Paul A McCarron

University of Ulster, Aontroim, Northern Ireland, United Kingdom

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Publications (91)257.36 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Poly(vinyl alcohol) hydrogels cross-linked with the tetrahydroxyborate anion possess textural and rheological properties that can be used as novel drug-loaded vehicles for application to traumatic wounds. However, addition of soluble drug substances causes concentration-dependent phase separation and rheological changes. The aim of this work was to investigate the effect of adding a local anaesthetic, but keeping the concentration low in an attempt to prevent these changes. Cross-linked hydrogels prepared from three grades of poly(vinyl alcohol) were characterised rheologically. Temperature sweep studies showed an elevated complex viscosity upon moving from 25 °C to 80 °C, which remained high for 48 h following completion of the cycle. Adhesion to model dermal surfaces achieved a maximum of 2.62 N cm−2 and were greater than that observed to epidermal substrates, with a strong dependence on the rate of detachment used during testing. An optimised formulation (6% w/w PVA (31–50; 99) and 2% w/w THB) containing lidocaine hydrochloride loaded to an upper maximum concentration of 1.5% w/w was assessed for phase separation and drug crystallisation. After six months, crystallisation was present in formulations containing 0.7% and 1.5% lidocaine HCl. Changes in pH in response to increases in lidocaine loading were low. Drug release was shown to operate via a non-Fickian process for all three concentrations, with 60% occurring after approximately 24 h. It can be concluded that using a low concentration of lidocaine hydrochloride in hydrogels based on poly(vinyl alcohol) will result in crystallisation. Furthermore, these hydrogels are unlikely to induce rapid anaesthesia due to the low loading and slow release kinetics.
    No preview · Article · Jan 2016 · International Journal of Pharmaceutics
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    ABSTRACT: The aim of this study was to design a controlled release vehicle for insulin to preserve its stability and biological activity during fabrication and release. A modified, double emulsion, solvent evaporation, technique using homogenisation force optimised entrapment efficiency of insulin into biodegradable nanoparticles (NP) prepared from poly (dl-lactic-co-glycolic acid) (PLGA) and its PEGylated diblock copolymers. Formulation parameters (type of polymer and its concentration, stabiliser concentration and volume of internal aqueous phase) and physicochemical characteristics (size, zeta potential, encapsulation efficiency, in vitro release profiles and in vitro stability) were investigated. In vivo insulin sensitivity was tested by diet-induced type II diabetic mice. Bioactivity of insulin was studied using Swiss TO mice with streptozotocin-induced type I diabetic profile. Insulin-loaded NP were spherical and negatively charged with an average diameter of 200–400 nm. Insulin encapsulation efficiency increased significantly with increasing ratio of co-polymeric PEG. The internal aqueous phase volume had a significant impact on encapsulation efficiency, initial burst release and NP size. Optimised insulin NP formulated from 10% PEG-PLGA retained insulin integrity in vitro, insulin sensitivity in vivo and induced a sustained hypoglycaemic effect from 3 hours to 6 days in type I diabetic mice.
    Full-text · Article · Dec 2015 · International Journal of Pharmaceutics
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    ABSTRACT: Breast cancer is one of the most prevalent malignancies worldwide. It consists of a group of tumor cells that have the ability to grow uncontrollably, overcome replicative senescence (tumor progression) and metastasize within the body. Metastases are processes that consist of an array of complex gene dysregulation events. Although these processes are still not fully understood, the dysregulation of a number of key proteins must take place if the tumor cells are to disseminate and metastasize. It is now widely accepted that future effective and innovative treatments of cancer metastasis will have to encompass all the major components of malignant transformation. For this reason, much research is now being carried out into the mechanisms that govern the malignant transformation processes. Recent research has identified key genes involved in the development of metastases, as well as their mechanisms of action. A detailed understanding of the encoded proteins and their interrelationship generates the possibility of developing novel therapeutic approaches. This review will focus on a select group of proteins, often deregulated in breast cancer metastasis, which have shown therapeutic promise, notably, EMT, E-cadherin, Osteopontin, PEA3, Transforming Growth Factor Beta (TGF-β) and Ran. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · May 2015 · Cytokine & growth factor reviews
  • D. AbdelKader · M. Osman · S. Elgizawy · A. Faheem · P. McCarron

    No preview · Article · Feb 2015 · International Journal of Cosmetic Science
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    ABSTRACT: Purpose Stability is considered as one of the most important problems that should be discussed when a biodegradable polymer is used for controlled-release delivery of peptides and protein drugs. This research aimed to investigate the impact of the harsh formulation stress employed by the processing technique as well as the different formulation parameters on the physicochemical properties, stability and bioactivity of insulin loaded nanoparticles. Methods Insulin loaded nanoparticles were spherical, negatively charged with an average size of 200–400nm (Image 1). Insulin encapsulation efficiency increased significantly with increasing PEG concentration. Internal aqueous phase volume and poly vinyl alcohol concentration in the external aqueous phase are key factors affecting the nanoparticles' size, encapsulation efficiency and initial burst release. Optimized insulin nanoparticle formulation showed the same peptide integrity as free insulin in vitro (Image 2) and similar hypoglycemic effect in diabetic mice in vivo. Results Insulin loaded nanoparticles were spherical, negatively charged with an average size of 200–400nm. Insulin encapsulation efficiency increased significantly with increasing PEG concentration. Poly vinyl alcohol concentration in the external aqueous phase is a key factor affecting the nanoparticles' size, encapsulation efficiency and initial burst release. However, polymer concentration showed different effects on nanoparticles' size, encapsulation efficiency and initial burst release. Moreover, internal aqueous phase volume had a significant impact on encapsulation efficiency, initial burst release and nanoparticles' size. Optimized insulin nanoparticle formulation showed the same peptide integrity as free insulin in vitro and similar hypoglycemic effect in diabetic mice in vivo. Conclusion Optimising the entrapment efficiency of insulin using a modified double emulsion solvent evaporation technique adopting homogenising force while maintaining its stability and biological activity during fabrication, release and storage conditions can be achieved. The amphiphilic nature of the PLGA-PEG block copolymers allowed a better dispersion of the insulin aqueous phase into the double emulsion structure thus improving its encapsulation efficiency. Moreover, PEG chains in the matrix retained the insulin stability during processing and storage by providing a stabilizing shell which minimize the interactions between the hydrophobic matrix and the entrapped insulin and thereby minimising its inactivation as confirmed by the in vivo results.
    Full-text · Conference Paper · Nov 2014
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    ABSTRACT: Gene delivery into cells offers opportunities to treat various human genetic diseases. Effective gene delivery is dependent on its stability and ability to transfect across cells. DNA is susceptible to enzymatic degradation and its negatively charge are barriers towards successful transfection. DNA has to be protected from degradation and neutralised. Non-viral vectors are preferred carrier systems, therefore, the use of cyclodextrins with Pluronic®-F127 and folic acid at different concentrations to stabilise the formulation was investigated. Formulations were characterised in fresh and freeze dried forms. DNA stability in formulations was tested by determining the stability of DNA against enzymatic degradation. Degree of DNA inclusion into cyclodextrins was investigated using fluorescence spectroscopy. Thermal behaviour was studied using Differential Scanning Calorimetry (DSC). Incorporation of Pluronic®-F127 produced most stable formulations regarding enzymatic degradation. These formulations show high percentage inclusion. Shift of peaks in FTIR data, appearance of uniform particulate as detected by SEM and changing in the denaturation temperature as demonstrated by DSC data for Pluronic®-F127 containing formulations confirm clear interaction between Pluronic®-F127 and cyclodextrin/ DNA complex. It was noted that γ-cyclodextrin provide better protection and inclusion compared to β-cyclodextrin. Pluronic®-F127 with cyclodextrins is a promising combination to improve stability.
    No preview · Article · Aug 2014 · Current Pharmaceutical Biotechnology
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    ABSTRACT: We test the hypothesis that anesthesia, measured as pain scores, induced by a novel topical anesthetic putty is non-inferior (margin=1.3) to that provided by conventional lidocaine infiltration for the repair of lacerations. A randomized controlled trial was conducted in the emergency department (ED) of a local hospital. Participants were randomly allocated to receive either infiltration anesthesia or topical anesthetic putty as per the trial protocol. Pain scores were recorded 15 minutes after infiltration and 30 minutes after topical anesthetic putty application. Median pain scores were compared between groups. Wound evaluation scores were conducted after 7 to 10 days and adverse events were monitored for both groups of participants throughout the study. One hundred and ten participants were enrolled in the study, with 56 receiving infiltration and 54 receiving topical anesthetic putty. The median difference between the pain scores of the 2 groups was 0 (95% confidence interval -1 to 0). There were no substantial differences between the 2 groups in terms of either the wound evaluation scores or the incidence of adverse events. The novel topical anesthetic putty was not inferior to infiltration with lidocaine with respect to the pain experienced during suturing, and this putty is a feasible alternative to infiltration anesthesia of lacerations in the ED.
    No preview · Article · Jan 2014 · Annals of emergency medicine
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    ABSTRACT: We present "one-step application" dissolving and hydrogel-forming microneedle arrays (MN) for enhanced delivery of photosensitisers/precursors. MN (280 μm) prepared from 20% w/w poly(methylvinylether/maelic acid) and crosslinked with glycerol by esterification to form hydrogels upon skin insertion, or allowed to dissolve rapidly in skin, were combined with patches containing 19 mg cm(-2) of 5-aminolevulinic acid (ALA) or meso-tetra (N-methyl-4-pyridyl) porphine-tetra-tosylate (TMP) for drug delivery. Both MN types were mechanically-robust, with compression forces of 20.0 N only causing height reductions of 14%. Application forces as low as 8.0 N per array allowed >95% of the MN in each array type to penetrate excised porcine skin, with the MN penetrating to approximately 220 μm. MN significantly enhanced transdermal delivery of ALA and TMP in vitro, with the hydrogel-forming system comparable to the dissolving system for ALA delivery (approximately 3000 nmol cm(-2) over 6 hours), but superior for delivery of the much larger TMP molecule (approximately 14 nmol cm(-2) over 24 hours, compared to 0.15 nmol cm(-2) ). As this technology clearly has potential in enhanced photodynamic therapy of neoplastic skin lesions, we are currently planning animal studies, to be followed by preliminary human evaluations. GMP manufacturing scale-up is ongoing. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2013 · Photochemistry and Photobiology
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    ABSTRACT: No bioadhesive patch-based system is currently marketed. This is despite an extensive number of literature reports on such systems detailing their advantages over conventional pressure sensitive adhesive-based patches in wet environments and describing successful delivery of a diverse array of drug substances. This lack of proprietary bioadhesive patches is largely due to the fact that such systems are exclusively water-based, meaning drying is difficult. In this paper we describe, for the first time, a novel multiple lamination method for production of bioadhesive patches. In contrast to patches produced using a conventional casting approach, which took 48 hours to dry, bioadhesive films prepared using the novel multiple lamination method were dried in 15 min and were folded into formed patches in a further 10 min. Patches prepared by both methods had comparable physicochemical properties. The multiple lamination method allowed supersaturation of 5-aminolevulinic acid to be achieved in formed patch matrices. However, drug release studies were unable to show an advantage for supersaturation with this particular drug, due to its water high solubility. The multiple lamination method allowed greater than 90% of incorporated nicotine to remain within formed patches, in contrast to the 48% achieved for patches prepared using a conventional casting approach. The procedure described here could readily be adapted for automation by industry. Due to the reduced time, energy and ensuing finance now required, this could lead to bioadhesive patch-based drug delivery systems becoming commercially viable. This would, in turn, mean that pathological conditions occurring in wet or moist areas of the body could now be routinely treated by prolonged site-specific drug delivery, as mediated by a commercially produced bioadhesive patch.
    No preview · Article · Nov 2012 · Drug Development and Industrial Pharmacy
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    ABSTRACT: In search of strategies to develop deeply penetrating agents for use in Photodynamic Therapy (PDT), we have devised a Quantum Dot-Rose Bengal conjugate that is effective at producing singlet oxygen upon two-photon irradiation. The CdSe/ZnS Quantum Dot, with its high two photon absorption cross section, serves as a two-photon absorbing antenna and transfers its excited state energy to the attached photosensitiser which engages with molecular oxygen to produce cytotoxic singlet oxygen. Thus, we were able to excite the photosensitiser indirectly, which has an absorption maximum of 565 nm, with two-photon irradiation at 800 nm. Given the tissue penetration depth of 800 nm light is at least four times greater than 565 nm light, this offers the opportunity to access much deeper-seated tumours than is currently possible with pharmaceutically approved photosensitisers. Furthermore, the attachment of the photosensitiser to the hydrophilic quantum dot improved the aqueous solubility of the photosensitiser by 48
    No preview · Article · Mar 2012 · Journal of Materials Chemistry
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    ABSTRACT: A combination of light and ultrasound activation of two conventional photosensitising drugs, methylene blue and rose bengal, was shown to generate higher levels of reactive oxygen species (ROS) and lower LD50 values than either light or ultrasound activation alone.
    No preview · Article · Aug 2011 · Bioorganic & medicinal chemistry letters
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    ABSTRACT: The aim of this study was to assess a novel semisolid material as a potential topical drug delivery system for acute laceration. The objectives were to correlate physical characterization data using rheologic studies and to compare with clinical assessment of performance in an emergency department (ED). Polyvinyl alcohol (PVA) hydrogels, cross-linked using tetrahydroxyborate (THB), were characterized using texture profile analysis. Formulation samples were applied to acute lacerations presented to the ED and factors, such as in vivo residency time and cohesive removal, were assessed. Viscosity was shown to be related to mechanical characteristics, whereas adhesiveness depended on the THB concentration. Residence in, and clean removal from, lacerations was evaluated on 29 patients. Formulation F3 (10.0% PVA, 2.5% w/w THB) displayed the most appropriate characteristics for clinical use by scoring highest in qualitative assessments. Other formulations exhibited difficulties in application and removal due to excessive adhesiveness. The release of a model local anesthetic drug was proportional to the concentration of drug incorporated, but was not substantially affected by small changes in the formulation constituents. Using a combination of pharmaceutical evaluation and clinical assessment, it was shown that cross-linked PVA semisolids are a suitable formulation for drug administration to acute lacerations, with potential for induction of anesthesia prior to wound repair.
    Preview · Article · Apr 2011 · Academic Emergency Medicine
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    Francois Fay · Christopher J. Scott · Paul A. McCarron
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    ABSTRACT: Research into the targeting of drug substances to a specific disease site has enjoyed sustained activity for many decades. The reason for such fervent activity is the considerable clinical advantages that can be gained when the delivery system plays a pivotal role in determining where the drug is deposited. When compared to conventional formulations where no such control exists, such as parenteral and oral systems, the sophisticated targeting device can reduce side effects and limit collateral damage to surrounding normal tissue. No more so is this important than in the area of oncology when dose-limiting side effects are often encountered as an ever present difficulty. In this review, the types of colloidal carrier commonly used in targeted drug delivery are discussed, such as gold and polymeric colloids. In particular, the process of attaching targeting capabilities is considered, with reference to antibody technologies used as the targeting motifs. Nanotechnology has brought together a means to carry both a drug and targeting ligand in self-contained constructs and their applications to both clinical therapy and diagnosis are discussed.
    Full-text · Article · Nov 2010 · Current Nanoscience
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    ABSTRACT: In photodynamic therapy (PDT) a combination of visible light and a sensitising drug causes the destruction of selected cells. Aminolaevulinic acid (ALA) has been widely used in topical PDT for over 15 years. However, ALA does not possess favourable physicochemical properties for skin penetration. Consequently, the clearance rates for difficult to treat lesions, such as nodular basal cell carcinomas are relatively low. For the first time, equimolar concentrations of ALA, methyl-ALA (m-ALA) and hexyl-ALA (h-ALA) have been incorporated into a bioadhesive patch-based system. In vitro penetration studies into excised porcine skin revealed that ALA patches containing relatively high loadings (226.7 micromol cm(-2)) were associated with significantly greater tissue concentrations (70.7 micromol cm(-3)) than patches containing m-ALA (16.3 micromol cm(-3)) or h-ALA (17.4 micromol cm(-3)). ALA was also found to be the most efficient inducer of protoporphyrin (PpIX) fluorescence in mice, in vivo (maximum mean fluorescence: ALA=236.2 a.u., m-ALA=175.1 a.u., h-ALA=193.5 a.u.). However, when the lipophilic hexylester was formulated in a pressure sensitive adhesive (PSA) patch, significantly higher PpIX levels were achieved compared to all bioadhesive systems tested. Of major importance, PSA patches containing relatively low h-ALA loadings induced high PpIX levels, which were localised to the application area. This study has highlighted the importance of rational selection of both the active agent and the delivery system. Bioadhesive preparations containing ALA are ideal for delivery to moist environments; whereas h-ALA-loaded PSA systems may facilitate enhanced delivery to dry areas of skin. In addition, owing to the relatively low loadings of h-ALA required in PSA patches, the costs of clinical PDT may potentially be reduced.
    No preview · Article · Oct 2010 · Journal of photochemistry and photobiology. B, Biology
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    ABSTRACT: Aminolaevulinic acid (ALA) is known to poorly penetrate into thick lesions, such as nodular basal cell carcinomas. Short chain ALA esters, possessing increased lipophilicity relative to their hydrophilic parent, have previously been shown to be highly efficient at inducing protoporphyrin IX (PpIX) production in cell culture, at equimolar concentrations. In contrast, in vitro skin permeation and in vivo animal studies, which up to now have compared prodrugs on a % w/w basis, have failed to demonstrate such benefits. For the first time, equimolar concentrations of ALA, methyl-ALA (m-ALA) and hexyl-ALA (h-ALA) have been incorporated into an o/w cream preparation. In vitro penetration studies into excised porcine skin revealed that increased levels of h-ALA, compared to ALA and m-ALA were found in the upper skin layers, at all drug loadings studied. Topical application of the formulations to nude murine skin in vivo, revealed that creams containing h-ALA induced significantly higher levels of peak PpIX fluorescence (F(max) = 289.0) at low concentrations compared to m-ALA (F(max) = 159.2) and ALA (F(max) = 191.9). Importantly, this study indicates that when compared on an equimolar basis, h-ALA has improved skin penetration, leading to enhanced PpIX production compared to the parent drug and m-ALA.
    No preview · Article · Aug 2010 · Journal of Pharmaceutical Sciences
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    ABSTRACT: The inclusion of chemical penetration enhancers in a novel patch-based system for the delivery of 5-aminolevulinic acid (ALA) was examined in vitro and in vivo. Poor penetration of ALA has been implicated as the primary factor for low response rates achieved with topical ALA-based photodynamic therapy of thicker neoplastic lesions, such as nodular basal cell carcinomas. Several chemical permeation enhancers (dimethylsulfoxide, Labrafac CC, Labrafac PG and Labrafil M1944CS) were incorporated into bioadhesive patches tailored to deliver 19 mg ALA/cm(2). In-vitro depth penetration studies into excised porcine skin showed that high concentrations of ALA (>9 micromol/cm(3)) could be delivered to a depth of 1.875 mm. However, inclusion of permeation enhancers did not significantly increase ALA delivery, relative to the control (P > 0.05). In-vivo studies were in strong agreement with in-vitro results, with formulations containing chemical enhancers showing no improvement in delivery compared with the control. The patches designed in this work are suited to defineable ALA delivery without the need to immobilise patients for up to 6 h, as is common with the cream-under-occlusion approach. Overall, permeation enhancers were not found to markedly enhance the topical delivery of ALA. However, chemical penetration enhancers may have a greater effect on the delivery of more lipophilic ALA prodrugs, which are thought to primarily permeate the stratum corneum via the intercellular pathway.
    No preview · Article · Jun 2010
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    ABSTRACT: In this present work we describe a poly(lactic-co-glycolic acid) (PLGA) nanoparticle formulation for intracellular delivery of plasmid DNA. This formulation was developed to encapsulate DNA within PLGA nanoparticles that combined salting out and emulsion-evaporation processes. This process reduced the requirement for sonication which can induce degradation of the DNA. A monodispersed nanoparticle population with a mean diameter of approximately 240 nm was produced, entrapping a model plasmid DNA in both supercoiled and open circular structures. To induce endosomal escape of the nanoparticles, a superficial cationic charge was introduced using positively charged surfactants cetyl trimethylammonium bromide (CTAB) and dimethyldidodecylammonium bromide (DMAB), which resulted in elevated zeta potentials. As expected, both cationic coatings reduced cell viability, but at equivalent positive zeta potentials, the DMAB coated nanoparticles induced significantly less cytotoxicity than those coated with CTAB. Fluorescence and transmission electron microscopy demonstrated that the DMAB coated cationic nanoparticles were able to evade the endosomal lumen and localise in the cytosol of treated cells. Consequently, DMAB coated PLGA nanoparticles loaded with a GFP reporter plasmid exhibited significant improvements in transfection efficiencies with comparison to non-modified particles, highlighting their functional usefulness. These nanoparticles may be useful in delivery of gene therapies to targeted cells.
    No preview · Article · Feb 2010 · Biomaterials
  • Paul A McCarron · Ahmed Moustafa Faheem

    No preview · Article · Jan 2010 · Nanomedicine
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    ABSTRACT: Background: The aim of this project was to assess the potential role of an innovative, cross-linked, semi-solid dosage form as a means of topical drug delivery to acute lacerations. Aim: The objectives of the project were to formulate and evaluate a number of semi-solid dosage forms clinically, which have a range of viscosities and have been specifically designed to allow them to reside in, achieve intimate contact with, and be removed cleanly from a laceration that requires suturing. Methods: This trial was conducted in a busy urban Emergency Medicine (EM) department. All adult patients that presented to the EM department with a laceration were invited to enrol in the study. The study population consisted of 25 adults, older than 18 years, who had a laceration which required anaesthesia before repair. Results: In this pilot study of formulation suitability, formulation III was shown to have the most appropriate physical characteristics for use in the treatment of lacerations. Conclusion: It has been shown that an innovative, cross-linked, semi-solid dosage form has the properties to be used for the potential topical delivery of drug substances into lacerations. Conflict of interest: None.
    Preview · Article · Dec 2009
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    ABSTRACT: Methods In this study we determined, for the first time, the ability of microorganisms to traverse microneedle-induced holes using two different in vitro models. Results When employing Silescol® membranes, the numbers of Candida albicans, Pseudomonas aeruginosa and Staphylococcus epidermidis crossing the membranes were an order of magnitude lower when the membranes were punctured by microneedles rather than a 21G hypodermic needle. Apart from the movement of C. albicans across hypodermic needle-punctured membranes, where 40.2% of the microbial load on control membranes permeated the barrier over 24 h, the numbers of permeating microorganisms was less than 5% of the original microbial load on control membranes. Experiments employing excised porcine skin and radiolabelled microorganisms showed that the numbers of microorganisms penetrating skin beyond the stratum corneum were approximately an order of magnitude greater than the numbers crossing Silescol® membranes in the corresponding experiments. Approximately 103 cfu of each microorganism adhered to hypodermic needles during insertion. The numbers of microorganisms adhering to MN arrays were an order of magnitude higher in each case. Conclusion We have shown here that microneedle puncture resulted in significantly less microbial penetration than did hypodermic needle puncture and that no microorganisms crossed the viable epidermis in microneedle—punctured skin, in contrast to needle-punctured skin. Given the antimicrobial properties of skin, it is, therefore, likely that application of microneedle arrays to skin in an appropriate manner would not cause either local or systemic infection in normal circumstances in immune-competent patients. In supporting widespread clinical use of microneedle-based delivery systems, appropriate animal studies are now needed to conclusively demonstrate this in vivo. Safety in patients will be enhanced by aseptic or sterile manufacture and by fabricating microneedles from self-disabling materials (e.g. dissolving or biodegradable polymers) to prevent inappropriate or accidental reuse.
    Full-text · Article · Nov 2009 · Pharmaceutical Research

Publication Stats

2k Citations
257.36 Total Impact Points

Institutions

  • 2008-2015
    • University of Ulster
      • School of Pharmacy and Pharmaceutical Science
      Aontroim, Northern Ireland, United Kingdom
  • 2009
    • Antrim Area Hospital
      Aontroim, N Ireland, United Kingdom
  • 1992-2009
    • Queen's University Belfast
      • School of Pharmacy
      Béal Feirste, N Ireland, United Kingdom
  • 2000
    • The School of Pharmacy
      • School of Pharmacy
      Béal Feirste, Northern Ireland, United Kingdom