((13)C, (1)H, (1)H COSY and HMBC) techniques were used to analyze and compare the composition of two batches of Tween 60 with particular emphasis on the number of POE groups and their distribution within the molecule. Acid and saponification values were also determined. The batches contained different proportions of components (sorbitan polyethoxylates, sorbitan monoester-diester-polyethoxylates and isosorbide monoester-diester-polyethoxylates). The number of POE groups were averaged over the four sites in sorbitan and the two sites in isosorbide molecules. The batches differed from each other in terms of (i) the POE sorbitan stearate/POE sorbitan palmitate ratios (batch 1, 3:2 and batch 2, 4:5), (ii) the ratio of sorbitans to isosorbides (batch 1, 2:3; batch 2, 7:13); and (iii) the acid values (batch 1, 3.1; batch 2, 0). It is concluded that liquid chromatography combined with electrospray mass spectrometry and ion trap separation is a useful tool for establishing the compositional profile of different batches of Tweens. (1)H NMR could provide a simple and rapid pharmacopoeial test for the ratio of sorbitan to isosorbide in Tweens.
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Papers by Gillian Eccleston