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Wood D.G.,MedPharm Ltd. | Wood D.G.,King's College London | Brown M.B.,MedPharm Ltd. | Brown M.B.,University of Hertfordshire | Jones S.A.,King's College London
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2012

The application of moderate heat is a safe and effective means to increase drug transport across human skin. However, the cascade of events that follows the exposure of a topical skin formulation to a heating source is not well understood. The aim of this study was to elucidate how three potential rate limiting stages in the drug transport process; formulation release, drug partitioning and epidermal diffusion, responded to changes in local temperature using the model drug lidocaine. Release from the formulation measured using regenerated cellulose membrane was shown to be driven by drug diffusion in the vehicle; it responded linearly when the local temperature was changed (21.6 μg/cm2/h for every 1°C rise) and displayed no measurable partitioning of lidocaine into RCM. Once the drug was within the human epidermis, the structural changes of the barrier controlled its transport. The apparent lidocaine diffusion coefficient through silicone membrane increased from 6.52 to 8.43 × 10-4 over the 32-45°C temperature range, but it increased from 7.74 × 10-5 cm2 h -1 to 4.8 × 10-4 cm2 h-1 in the human epidermis. In the absence of large increases in drug partitioning, fluidisation of the lipids in the upper layers of the epidermis at 37-45°C was shown to facilitate lidocaine diffusion which for human skin transport was the rate limiting process. © 2012 Elsevier B.V. All rights reserved.


Zhao Y.,Tianjin University | Zhao Y.,King's College London | Jones S.A.,King's College London | Brown M.B.,University of Hertfordshire | Brown M.B.,MedPharm Ltd.
Journal of Pharmacy and Pharmacology | Year: 2010

Objectives: Pharmaceutical foams are not new inventions and their application in topical therapy can be traced back three decades. However, foam formulations have been gaining in popularity with over 100 patents published globally in the last 10 years alone. The aim of this paper is to review the current status and explore the future potential of dynamic foam vehicles in the field of topical drug delivery. Key findings: The use of foam technology to deliver a range of topical active agents has been claimed, including sun-screening compounds, corticosteroids, and antibacterial, antifungal and antiviral agents. Although foams present distinct application advantages and improved patient compliance, the real reason for the rapid growth of topical foam technology is that foams as elegant, aesthetic and cosmetically appealing vehicles provide an alternative, promising formulation strategy in the highly competitive dermatological market. Although there is a plethora of published data proving the safety profiles of topical foams there is a lack of sufficient clinical evidence to demonstrate any superiority of foams over other traditional topical vehicles such as creams and ointments for drug delivery. Summary: Recent literature suggests that when foams are properly engineered using the advances of in situ analysis techniques, the enhancement of topical drug delivery via engineering this type of vehicle can be achieved. © 2010 Royal Pharmaceutical Society of Great Britain.


Benaouda F.,King's College London | Brown M.B.,MedPharm Ltd. | Brown M.B.,University of Hertfordshire | Ganguly S.,King's College London | And 2 more authors.
Molecular Pharmaceutics | Year: 2012

There is a need to understand how solvent structuring influences drug presentation in pharmaceutical preparations, and the aim of this study was to characterize the properties of propylene glycol (PG)/water supramolecular structures such that their functional consequences on drug delivery could be assessed. Shifts to higher wavenumbers in the C-H and C-O infrared stretching vibrations of PG (up to 8.6 and 11 cm-1, respectively) implied that water supramolecular structures were being formed as a consequence of hydrophobic hydration. However, unlike analogous binary solvent systems, water structuring was not enhanced by the presence of the cosolvent. Two discrete populations of supramolecular structures were evident from the infrared spectroscopy: water-rich structures, predominant below a PG volume fraction (fPG) of 0.4 (unmoving water bending vibration at 1211 cm -1) and PG-rich structures, predominant above 0.4 fPG (both C-H and water peaks moved to lower wavenumbers). The un-ionized diclofenac log-linear solubility and transmembrane transport altered dramatically when fPG > 0.55 (a 10-fold increase in transport from 0.28 ± 0.06 μgcm-2h-1 at 0.2 fPG to 2.81 ± 0.16 μgcm-2h-1 at 0.9 fPG), and this demonstrated the ability of the PG rich supramolecular structures, formed in the PG/water solvent, to specifically modify the behavior of un-ionized diclofenac. © 2012 American Chemical Society.


Zhao Y.,King's College London | Brown M.B.,MedPharm Ltd. | Brown M.B.,University of Hertfordshire | Jones S.A.,King's College London
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2010

Nanoparticulate systems have the potential to improve topical drug delivery because of their capacity to enhance drug loading and dissolution, protect chemically unstable therapeutic agents, and improve product aesthetics. However, the commercial use of nanoparticles in topical products is limited because the evidence that they penetrate intact skin is contradictory, and their ability to release active agents in traditional semisolid vehicles is poor. One way to overcome this problem is to formulate nanoparticles in a dynamic delivery system-that is, one that induces a change upon dose actuation so as to promote drug release. Pressurized pharmaceutical foams are one type of dynamic system that can drive a change of state and excipient concentration after dose actuation. This review summarizes the current status of topical products containing nanoparticles, discusses the recent scientific advances in foam production, and investigates the prospect of incorporating nanoparticles into dynamic topical foams. Recent literature suggests that dynamic foams have the potential to break down the nanoparticles loaded within them, improve drug release from nanoparticles, and enhance topical efficacy. Although the published data to support the use of dynamic systems are limited, it is clear that they provide a promising solution to enhance drug release from nanoparticles, and future research work should aim to investigate these systems in more detail. From the Clinical Editor: The use of nanoparticulate systems in topical products is limited as skin penetration and release of active agents remains controversial. Pressurized pharmaceutical foams represent a dynamic system characterized by a change of state and excipient concentration after dose actuation. The review summarizes the current status of topical nanoparticles utilizing this delivery system. © 2010 Elsevier Inc. All rights reserved.


Ali J.,University of Hertfordshire | Camilleri P.,Bio Chemical Solutions | Brown M.B.,University of Hertfordshire | Brown M.B.,MedPharm Ltd. | And 2 more authors.
Journal of Chemical Information and Modeling | Year: 2012

The General Solubility Equation (GSE) is a QSPR model based on the melting point and log P of a chemical substance. It is used to predict the aqueous solubility of nonionizable chemical compounds. However, its reliance on experimentally derived descriptors, particularly melting point, limits its applicability to virtual compounds. The studies presented show that the GSE is able to predict, to within 1 log unit, the experimental aqueous solubility (log S) for 81% of the compounds in a data set of 1265 diverse chemical structures (-8.48 < log S < 1.58). However, the predictive ability of the GSE is reduced to 75% when applied to a subset of the data (1160 compounds -6.00 < log S < 0.00), which discounts those compounds occupying the sparsely populated regions of data space. This highlights how sparsely populated extremities of data sets can significantly skew results for linear regression-based models. Replacing the melting point descriptor of the GSE with a descriptor which accounts for topographical polar surface area (TPSA) produces a model of comparable quality to the GSE (the solubility of 81% of compounds in the full data set predicted accurately). As such, we propose an alternative simple model for predicting aqueous solubility which replaces the melting point descriptor of the GSE with TPSA and hence can be applied to virtual compounds. In addition, incorporating TPSA into the GSE in addition to log P and melting point gives a three descriptor model that improves accurate prediction of aqueous solubility over the GSE by 5.1% for the full and 6.6% for the reduced data set, respectively. © 2011 American Chemical Society.


Benaouda F.,King's College London | Brown M.B.,MedPharm Ltd. | Martin G.P.,King's College London | Jones S.A.,King's College London
Pharmaceutical Research | Year: 2012

Purpose: To understand in situ drug thermodynamic activity when embedded in a supramolecular structured hydrophilic matrix that simultaneously self-assembled during drug supersaturation. Methods: A propylene glycol (PG)/water, hydroxypropyl methyl cellulose matrix containing ethanol was used to support diclofenac supersaturation. Phase behaviour, thermodynamics and drug transport were assessed through the determination of evaporation kinetics, supersaturation kinetics and transmembrane penetration. Results: Initial ethanol evaporation from the drug loaded matrix (2.9±0.4 mg.min -1.cm-2) was comparable to that of the pure solvent (ca. 3 mg.min-1.cm-2). When 25% w/w of the total ethanol from the applied phase was lost (ethanol/water/PG molar ratio of 7:5:1.2), an inflection point in the evaporation profile and a sudden decrease in drug solubility demonstrated that a defined supramolecular structure was formed. The 55-fold decrease in drug solubility observed over the subsequent 8 h drove in situ supersaturation, the rate of which was a function of the drug load in the matrix (y=0.0078x, R2<0.99). Conclusion The self-assembling supramolecular matrix prevented drug re-crystallisation for >24 h, but did not hinder mobility and this allowed the thermodynamic activity of the drug to be directly translated into highly efficient transmembrane penetration. © Springer Science+Business Media, LLC 2012.


Grant
Agency: GTR | Branch: BBSRC | Program: | Phase: Training Grant | Award Amount: 99.93K | Year: 2011

Whole body exposure changes in atmospheric pressure are common. For example, passengers on commercial air flights are exposed to a hypobaric pressure of approximately 170 mm Hg for the duration of the flight. Similarly activities such as deep sea diving and hyperbaric medicine, both of which are becoming more popular, can expose the body pressures of up to 6,000 mm Hg. Physiological changes in blood circulation and respiration under hyper and hypo baric pressures have been well documented, but the effects on xenobiotic entry into the body have not been systematically investigated. Whole body exposure to barometric pressure changes would be expected to have very different effects to local pressure changes induced by methods such as suction because the latter generates a pressure differential which could draw molecules across the barrier and has less profound effects on whole body physiology. The comparative effects of these two means of inducing barometric pressure changes to externally facing barriers such as the skin are at present unknown. The aim of this project is to determine the effects of whole body and local barometric pressure changes on membrane physiology and transmembrane chemical penetration. In oder to achieve this aim the project will: - Design and build a series of specialised cells that will allow the assessment of membrane physiology and penetration under both equilibrated and differential hyper and hypo baric conditions in vitro - Determine the effects of locally induced barometric changes upon membrane physiology and permeability using a complimentry range of transport models and analytical techniques - Mathematically model the process of barrier penetration using the in vitro data and design a series of in vivo tests. - Test whole body exposure changes to acute hyperbaric and hypobarric conditions, compare and contrast this data to the in vitro data and adapt the in silico model describing permeation It is anticipated that the data generated from this work can be used to assess both the toxicological exposure risk and potential to improve the delivery of therapeutic agents when applying barometric stress to biological membranes. Work Plan A systems biology approach to the design will be taken. The employment of a hierarchal series of membranes will allow mathematical modelling and descrition of barrier transport in multiple tissue types. Part 1 - In vitro assessment of barometric pressure changes on transport. A specially designed jacket that can independently seal the donor and receiver compartment of a Franz cell will be designed and tested. A series of both porous and non porous synthetic membranes will be employed to investigate the influence of pressure on permeate diffusion and partition. Part 2 - Mathematical modelling. The data sets generated in Part 1 will be fitted to the ideal behaviour expected from non-porous or porous membrane transport processes. A mathematical model to describing transmembrane transport in the absence of barrier changes under different barometric pressures will be developed and this will inform the study design for Part 3. Part 3 - Skin physiology and barrier changes. The cells designed in Part 1 will be used to assess transmembrane penetration through full thickness skin. Pre and post pressure exposure transepidermal water loss, skin lipid packing, water permeability, coenocyte size and skin anatomy will be characterised using analytical techniques and structural changes correlated to barrier properties. The findings will be used to adapt and test the mathematical model generated in Part 2. Part 4 - In vivo assessment. Whole animal protocols developed in previous work (Staff PhD student, 2010) but adapted to specalised hyper and hypobarric chambers will assess animal physiology, skin barrier properties and skin permeability under differential pressure condi


Patent
MEDPHARM Ltd and University of Reading | Date: 2013-11-12

Unnatural, hygroscopic amino acids are useful to enhance the moisture retention and uptake properties of skin. In particular, such amino acids are N-hydroxyserine, N-hydroxyglycine, L-homoserine, alpha-hydroxyglycine, 2-(aminooxy)-2-hydroxyacetic acid, 2-hydroxy-2-(hydroxyamino) acetic acid, 2-(aininooxy)acetic acid, and combinations thereof.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: Smart - Proof of Concept | Award Amount: 100.00K | Year: 2012

Psoriasis is an autoimmune-mediated chronic disease that reportedly affects 2 % of the world’s population. To date it has been difficult to treat with majority of the successful treatments being systemically active such as methotrexate (MTX) and acitretin, administered orally and biologics, administered by injection. All have serious side effects and although topical treatments have been developed to overcome these issues, none are used when the condition passes its early stages. MTX has demonstrated excellent efficacy for psoriasis however oral administration of MTX is associated with side effects such as liver and kidney disease and gastrointestinal irritation. However, currently there are no approved topical formulations that contain MTX mainly because it is believed that therapeutic levels of MTX at the pathological site are hard to achieve with topical administration. Development of a product that could deliver sufficient levels of MTX to the target site would significantly reduce systemic toxicity and increase patient compliance by reducing treatment times associated with current topical medications. A promising novel strategy to enhance skin permeation is the application of superficial heat in conjunction with chemical enhancers e.g. MedTherm. Superficial heat in combination with certain chemical enhancers results in increased drug delivery to the skin without elevated systemic absorption by temporarily increasing barrier fluidity and drug diffusivity making it easier for the MTX to permeate. The applied heat also provides a relief to itching associated with the psoriasis, a benefit not offered by other topical products. As such, the overall objective of this project is to develop a topical MTX treatment for psoriasis using this novel combination of heat generation and chemical enhancers. Inevitably, this will contribute to reducing the financial burden to the NHS, as well as society in the form of “sick days” taken due to the debilitating condition.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: European | Award Amount: 94.79K | Year: 2014

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