Adrian Williams - Academia.edu (original) (raw)

Papers by Adrian Williams

Biomaterials science, Jan 11, 2016

Functionalised nanomaterials are gaining popularity for use as drug delivery vehicles and, in par... more Functionalised nanomaterials are gaining popularity for use as drug delivery vehicles and, in particular, mucus penetrating nanoparticles may improve drug bioavailability via the oral route. To date, few polymers have been investigated for their muco-penetration, and the effects of systematic structural changes to polymer architectures on the penetration and diffusion of functionalised nanomaterials through mucosal tissue have not been reported. We investigated the influence of poly(2-oxazoline) alkyl side chain length on nanoparticle diffusion; poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), and poly(2-n-propyl-2-oxazoline) were grafted onto the surface of thiolated silica nanoparticles and characterised by FT-IR, Raman and NMR spectroscopy, thermogravimetric analysis, and small angle neutron scattering. Diffusion coefficients were determined in water and in a mucin dispersion (using Nanoparticle Tracking Analysis), and penetration through a mucosal barrier was assessed usin...

Temperature-Responsive Polymers

This chapter provides insights into the applications of different temperature-responsive polymers... more This chapter provides insights into the applications of different temperature-responsive polymers (TRPs) grafted to solid core inorganic nanoparticles, and how their thermo-responsive nature can provide solutions to many of the problems associated with other nanoparticles. It describes the most common forms of TRPs reported in the literature, pNIPAM and poloxamers, as well as some more unusual TRPs, and considers how their use and function can be varied depending on the particle core.

Toxicology in Vitro, 2020

Here we report a new planarian (Dugesia lugubris) fluorescent assay as a rapid and cheap prescree... more Here we report a new planarian (Dugesia lugubris) fluorescent assay as a rapid and cheap prescreening tool to predict strong skin irritants. Our aim was to provide a simple and costeffective in vivo method that avoided use of higher vertebrates. Adapting previously reported methods for planaria mobility alongside an acute toxicity assay, different irritants at five concentrations (0.1%, 0.05%, 0.025%, 0.01% and 0.005% w/v) were tested but both methods failed to discriminate the irritation potential of the test compounds. Therefore, a new alternative fluorescence assay was developed, hypothesising that increasing damage from the irritant to the planarian outer protective membrane will increase accumulation of sodium fluorescein in the flatworm. Fourteen test chemicals were selected representing strong, moderate, mild and non-irritants. In general, results showed increasing sodium fluorescein accumulation within planaria following acute exposure to increasingly strong skin irritants; on exposure to the strong irritants, benzalkonium chloride, citronellal, methyl palmitate, 1-bromohexane and carvacrol, fluorescence within the planaria was significantly greater (P<0.05) than the negative controls and the common non-irritants PEG-400, dipropylene glycol and isopropyl alcohol; fluorescence values of planaria tested with negative controls and non-irritants were not significantly different. For all test compounds, fluorescence intensity of the planaria was compared with literature primary irritation index data and generated a statistically significant (P<0.005) Pearson correlation (r) of 0.87. Thus, the planarian fluorescent assay is a promising tool for rapid early testing of potential strong skin irritants, and non-irritants, and avoids use of higher vertebrate models.

RSC Advances, 2018

Polymer-coated thiolated silica nanoparticles were synthesised by self-condensation of 3-mercapto... more Polymer-coated thiolated silica nanoparticles were synthesised by self-condensation of 3-mercaptopropyltrimethoxysilane in the presence of hydroxyethylcellulose.

Journal of Applied Crystallography, 2017

The effect of introducing conformational information to theDASHimplementation of crystal structur... more The effect of introducing conformational information to theDASHimplementation of crystal structure determination from powder diffraction data is investigated using 51 crystal structures, with the aim of allowing increasingly complex crystal structures to be solved more easily. The findings confirm that conformational information derived from the Cambridge Structural Database is indeed of value, considerably increasing the chances of obtaining a successful structure determination. Its routine use is therefore encouraged.

Journal of Applied Crystallography, 2017

Significant gains in the performance of the simulated annealing algorithm in theDASHsoftware pack... more Significant gains in the performance of the simulated annealing algorithm in theDASHsoftware package have been realized by using theiraceautomatic configuration tool to optimize the values of three key simulated annealing parameters. Specifically, the success rate in finding the global minimum in intensity χ2space is improved by up to an order of magnitude. The general applicability of these revised simulated annealing parameters is demonstrated using the crystal structure determinations of over 100 powder diffraction datasets.

International Journal of Pharmaceutics, 2021

Targeting drug delivery to hair follicles is valuable to treat conditions such as alopecia's and ... more Targeting drug delivery to hair follicles is valuable to treat conditions such as alopecia's and acne, and this shunt route may also allow drug delivery to deeper skin layers and the systemic circulation by avoiding the intact stratum corneum. Here, we investigated the effects of nanoparticle surface chemistry on their delivery into hair follicles by synthesizing fluorescent thiolated silica nanoparticles and functionalizing with 750 Da and 5000 Da methoxypolyethylene glycol maleimide (PEG). The stability of the nanoparticles in skin homogenate was verified before tape stripping of porcine-dosed tissue showed the distribution of the free fluorescent dye and different nanoparticles in the skin. Analysis of microscopic images of the skin sections revealed penetration of nanoparticles functionalized with PEG into the appendages whereas thiolated nanoparticles stayed on the surface of the skin and were removed by tape stripping. Nanoparticles functionalized with PEG 5000 Da penetrated deeper into the hair follicles compared to counterparts functionalized with PEG 750 Da. PEGylation can thus enhance targeted delivery of nanoparticulates into hair follicles.

International Journal of Pharmaceutics, 2003

... Drug Delivery Second Edition, Revised and Expanded edited by Richard H. Guy Universities of G... more ... Drug Delivery Second Edition, Revised and Expanded edited by Richard H. Guy Universities of Geneva and Lyon, Archamps, France and University of Geneva, Geneva, Switzerland Jonathan Hadgraft NRI, University of Greenwich, Chatham, England Marcel Dekker, Inc. ...

International journal of pharmaceutics, Jan 19, 2004

Incorporating edge activators (surfactants) into liposomes was shown previously to improve estrad... more Incorporating edge activators (surfactants) into liposomes was shown previously to improve estradiol vesicular skin delivery; this phenomenon was concentration dependent with low or high concentrations being less effective. Replacing surfactants with limonene produced similar behaviour, but oleic acid effects were linear with concentration up to 16% (w/w), beyond which it was incompatible with the phospholipid. This present study thus employed high sensitivity differential scanning calorimetry to probe interactions of additives with dipalmitoylphosphatidylcholine (DPPC) membranes to explain such results. Cholesterol was included as an example of a membrane stabiliser that removed the DPPC pre-transition and produced vesicles with a higher transition temperature (T(m)). Surfactants also removed the lipid pre-transition but reduced T(m) and co-operativity of the main peak. At higher concentrations, surfactants also formed new species, possibly mixed micelles with a lower T(m). The for...

International Journal of Pharmaceutics, 2000

The aim of this study was to investigate the importance of liposome structure in oestradiol skin ... more The aim of this study was to investigate the importance of liposome structure in oestradiol skin delivery as a tool for understanding the delivery mechanism from lipid vesicles. Liposomes of phosphatidylcholine (PC) (1), PC, sodium cholate; 86:14 w/w (II), PC, Span 80; 86.7:13.3 w/w (III) and PC, oleic acid: 84:16 w/w (IV) with 1 mg/ml radiolabelled drug were prepared. Saturated radiolabelled oestradiol solutions containing the components of I-IV were separately prepared in 90% w/w propylene glycol in water. In addition, saturated solutions containing cholate, Span, oleic acid and ethanol at the same concentrations used in vesicles were formulated. Oestradiol permeation through human epidermis was studied. Formulations I-IV increased oestradiol flux by 8.6, 17, 17 and 13-fold when used as vesicles compared with control and by 2.9. 4.0, 4.7 and 6.9-fold when used in solution with drug. Testing individual components in solution, relative fluxes were 2.9, 0.87, 1.1, 2.9 and 1.1 for PC, cholate. Span, oleic acid and 7% ethanol, respectively. Accordingly, it is important to prepare phospholipids as vesicles for efficient oestradiol skin delivery even after inclusion of oleic acid. Penetration enhancement is not the main mechanism for improved flux. Liposome components in solution have additive effect with a possible synergism in some cases.

International Journal of Pharmaceutics, 2000

The aims of this study were to refine ultradeformable liposomes for oestradiol skin delivery and ... more The aims of this study were to refine ultradeformable liposomes for oestradiol skin delivery and to evaluate Span 80 and Tween 80 as edge activators compared with sodium cholate. Vesicles containing phosphatidylcholine (PC) mixed with edge activators and oestradiol were prepared. Entrapment efficiency and vesicle size were determined. Interactions between activators and vesicles were investigated using differential scanning calorimetry. Transepidermal permeation of oestradiol from vesicles was studied compared to saturated aqueous control in vitro. The maximum flux (J(max)) and its time (T(max)) were calculated from the flux curves and skin deposition was assessed. The compositions of refined formulations were predicted, liposomes prepared, and tested against control. Entrapment efficiency depended on PC concentration with some contribution from sodium cholate and Tween 80. Vesicle sizes ranged from 124 to 135 nm. Edge activators interacted with lipid bilayers and disrupted packing. The refined edge activator concentrations in PC vesicles were 14.0, 13.3 and 15.5% w/w for sodium cholate, Span 80 and Tween 80, respectively; they increased J(max) by 18, 16 and 15-fold and skin deposition by 8, 7 and 8-fold compared with control. Ultradeformable vesicles thus improved skin delivery of oestradiol compared to control and Span 80 and Tween 80 were equivalent to sodium cholate as edge-activators.

Journal of Pharmacy and Pharmacology, 2006

Using liposomes to deliver drugs to and through human skin is controversial, as their function va... more Using liposomes to deliver drugs to and through human skin is controversial, as their function varies with type and composition. Thus they may act as drug carriers controlling release of the medicinal agent. Alternatively, they may provide a localized depot in the skin so minimizing systemic effects or can be used for targeting delivery to skin appendages (hair follicles and sweat glands). Liposomes may also enhance transdermal drug delivery, increasing systemic drug concentrations. With such a multiplicity of functions, it is not surprising that mechanisms of liposomal delivery of therapeutic agents to and through the skin are unclear. Accordingly, this article provides an overview of the modes and mechanisms of action of different vesicles as drug delivery vectors in human skin. Our conclusion is that vesicles, depending on the composition and method of preparation, can vary with respect to size, lamellarity, charge, membrane fluidity or elasticity and drug entrapment. This variab...

Journal of Pharmacy and Pharmacology, 2001

The potential use of ultradeformable and standard liposomes as skin drug delivery systems was inv... more The potential use of ultradeformable and standard liposomes as skin drug delivery systems was investigated in-vitro. An improved experimental design gave a good measure for skin deposition of drug. This avoided the contamination that can occur due to incomplete washing of the donor before direct determination of the amount of drug in the skin. The design used aqueous ethanolic receptor which is believed to diffuse into skin, disrupting deposited liposomes (if any) and thus releasing both bound and free drug. The receptor fluid was refined by testing different concentrations of ethanol. The applied dose was also optimized. Using the improved design and the optimum dose, an ultradeformable formulation was compared with four traditional liposomes for skin delivery of 5-fluorouracil (5-FU). The best receptor was 50% aqueous ethanol and the optimum dose was 20 μL. The ultradeformable formulation was superior to standard liposomes in the skin delivery of 5-FU. Of the traditional liposomes...

European Journal of Pharmaceutical Sciences, 2008

Advanced Drug Delivery Reviews, 2004

One long-standing approach for improving transdermal drug delivery uses penetration enhancers (al... more One long-standing approach for improving transdermal drug delivery uses penetration enhancers (also called sorption promoters or accelerants) which penetrate into skin to reversibly decrease the barrier resistance. Numerous compounds have been evaluated for penetration enhancing activity, including sulphoxides (such as dimethylsulphoxide, DMSO), Azones (e.g. laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (for example propylene glycol, PG, a common excipient in topically applied dosage forms), surfactants (also common in dosage forms) and terpenes. Many potential sites and modes of action have been identified for skin penetration enhancers; the intercellular lipid matrix in which the accelerants may disrupt the packing motif, the intracellular keratin domains or through increasing drug partitioning into the tissue by acting as a solvent for the permeant within the membrane. Further potential mechanisms of action, for example with the enhancers acting on desmosomal connections between corneocytes or altering metabolic activity within the skin, or exerting an influence on the thermodynamic activity/solubility of the drug in its vehicle are also feasible, and are also considered in this review.

Journal of Pharmacy and Pharmacology, 2001

Human skin delivery of estradiol from ultradeformable and traditional liposomes was explored, com... more Human skin delivery of estradiol from ultradeformable and traditional liposomes was explored, comparing occlusive and open application, with the aim of examining the role of skin hydration. Partially hydrated epidermis was used for open hydration, but fully hydrated membranes were used for occluded studies. In addition, we developed a novel technique to investigate the role of shunt route penetration in skin delivery of liposomal estradiol. This compared delivery through epidermis with that through a stratum corneum (SC)/epidermis sandwich from the same skin with the additional SC forming the top layer of the sandwich. This design was based on the fact that orifices of shunts only occupy 0.1% of skin surface area and thus for SC/epidermis sandwiches there will be a negligible chance for shunts to superimpose. The top SC thus blocks most shunts available on the bottom membrane. If shunts play a major role then the delivery through sandwiches should be much reduced compared with that ...

Poly(N-vinyl pyrrolidone) (PVP), poly(2-methyl-2-oxazoline) (PMOZ), poly(2-ethyl-2-oxazoline) (PE... more Poly(N-vinyl pyrrolidone) (PVP), poly(2-methyl-2-oxazoline) (PMOZ), poly(2-ethyl-2-oxazoline) (PEOZ), poly(2-n-propyl-2-oxazoline) (PnPOZ), and poly(2-isopropyl-2-oxazoline) (PiPOZ) were used to prepare solid dispersions with ibuprofen (IB), a model poorly-water soluble drug. Dispersions, prepared by solvent evaporation, were investigated using powder X-ray diffractometry, differential scanning calorimetry, and FTIR spectroscopy; hydrogen bonds formed between IB and all polymers in solid dispersions. PMOZ, the most hydrophilic polymer, showed the poorest ability to reduce or inhibit the crystallinity of IB. In contrast, the more hydrophobic polymers PVP, PEOZ, PnPOZ, and PiPOZ provided greater but similar abilities to reduce IB crystallinity, despite the differing polymer hydrophobicity and that PiPOZ is semi-crystalline. These results indicate that crystallinity disruption is predominantly due to hydrogen bonding between the drug molecules and the polymer. However, carrier properti...

Pharmaceutics

Background: We developed a novel polymer insect repellent conjugate for extended release and decr... more Background: We developed a novel polymer insect repellent conjugate for extended release and decreased skin permeation of the volatile insect repellent p-menthane-3,8-diol (PMD). Methods: PMD was conjugated with acryloyl chloride via an ester bond to form acryloyl–PMD, which was subsequently copolymerised with acrylic acid at varying molar ratios. Copolymer structures were characterised by 1H NMR and FT-IR, analysed by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), molecular weights and reactivity ratios determined, and repellent loading assessed. Results: Using porcine liver esterases, ~45% of the insect repellent was released over five days. Penetration and permeation studies of the copolymer and free repellent using excised, full-thickness porcine ear skin showed no detectable permeation of the copolymer through skin compared to the PMD. Moreover, tape stripping revealed that over 90% of the copolymer remained on the outer surface of the skin, whereas ...

Langmuir : the ACS journal of surfaces and colloids, Jul 17, 2018

Nanoparticle characteristics, including their size, are governed by the reagents employed and the... more Nanoparticle characteristics, including their size, are governed by the reagents employed and the reaction parameters. Here, we systemically vary the catalyst, oxygen content, temperature, and solvent to modify the size and zeta-potential of thiolated organosilica nanoparticles. The particles were synthesized by self-condensation of 3-mercaptopropyltrimethoxysilane in a range of organic solvents in contact with oxygen, with NaOH and other catalysts. The particle size increased with increasing reaction temperature (70 ± 1 nm at 50 °C; 50 ± 1 nm at room temperature) but decreased when air was bubbled through the reaction mixture compared to no bubbling. A significant decrease in the particle size was seen when increasing the dielectric constant of the solvent and when increasing the catalyst concentration; from these, we provide empirical equations that can be used to design particle sizes by manipulating the dielectric constant of the solvent (or cosolvents) or by varying the NaOH ca...

The Science of the total environment, Jan 22, 2017

Human uptake of flame retardants (FRs) such as polybrominated diphenyl ethers (PBDEs) via indoor ... more Human uptake of flame retardants (FRs) such as polybrominated diphenyl ethers (PBDEs) via indoor dust ingestion is commonly considered as 100% bioaccessible, leading to potential risk overestimation. Here, we present a novel in vitro colon-extended physiologically-based extraction test (CE-PBET) with Tenax TA® as an absorptive "sink" capable to enhance PBDE gut bioaccessibility. A cellulose-based dialysis membrane (MW cut-off 3.5kDa) with high pH and temperature tolerance was used to encapsulate Tenax TA®, facilitating efficient physical separation between the absorbent and the dust, while minimizing re-absorption of the ingested PBDEs to the dust particles. As a proof of concept, PBDE-spiked indoor dust samples (n=3) were tested under four different conditions; without any Tenax TA® addition (control) and with three different Tenax TA® loadings (i.e. 0.25, 0.5 or 0.75g). Our results show that in order to maintain a constant sorptive gradient for the low MW PBDEs, 0.5g of ...

Biomaterials science, Jan 11, 2016

Functionalised nanomaterials are gaining popularity for use as drug delivery vehicles and, in par... more Functionalised nanomaterials are gaining popularity for use as drug delivery vehicles and, in particular, mucus penetrating nanoparticles may improve drug bioavailability via the oral route. To date, few polymers have been investigated for their muco-penetration, and the effects of systematic structural changes to polymer architectures on the penetration and diffusion of functionalised nanomaterials through mucosal tissue have not been reported. We investigated the influence of poly(2-oxazoline) alkyl side chain length on nanoparticle diffusion; poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), and poly(2-n-propyl-2-oxazoline) were grafted onto the surface of thiolated silica nanoparticles and characterised by FT-IR, Raman and NMR spectroscopy, thermogravimetric analysis, and small angle neutron scattering. Diffusion coefficients were determined in water and in a mucin dispersion (using Nanoparticle Tracking Analysis), and penetration through a mucosal barrier was assessed usin...

Temperature-Responsive Polymers

This chapter provides insights into the applications of different temperature-responsive polymers... more This chapter provides insights into the applications of different temperature-responsive polymers (TRPs) grafted to solid core inorganic nanoparticles, and how their thermo-responsive nature can provide solutions to many of the problems associated with other nanoparticles. It describes the most common forms of TRPs reported in the literature, pNIPAM and poloxamers, as well as some more unusual TRPs, and considers how their use and function can be varied depending on the particle core.

Toxicology in Vitro, 2020

Here we report a new planarian (Dugesia lugubris) fluorescent assay as a rapid and cheap prescree... more Here we report a new planarian (Dugesia lugubris) fluorescent assay as a rapid and cheap prescreening tool to predict strong skin irritants. Our aim was to provide a simple and costeffective in vivo method that avoided use of higher vertebrates. Adapting previously reported methods for planaria mobility alongside an acute toxicity assay, different irritants at five concentrations (0.1%, 0.05%, 0.025%, 0.01% and 0.005% w/v) were tested but both methods failed to discriminate the irritation potential of the test compounds. Therefore, a new alternative fluorescence assay was developed, hypothesising that increasing damage from the irritant to the planarian outer protective membrane will increase accumulation of sodium fluorescein in the flatworm. Fourteen test chemicals were selected representing strong, moderate, mild and non-irritants. In general, results showed increasing sodium fluorescein accumulation within planaria following acute exposure to increasingly strong skin irritants; on exposure to the strong irritants, benzalkonium chloride, citronellal, methyl palmitate, 1-bromohexane and carvacrol, fluorescence within the planaria was significantly greater (P<0.05) than the negative controls and the common non-irritants PEG-400, dipropylene glycol and isopropyl alcohol; fluorescence values of planaria tested with negative controls and non-irritants were not significantly different. For all test compounds, fluorescence intensity of the planaria was compared with literature primary irritation index data and generated a statistically significant (P<0.005) Pearson correlation (r) of 0.87. Thus, the planarian fluorescent assay is a promising tool for rapid early testing of potential strong skin irritants, and non-irritants, and avoids use of higher vertebrate models.

RSC Advances, 2018

Polymer-coated thiolated silica nanoparticles were synthesised by self-condensation of 3-mercapto... more Polymer-coated thiolated silica nanoparticles were synthesised by self-condensation of 3-mercaptopropyltrimethoxysilane in the presence of hydroxyethylcellulose.

Journal of Applied Crystallography, 2017

The effect of introducing conformational information to theDASHimplementation of crystal structur... more The effect of introducing conformational information to theDASHimplementation of crystal structure determination from powder diffraction data is investigated using 51 crystal structures, with the aim of allowing increasingly complex crystal structures to be solved more easily. The findings confirm that conformational information derived from the Cambridge Structural Database is indeed of value, considerably increasing the chances of obtaining a successful structure determination. Its routine use is therefore encouraged.

Journal of Applied Crystallography, 2017

Significant gains in the performance of the simulated annealing algorithm in theDASHsoftware pack... more Significant gains in the performance of the simulated annealing algorithm in theDASHsoftware package have been realized by using theiraceautomatic configuration tool to optimize the values of three key simulated annealing parameters. Specifically, the success rate in finding the global minimum in intensity χ2space is improved by up to an order of magnitude. The general applicability of these revised simulated annealing parameters is demonstrated using the crystal structure determinations of over 100 powder diffraction datasets.

International Journal of Pharmaceutics, 2021

Targeting drug delivery to hair follicles is valuable to treat conditions such as alopecia's and ... more Targeting drug delivery to hair follicles is valuable to treat conditions such as alopecia's and acne, and this shunt route may also allow drug delivery to deeper skin layers and the systemic circulation by avoiding the intact stratum corneum. Here, we investigated the effects of nanoparticle surface chemistry on their delivery into hair follicles by synthesizing fluorescent thiolated silica nanoparticles and functionalizing with 750 Da and 5000 Da methoxypolyethylene glycol maleimide (PEG). The stability of the nanoparticles in skin homogenate was verified before tape stripping of porcine-dosed tissue showed the distribution of the free fluorescent dye and different nanoparticles in the skin. Analysis of microscopic images of the skin sections revealed penetration of nanoparticles functionalized with PEG into the appendages whereas thiolated nanoparticles stayed on the surface of the skin and were removed by tape stripping. Nanoparticles functionalized with PEG 5000 Da penetrated deeper into the hair follicles compared to counterparts functionalized with PEG 750 Da. PEGylation can thus enhance targeted delivery of nanoparticulates into hair follicles.

International Journal of Pharmaceutics, 2003

... Drug Delivery Second Edition, Revised and Expanded edited by Richard H. Guy Universities of G... more ... Drug Delivery Second Edition, Revised and Expanded edited by Richard H. Guy Universities of Geneva and Lyon, Archamps, France and University of Geneva, Geneva, Switzerland Jonathan Hadgraft NRI, University of Greenwich, Chatham, England Marcel Dekker, Inc. ...

International journal of pharmaceutics, Jan 19, 2004

Incorporating edge activators (surfactants) into liposomes was shown previously to improve estrad... more Incorporating edge activators (surfactants) into liposomes was shown previously to improve estradiol vesicular skin delivery; this phenomenon was concentration dependent with low or high concentrations being less effective. Replacing surfactants with limonene produced similar behaviour, but oleic acid effects were linear with concentration up to 16% (w/w), beyond which it was incompatible with the phospholipid. This present study thus employed high sensitivity differential scanning calorimetry to probe interactions of additives with dipalmitoylphosphatidylcholine (DPPC) membranes to explain such results. Cholesterol was included as an example of a membrane stabiliser that removed the DPPC pre-transition and produced vesicles with a higher transition temperature (T(m)). Surfactants also removed the lipid pre-transition but reduced T(m) and co-operativity of the main peak. At higher concentrations, surfactants also formed new species, possibly mixed micelles with a lower T(m). The for...

International Journal of Pharmaceutics, 2000

The aim of this study was to investigate the importance of liposome structure in oestradiol skin ... more The aim of this study was to investigate the importance of liposome structure in oestradiol skin delivery as a tool for understanding the delivery mechanism from lipid vesicles. Liposomes of phosphatidylcholine (PC) (1), PC, sodium cholate; 86:14 w/w (II), PC, Span 80; 86.7:13.3 w/w (III) and PC, oleic acid: 84:16 w/w (IV) with 1 mg/ml radiolabelled drug were prepared. Saturated radiolabelled oestradiol solutions containing the components of I-IV were separately prepared in 90% w/w propylene glycol in water. In addition, saturated solutions containing cholate, Span, oleic acid and ethanol at the same concentrations used in vesicles were formulated. Oestradiol permeation through human epidermis was studied. Formulations I-IV increased oestradiol flux by 8.6, 17, 17 and 13-fold when used as vesicles compared with control and by 2.9. 4.0, 4.7 and 6.9-fold when used in solution with drug. Testing individual components in solution, relative fluxes were 2.9, 0.87, 1.1, 2.9 and 1.1 for PC, cholate. Span, oleic acid and 7% ethanol, respectively. Accordingly, it is important to prepare phospholipids as vesicles for efficient oestradiol skin delivery even after inclusion of oleic acid. Penetration enhancement is not the main mechanism for improved flux. Liposome components in solution have additive effect with a possible synergism in some cases.

International Journal of Pharmaceutics, 2000

The aims of this study were to refine ultradeformable liposomes for oestradiol skin delivery and ... more The aims of this study were to refine ultradeformable liposomes for oestradiol skin delivery and to evaluate Span 80 and Tween 80 as edge activators compared with sodium cholate. Vesicles containing phosphatidylcholine (PC) mixed with edge activators and oestradiol were prepared. Entrapment efficiency and vesicle size were determined. Interactions between activators and vesicles were investigated using differential scanning calorimetry. Transepidermal permeation of oestradiol from vesicles was studied compared to saturated aqueous control in vitro. The maximum flux (J(max)) and its time (T(max)) were calculated from the flux curves and skin deposition was assessed. The compositions of refined formulations were predicted, liposomes prepared, and tested against control. Entrapment efficiency depended on PC concentration with some contribution from sodium cholate and Tween 80. Vesicle sizes ranged from 124 to 135 nm. Edge activators interacted with lipid bilayers and disrupted packing. The refined edge activator concentrations in PC vesicles were 14.0, 13.3 and 15.5% w/w for sodium cholate, Span 80 and Tween 80, respectively; they increased J(max) by 18, 16 and 15-fold and skin deposition by 8, 7 and 8-fold compared with control. Ultradeformable vesicles thus improved skin delivery of oestradiol compared to control and Span 80 and Tween 80 were equivalent to sodium cholate as edge-activators.

Journal of Pharmacy and Pharmacology, 2006

Using liposomes to deliver drugs to and through human skin is controversial, as their function va... more Using liposomes to deliver drugs to and through human skin is controversial, as their function varies with type and composition. Thus they may act as drug carriers controlling release of the medicinal agent. Alternatively, they may provide a localized depot in the skin so minimizing systemic effects or can be used for targeting delivery to skin appendages (hair follicles and sweat glands). Liposomes may also enhance transdermal drug delivery, increasing systemic drug concentrations. With such a multiplicity of functions, it is not surprising that mechanisms of liposomal delivery of therapeutic agents to and through the skin are unclear. Accordingly, this article provides an overview of the modes and mechanisms of action of different vesicles as drug delivery vectors in human skin. Our conclusion is that vesicles, depending on the composition and method of preparation, can vary with respect to size, lamellarity, charge, membrane fluidity or elasticity and drug entrapment. This variab...

Journal of Pharmacy and Pharmacology, 2001

The potential use of ultradeformable and standard liposomes as skin drug delivery systems was inv... more The potential use of ultradeformable and standard liposomes as skin drug delivery systems was investigated in-vitro. An improved experimental design gave a good measure for skin deposition of drug. This avoided the contamination that can occur due to incomplete washing of the donor before direct determination of the amount of drug in the skin. The design used aqueous ethanolic receptor which is believed to diffuse into skin, disrupting deposited liposomes (if any) and thus releasing both bound and free drug. The receptor fluid was refined by testing different concentrations of ethanol. The applied dose was also optimized. Using the improved design and the optimum dose, an ultradeformable formulation was compared with four traditional liposomes for skin delivery of 5-fluorouracil (5-FU). The best receptor was 50% aqueous ethanol and the optimum dose was 20 μL. The ultradeformable formulation was superior to standard liposomes in the skin delivery of 5-FU. Of the traditional liposomes...

European Journal of Pharmaceutical Sciences, 2008

Advanced Drug Delivery Reviews, 2004

One long-standing approach for improving transdermal drug delivery uses penetration enhancers (al... more One long-standing approach for improving transdermal drug delivery uses penetration enhancers (also called sorption promoters or accelerants) which penetrate into skin to reversibly decrease the barrier resistance. Numerous compounds have been evaluated for penetration enhancing activity, including sulphoxides (such as dimethylsulphoxide, DMSO), Azones (e.g. laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (for example propylene glycol, PG, a common excipient in topically applied dosage forms), surfactants (also common in dosage forms) and terpenes. Many potential sites and modes of action have been identified for skin penetration enhancers; the intercellular lipid matrix in which the accelerants may disrupt the packing motif, the intracellular keratin domains or through increasing drug partitioning into the tissue by acting as a solvent for the permeant within the membrane. Further potential mechanisms of action, for example with the enhancers acting on desmosomal connections between corneocytes or altering metabolic activity within the skin, or exerting an influence on the thermodynamic activity/solubility of the drug in its vehicle are also feasible, and are also considered in this review.

Journal of Pharmacy and Pharmacology, 2001

Human skin delivery of estradiol from ultradeformable and traditional liposomes was explored, com... more Human skin delivery of estradiol from ultradeformable and traditional liposomes was explored, comparing occlusive and open application, with the aim of examining the role of skin hydration. Partially hydrated epidermis was used for open hydration, but fully hydrated membranes were used for occluded studies. In addition, we developed a novel technique to investigate the role of shunt route penetration in skin delivery of liposomal estradiol. This compared delivery through epidermis with that through a stratum corneum (SC)/epidermis sandwich from the same skin with the additional SC forming the top layer of the sandwich. This design was based on the fact that orifices of shunts only occupy 0.1% of skin surface area and thus for SC/epidermis sandwiches there will be a negligible chance for shunts to superimpose. The top SC thus blocks most shunts available on the bottom membrane. If shunts play a major role then the delivery through sandwiches should be much reduced compared with that ...

Poly(N-vinyl pyrrolidone) (PVP), poly(2-methyl-2-oxazoline) (PMOZ), poly(2-ethyl-2-oxazoline) (PE... more Poly(N-vinyl pyrrolidone) (PVP), poly(2-methyl-2-oxazoline) (PMOZ), poly(2-ethyl-2-oxazoline) (PEOZ), poly(2-n-propyl-2-oxazoline) (PnPOZ), and poly(2-isopropyl-2-oxazoline) (PiPOZ) were used to prepare solid dispersions with ibuprofen (IB), a model poorly-water soluble drug. Dispersions, prepared by solvent evaporation, were investigated using powder X-ray diffractometry, differential scanning calorimetry, and FTIR spectroscopy; hydrogen bonds formed between IB and all polymers in solid dispersions. PMOZ, the most hydrophilic polymer, showed the poorest ability to reduce or inhibit the crystallinity of IB. In contrast, the more hydrophobic polymers PVP, PEOZ, PnPOZ, and PiPOZ provided greater but similar abilities to reduce IB crystallinity, despite the differing polymer hydrophobicity and that PiPOZ is semi-crystalline. These results indicate that crystallinity disruption is predominantly due to hydrogen bonding between the drug molecules and the polymer. However, carrier properti...

Pharmaceutics

Background: We developed a novel polymer insect repellent conjugate for extended release and decr... more Background: We developed a novel polymer insect repellent conjugate for extended release and decreased skin permeation of the volatile insect repellent p-menthane-3,8-diol (PMD). Methods: PMD was conjugated with acryloyl chloride via an ester bond to form acryloyl–PMD, which was subsequently copolymerised with acrylic acid at varying molar ratios. Copolymer structures were characterised by 1H NMR and FT-IR, analysed by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), molecular weights and reactivity ratios determined, and repellent loading assessed. Results: Using porcine liver esterases, ~45% of the insect repellent was released over five days. Penetration and permeation studies of the copolymer and free repellent using excised, full-thickness porcine ear skin showed no detectable permeation of the copolymer through skin compared to the PMD. Moreover, tape stripping revealed that over 90% of the copolymer remained on the outer surface of the skin, whereas ...

Langmuir : the ACS journal of surfaces and colloids, Jul 17, 2018

Nanoparticle characteristics, including their size, are governed by the reagents employed and the... more Nanoparticle characteristics, including their size, are governed by the reagents employed and the reaction parameters. Here, we systemically vary the catalyst, oxygen content, temperature, and solvent to modify the size and zeta-potential of thiolated organosilica nanoparticles. The particles were synthesized by self-condensation of 3-mercaptopropyltrimethoxysilane in a range of organic solvents in contact with oxygen, with NaOH and other catalysts. The particle size increased with increasing reaction temperature (70 ± 1 nm at 50 °C; 50 ± 1 nm at room temperature) but decreased when air was bubbled through the reaction mixture compared to no bubbling. A significant decrease in the particle size was seen when increasing the dielectric constant of the solvent and when increasing the catalyst concentration; from these, we provide empirical equations that can be used to design particle sizes by manipulating the dielectric constant of the solvent (or cosolvents) or by varying the NaOH ca...

The Science of the total environment, Jan 22, 2017

Human uptake of flame retardants (FRs) such as polybrominated diphenyl ethers (PBDEs) via indoor ... more Human uptake of flame retardants (FRs) such as polybrominated diphenyl ethers (PBDEs) via indoor dust ingestion is commonly considered as 100% bioaccessible, leading to potential risk overestimation. Here, we present a novel in vitro colon-extended physiologically-based extraction test (CE-PBET) with Tenax TA® as an absorptive "sink" capable to enhance PBDE gut bioaccessibility. A cellulose-based dialysis membrane (MW cut-off 3.5kDa) with high pH and temperature tolerance was used to encapsulate Tenax TA®, facilitating efficient physical separation between the absorbent and the dust, while minimizing re-absorption of the ingested PBDEs to the dust particles. As a proof of concept, PBDE-spiked indoor dust samples (n=3) were tested under four different conditions; without any Tenax TA® addition (control) and with three different Tenax TA® loadings (i.e. 0.25, 0.5 or 0.75g). Our results show that in order to maintain a constant sorptive gradient for the low MW PBDEs, 0.5g of ...