Papers by Gillian Eccleston
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.
Cosmetics and toiletries, 1998
Journal of Pharmacy and Pharmacology, Sep 1, 1977
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.
Journal of Pharmacy and Pharmacology, Oct 1, 2000
The rheological pro®les of four commercial nasal spray suspensions (Beconase, Flixonase, Nasacort... more The rheological pro®les of four commercial nasal spray suspensions (Beconase, Flixonase, Nasacort and Nasonex) were compared using rotational viscometry. Two of the nasal sprays (Beconase and Nasonex) were further examined in both shear and extension using a capillary rheometer under conditions similar to those experienced at the spray nozzle (i.e. extremely high shear rates with signi®cant stretching or extensional¯ow). In rotation, the shear viscosity fell rapidly with increase in shear rate. Plots of the viscosity derived at the lower shear rates in rotation were extrapolated to include the highshear rate capillary values. At very high shear rates, the shear viscosity of Beconase was higher than that of Nasonex with the cross-over occurring in the extrapolated region at approximately 10 000 s À1. In the transition region between laminar and turbulent¯ow (shear rate 6±8 6 10 4 s À1) there was a minimum in the shear viscosity to less than that of water for Nasonex and similar to water for Beconase, and a plateau region in extensional viscosity for Beconase but not Nasonex. These anomalies were due to the extensive aeration of both samples when sprayed. Whereas Beconase had de-aerated within 30 min of the experiment, Nasonex had not de-aerated completely after six weeks. The very low viscosity at the shear rates at the nozzle imply that it is unlikely that the low viscosity of the spray on delivery to the nose is a key factor in prolonging its residence time. The extensional viscosity for these rather¯uid samples was over 1000-times the shear viscosity (not 3-times as with Newtonian¯uids) and both sprays exhibited strain hardening over the range covered. The high extensional stress in the nozzle enables the¯uid to form as reasonably sized droplets rather than ®ne atomized droplets, which rather than settling in the nose, would be prone to redistribution through the normal respiratory function. Both sprays resisted degradation despite the high shear rates and extensional stresses experienced.
European Journal of Pharmaceutics and Biopharmaceutics, Sep 1, 2007
Over recent decades, the use of in vitro diffusion cell studies to assess skin permeability has e... more Over recent decades, the use of in vitro diffusion cell studies to assess skin permeability has evolved into a major research tool, providing key insights into the relationships between skin, drug and formulation. Sometimes, such studies involve synthetic membranes as this approach can yield useful inferences with respect to drug-skin partitioning and diffusion phenomena. Yet despite the popularity of such studies, it is still not at all known whether typical solute transport across synthetic barriers results in a normal distribution of permeability coefficients or alternatively some type of skewed distribution. The present study aims to shed light on this issue. To this end, five compounds (testosterone, oestradiol, corticosterone, aldosterone and adenosine) exhibiting a broad range of octanol-water partition coefficient values were selected as test penetrants. The protocol involved taking multiple replicate measurements of each drug's passive steady state flux through poly(dimethylsiloxane) membrane. Each penetrant's resultant permeability coefficient database was subjected to a Kolmogorov-Smirnov (KS) test for normality. It was found that the permeability coefficients of all five drugs were distributed in a Gaussian-normal fashion. The theoretical significance and practical impact of these findings are discussed.
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.
Journal of Colloid and Interface Science, Oct 1, 1976
Liquid paraffin-in-water emulsions prepared with cetrimide and alcohols cetostearyl (A), cetyl (B... more Liquid paraffin-in-water emulsions prepared with cetrimide and alcohols cetostearyl (A), cetyl (B), and stearyl (C) were examined by microscopical, particle size analytical and theological techniques at 25°C as they aged over 30 days. The rheological techniques included continuous shear and small strain creep and oscillatory experiments. The emulsions were white shiny semisolids of similar consistencies immediately after preparation. With age, the consistency of emulsion A did not change significantly. In contrast, the consistencies of the pure alcohol emulsions B and C reduced on storage. Reductions were most marked in emulsion C, which was nonlinear viscoelastic and mobile after 10 days, with marked creaming after 30 days. Emulsion B, although mobile after 20 days, only exhibited slight creaming during the 30 days test period. Particle sizes of the emulsions were similar, and in emulsions B and C increased only slightly with age. Thus theological stabilities were not correlated with the variations in particle size distributions, but rather with the stabilities of viscoelastic networks formed in the continuous phases when aqueous cetrimide interacted with long chain alcohol. The cetostearyl alcohol networks formed in emulsion A were extensive, in emulsion B the cetyl alcohol networks were initially extensive, but became tenuous on storage, and in emulsion C, although viscoelastic stearyl alcohol networks formed initially, they rapidly disintegrated. Microscopical examinations supported this view. The influence of homolog composition and alcohol chain length on the ternary structures responsible for the gel networks are discussed.
European Journal of Pharmaceutical Sciences, Mar 1, 2007
The aim of this study was to employ the novel skin sandwich system in order to quantify the influ... more The aim of this study was to employ the novel skin sandwich system in order to quantify the influence of the octanol-water partition coefficient on follicular drug absorption in human skin. To this end, seven different drugs-estradiol, corticosterone, hydrocortisone, aldosterone, cimetidine, deoxyadenosine and adenosine-exhibiting a wide range of log octanol-water partition coefficients (log K o/w) but relatively similar molecular weights were selected as candidate solutes. Application of the skin sandwich technique yielded an interesting relationship between % follicular contribution and log K o/w. The follicular contribution to total flux was small (4 and 2%) for the two most lipophilic drugs but varied between 34 and 60% for the remaining drugs of intermediate and low log K o/w values. Lipophilicity seems to be an important modulator of drug absorption into follicular orifices only above a critical log K o/w threshold. Below this critical log K o/w value, lipophilicity does not apparently influence the follicular contribution in an obvious way and the process is probably governed by other molecular properties. Identification of these other active properties would require performing this kind of a study on a much larger set of candidate drugs.
Journal of Pharmacy and Pharmacology, Dec 1, 1979
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.
Drug Development and Industrial Pharmacy, 2000
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.
International Journal of Pharmaceutics, Jun 1, 2008
The aim of the present study was to use the in vitro human skin sandwich system in order to quant... more The aim of the present study was to use the in vitro human skin sandwich system in order to quantify the influence of formulation variables on intrafollicular hydrocortisone permeation. The investigated variables were the pH and the viscosity of the topical formulation as well as the presence of chemical enhancers (carvone, menthone, oleic acid and sodium lauryl sulphate). Furthermore, skin sandwich hydration was also varied in order to determine if the method itself can be run using only partially hydrated skin tissues. It was determined that the follicular contribution to hydrocortisone flux decreased marginally with increasing alkalinity in the pH range 3-8.8. Intrafollicular penetration was markedly reduced when HPMC gels were used instead of an aqueous solution. Pretreating the skin with chemical enhancers also reduced the follicular contribution to flux, probably due to permeabilisation of the continuous stratum corneum. Furthermore, it was not possible to satisfactorily modify the skin sandwich method so that it could be deployed using less hydrated skin.
International Journal of Pharmaceutics, Dec 1, 1985
International Journal of Pharmaceutics, Apr 26, 2006
Lyophilised wafers are being developed as drug delivery systems that can be applied directly to t... more Lyophilised wafers are being developed as drug delivery systems that can be applied directly to the surface of suppurating wounds. They are produced by the freeze-drying of polymer solutions and gels. This study investigates the possibility of sterilising these glassy, solid dosage forms with gamma-irradiation and determining the rheological properties of rehydrated wafers post-irradiation. One series of wafers was formulated using sodium alginate (SA) modified with increasing amounts of methylcellulose (MC), the other being composed of xanthan gum (XG) and MC. Batches were divided into three lots, two of which were exposed to 25 and 40 kGrays (kGy) of Cobalt-60 gamma-irradiation, respectively, the third being retained as a non-irradiated control. Apparent viscosities of solutions/gels resulting from the volumetric addition of distilled water to individual wafers were determined using continuous shear, flow-rheometry. Flow behaviour on proprietary suppurating surfaces was also determined. Large reductions in viscosity were apparent for irradiated SA samples while those of XG appeared to be largely unaffected. In addition, an increase in the yield stress of xanthan formulations was observed. Xanthan wafers appeared to withstand large doses of irradiation with no detrimental effect on the rheology of reconstituted gels. This offers the possibility of manufacturing sterilisable delivery systems for wounds.
International Journal of Pharmaceutics, 2005
Lyophilised wafers have potential as drug delivery systems for suppurating wounds. A dual series ... more Lyophilised wafers have potential as drug delivery systems for suppurating wounds. A dual series of wafers made from low molecular weight sodium alginate (SA) and xanthan gum (XG) respectively, modified with high molecular weight methylcellulose (MC) were produced. The swelling and flow properties of these wafers on model suppurating surfaces were both qualitatively and quantitatively investigated. The wafers instantaneously adhered to the surfaces, absorbing water and transforming from glassy, porous solids to highly viscous gels. The rate at which this occurred varied for the series studied with clear distinctions between the behaviour of SA and XG systems. For SA wafers there was a distinct relationship between the flow-rate and MC content. Increased amounts of MC decreased the rate at which the SA wafers flowed across a model gelatine surface. Flow rheometry was used to quantify the effect of increased MC content on both series of wafers and for the SA series, highlighted a substantial increase in apparent viscosity as a function of incremental increases in MC content. These results reflected those from the gelatine model. Observations of the reluctance of a swollen, unmodified XG wafer to flow compared with the relative ease of unmodified, low molecular weight SA was attributed to the yield stress characteristic of xanthan gels. XG is known to exhibit complex, loosely bound network structures in solution via the association of helical backbone structures. The inclusion of sodium fluorescein as a visible model for a soluble drug highlighted the potential of lyophilised wafers as useful drug delivery systems for suppurating wounds.
Journal of Pharmacy and Pharmacology, Dec 1, 1974
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.
Taylor & Francis eBooks, Dec 4, 2015
International Journal of Cosmetic Science, Oct 1, 1985
Synopsis Theories of emulsion stability are discussed in relation to dilute, concentrated and sem... more Synopsis Theories of emulsion stability are discussed in relation to dilute, concentrated and semisolid emulsions. It is shown that whilst a unified theory cannot be applied quantitatively to emulsion systems, a better understanding of thc various mechanisms of stabilization and breakdown is emerging. Established concepls. eg, the HLB concept, are now given a less empirical gloss. The application of colloid stability theory, even to very dilute emulsions, is difficult. This is because of the polydispersity of the systems and because surfactant and stabilizers may be free to move on the globule surfaces, as well as dissolve in the dispersed or continuous phases. Further difficulties arise because flocculation is not necessarily a sign of emulsion instability in the practical sense, as creamed or flocculated emulsions often may be redispersed by shaking. Crucial to emulsion stability is the prevention of coalescence, and this is governed by the nature of the adsorbed emulsifier film. The flocculation and coalescence that can be understood in dilute emulsions from the DVLO theory and the metastability of thin films against rupture do not address themselves to flocculation and coalescence in concentrated, structured or semi-solid emulsions. These may possess surfactant multilayers rather than monolayers at the oillwater interfaces and the bulk phases are frequently structured. Some emulsions invert at critical temperatures. In semi-solid emulsions, stability is controlled by the phase behaviour of the emulsifier components, rather than by the forces governing stability in dilute colloids and thin films. Stability is usually considered to be product stability during storage. The stability of an emulsion in use, eg, during and after application to the skin, is a topic of equal importance but little documented. This related problem is also discussed.
Toxicology in Vitro, Oct 1, 2009
Skin barrier function is a key parameter to consider when performing in vitro percutaneous absorp... more Skin barrier function is a key parameter to consider when performing in vitro percutaneous absorption studies. Whilst tritiated water flux measurements were often used to assess skin integrity, recent decades have witnessed the emergence of the more rapid and user-friendly transepidermal water loss (TEWL) approach. Yet to date, the nature of the correlation between TEWL and skin barrier function in vitro has still not been comprehensively established. In this study, a novel TEWL device, operating on a cold-induced vapour sink principle, was used to probe the barrier function of full-thickness porcine skin. The method was sufficiently sensitive to show the influence of punctures on barrier function although the observed non-linear pattern suggested tissue swelling processes and/or capillary action could be occurring. The results of various surfactant application experiments strongly suggested that TEWL was indeed largely predictive of skin sample integrity. A key finding was that basal TEWL was linearly correlated with basal tritiated water flux (r 2 = 0.80, n = 63). Thus, a dedicated TEWL method can be used as a good alternative to water flux measurements for assessing full-thickness skin barrier function.
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