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Pharmaceutics, Volume 7, Issue 4 (December 2015) , Pages 363-564

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Open AccessArticle
Montelukast Disposition: No Indication of Transporter-Mediated Uptake in OATP2B1 and OATP1B1 Expressing HEK293 Cells
Pharmaceutics 2015, 7(4), 554-564; https://doi.org/10.3390/pharmaceutics7040554
Received: 15 September 2015 / Revised: 24 November 2015 / Accepted: 9 December 2015 / Published: 15 December 2015
Cited by 6 | Viewed by 1861 | PDF Full-text (715 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Clinical studies with montelukast show variability in effect and polymorphic OATP2B1-dependent absorption has previously been implicated as a possible cause. This claim has been challenged with conflicting data and here we used OATP2B1-transfected HEK293 cells to clarify the mechanisms involved. For montelukast, no [...] Read more.
Clinical studies with montelukast show variability in effect and polymorphic OATP2B1-dependent absorption has previously been implicated as a possible cause. This claim has been challenged with conflicting data and here we used OATP2B1-transfected HEK293 cells to clarify the mechanisms involved. For montelukast, no significant difference in cell uptake between HEK-OATP2B1 and empty vector cell lines was observed at pH 6.5 or pH 7.4, and no concentration-dependent uptake was detected. Montelukast is a carboxylic acid, a relatively potent inhibitor of OATP1B1, OATP1B3, and OATP2B1, and has previously been postulated to be actively transported into human hepatocytes. Using OATP1B1-transfected HEK293 cells and primary human hepatocytes in the presence of OATP inhibitors we demonstrate for the first time that active OATP-dependent transport is unlikely to play a significant role in the human disposition of montelukast. Full article
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Open AccessReview
Genomic Discoveries and Personalized Medicine in Neurological Diseases
Pharmaceutics 2015, 7(4), 542-553; https://doi.org/10.3390/pharmaceutics7040542
Received: 23 September 2015 / Revised: 30 November 2015 / Accepted: 2 December 2015 / Published: 7 December 2015
Cited by 4 | Viewed by 2165 | PDF Full-text (1279 KB) | HTML Full-text | XML Full-text
Abstract
In the past decades, we have witnessed dramatic changes in clinical diagnoses and treatments due to the revolutions of genomics and personalized medicine. Undoubtedly we also met many challenges when we use those advanced technologies in drug discovery and development. In this review, [...] Read more.
In the past decades, we have witnessed dramatic changes in clinical diagnoses and treatments due to the revolutions of genomics and personalized medicine. Undoubtedly we also met many challenges when we use those advanced technologies in drug discovery and development. In this review, we describe when genomic information is applied in personal healthcare in general. We illustrate some case examples of genomic discoveries and promising personalized medicine applications in the area of neurological disease particular. Available data suggest that individual genomics can be applied to better treat patients in the near future. Full article
(This article belongs to the Special Issue Personalized Medicine and Pharmacogenomics)
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Open AccessReview
Alignment of Short Reads: A Crucial Step for Application of Next-Generation Sequencing Data in Precision Medicine
Pharmaceutics 2015, 7(4), 523-541; https://doi.org/10.3390/pharmaceutics7040523
Received: 21 October 2015 / Revised: 14 November 2015 / Accepted: 17 November 2015 / Published: 23 November 2015
Cited by 7 | Viewed by 3036 | PDF Full-text (1583 KB) | HTML Full-text | XML Full-text
Abstract
Precision medicine or personalized medicine has been proposed as a modernized and promising medical strategy. Genetic variants of patients are the key information for implementation of precision medicine. Next-generation sequencing (NGS) is an emerging technology for deciphering genetic variants. Alignment of raw reads [...] Read more.
Precision medicine or personalized medicine has been proposed as a modernized and promising medical strategy. Genetic variants of patients are the key information for implementation of precision medicine. Next-generation sequencing (NGS) is an emerging technology for deciphering genetic variants. Alignment of raw reads to a reference genome is one of the key steps in NGS data analysis. Many algorithms have been developed for alignment of short read sequences since 2008. Users have to make a decision on which alignment algorithm to use in their studies. Selection of the right alignment algorithm determines not only the alignment algorithm but also the set of suitable parameters to be used by the algorithm. Understanding these algorithms helps in selecting the appropriate alignment algorithm for different applications in precision medicine. Here, we review current available algorithms and their major strategies such as seed-and-extend and q-gram filter. We also discuss the challenges in current alignment algorithms, including alignment in multiple repeated regions, long reads alignment and alignment facilitated with known genetic variants. Full article
(This article belongs to the Special Issue Personalized Medicine and Pharmacogenomics)
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Open AccessArticle
Insertion Process of Ceramic Nanoporous Microneedles by Means of a Novel Mechanical Applicator Design
Pharmaceutics 2015, 7(4), 503-522; https://doi.org/10.3390/pharmaceutics7040503
Received: 30 August 2015 / Revised: 7 November 2015 / Accepted: 13 November 2015 / Published: 18 November 2015
Cited by 5 | Viewed by 2641 | PDF Full-text (3762 KB) | HTML Full-text | XML Full-text
Abstract
Arrays of microneedles (MNAs) are integrated in an out-of-plane fashion with a base plate and can serve as patches for the release of drugs and vaccines. We used soft-lithography and micromolding to manufacture ceramic nanoporous (np)MNAs. Failure modes of ceramic npMNAs are as [...] Read more.
Arrays of microneedles (MNAs) are integrated in an out-of-plane fashion with a base plate and can serve as patches for the release of drugs and vaccines. We used soft-lithography and micromolding to manufacture ceramic nanoporous (np)MNAs. Failure modes of ceramic npMNAs are as yet poorly understood and the question remained: is our npMNA platform technology ready for microneedle (MN) assembly into patches? We investigated npMNAs by microindentation, yielding average crack fracture forces above the required insertion force for a single MN to penetrate human skin. We further developed a thumb pressure-actuated applicator-assisted npMNA insertion method, which enables anchoring of MNs in the skin by an adhesive in one handling step. Using a set of simple artificial skin models, we found a puncture efficiency of this insertion method a factor three times higher than by applying thumb pressure on the npMNA base plate directly. In addition, this new method facilitated zero MN-breakage due to a well-defined force distribution exerted onto the MNs and the closely surrounding area prior to bringing the adhesive into contact with the skin. Owing to the fact that such parameter space exists, we can conclude that npMNAs by soft lithography are a platform technology for MN assembly into a patch. Full article
(This article belongs to the Special Issue Microneedle Patches: Developing Strategies for Delivery)
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Open AccessReview
Microneedle Coating Techniques for Transdermal Drug Delivery
Pharmaceutics 2015, 7(4), 486-502; https://doi.org/10.3390/pharmaceutics7040486
Received: 21 September 2015 / Revised: 28 October 2015 / Accepted: 28 October 2015 / Published: 5 November 2015
Cited by 21 | Viewed by 4252 | PDF Full-text (965 KB) | HTML Full-text | XML Full-text
Abstract
Drug administration via the transdermal route is an evolving field that provides an alternative to oral and parenteral routes of therapy. Several microneedle (MN) based approaches have been developed. Among these, coated MNs (typically where drug is deposited on MN tips) are a [...] Read more.
Drug administration via the transdermal route is an evolving field that provides an alternative to oral and parenteral routes of therapy. Several microneedle (MN) based approaches have been developed. Among these, coated MNs (typically where drug is deposited on MN tips) are a minimally invasive method to deliver drugs and vaccines through the skin. In this review, we describe several processes to coat MNs. These include dip coating, gas jet drying, spray coating, electrohydrodynamic atomisation (EHDA) based processes and piezoelectric inkjet printing. Examples of process mechanisms, conditions and tested formulations are provided. As these processes are independent techniques, modifications to facilitate MN coatings are elucidated. In summary, the outcomes and potential value for each technique provides opportunities to overcome formulation or dosage form limitations. While there are significant developments in solid degradable MNs, coated MNs (through the various techniques described) have potential to be utilized in personalized drug delivery via controlled deposition onto MN templates. Full article
(This article belongs to the Special Issue Microneedle Patches: Developing Strategies for Delivery)
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Open AccessArticle
Investigation of Plasma Treatment on Micro-Injection Moulded Microneedle for Drug Delivery
Pharmaceutics 2015, 7(4), 471-485; https://doi.org/10.3390/pharmaceutics7040471
Received: 28 August 2015 / Revised: 22 October 2015 / Accepted: 22 October 2015 / Published: 30 October 2015
Cited by 11 | Viewed by 2759 | PDF Full-text (3040 KB) | HTML Full-text | XML Full-text
Abstract
Plasma technology has been widely used to increase the surface energy of the polymer surfaces for many industrial applications; in particular to increase in wettability. The present work was carried out to investigate how surface modification using plasma treatment modifies the surface energy [...] Read more.
Plasma technology has been widely used to increase the surface energy of the polymer surfaces for many industrial applications; in particular to increase in wettability. The present work was carried out to investigate how surface modification using plasma treatment modifies the surface energy of micro-injection moulded microneedles and its influence on drug delivery. Microneedles of polyether ether ketone and polycarbonate and have been manufactured using micro-injection moulding and samples from each production batch have been subsequently subjected to a range of plasma treatment. These samples were coated with bovine serum albumin to study the protein adsorption on these treated polymer surfaces. Sample surfaces structures, before and after treatment, were studied using atomic force microscope and surface energies have been obtained using contact angle measurement and calculated using the Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness of the microneedles resulting in better adsorption and release of BSA. Full article
(This article belongs to the Special Issue Microneedle Patches: Developing Strategies for Delivery)
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Open AccessReview
Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the Stratum Corneum
Pharmaceutics 2015, 7(4), 438-470; https://doi.org/10.3390/pharmaceutics7040438
Received: 19 August 2015 / Revised: 29 September 2015 / Accepted: 13 October 2015 / Published: 22 October 2015
Cited by 69 | Viewed by 5624 | PDF Full-text (3307 KB) | HTML Full-text | XML Full-text
Abstract
The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner [...] Read more.
The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner much time and investment with the continuous advancement of new and innovative approaches. This review details the progress and current status of the transdermal drug delivery field and describes numerous pharmaceutical developments which have been employed to overcome limitations associated with skin delivery systems. Advantages and disadvantages of the various approaches are detailed, commercially marketed products are highlighted and particular attention is paid to the emerging field of microneedle technologies. Full article
(This article belongs to the Special Issue Microneedle Patches: Developing Strategies for Delivery)
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Open AccessReview
Recent Advances in the Synthesis and Biomedical Applications of Nanocomposite Hydrogels
Pharmaceutics 2015, 7(4), 413-437; https://doi.org/10.3390/pharmaceutics7040413
Received: 31 July 2015 / Revised: 7 September 2015 / Accepted: 30 September 2015 / Published: 13 October 2015
Cited by 15 | Viewed by 3010 | PDF Full-text (974 KB) | HTML Full-text | XML Full-text
Abstract
Hydrogels sensitive to electric current are usually made of polyelectrolytes and undergo erosion, swelling, de-swelling or bending in the presence of an applied electric field. The electrical conductivity of many polymeric materials used for the fabrication of biomedical devices is not high enough [...] Read more.
Hydrogels sensitive to electric current are usually made of polyelectrolytes and undergo erosion, swelling, de-swelling or bending in the presence of an applied electric field. The electrical conductivity of many polymeric materials used for the fabrication of biomedical devices is not high enough to achieve an effective modulation of the functional properties, and thus, the incorporation of conducting materials (e.g., carbon nanotubes and nanographene oxide) was proposed as a valuable approach to overcome this limitation. By coupling the biological and chemical features of both natural and synthetic polymers with the favourable properties of carbon nanostructures (e.g., cellular uptake, electromagnetic and magnetic behaviour), it is possible to produce highly versatile and effective nanocomposite materials. In the present review, the recent advances in the synthesis and biomedical applications of electro-responsive nanocomposite hydrogels are discussed. Full article
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Open AccessArticle
Methylene Blue-Loaded Dissolving Microneedles: Potential Use in Photodynamic Antimicrobial Chemotherapy of Infected Wounds
Pharmaceutics 2015, 7(4), 397-412; https://doi.org/10.3390/pharmaceutics7040397
Received: 17 August 2015 / Revised: 22 September 2015 / Accepted: 22 September 2015 / Published: 28 September 2015
Cited by 12 | Viewed by 2751 | PDF Full-text (2555 KB) | HTML Full-text | XML Full-text
Abstract
Photodynamic therapy involves delivery of a photosensitising drug that is activated by light of a specific wavelength, resulting in generation of highly reactive radicals. This activated species can cause destruction of targeted cells. Application of this process for treatment of microbial infections has [...] Read more.
Photodynamic therapy involves delivery of a photosensitising drug that is activated by light of a specific wavelength, resulting in generation of highly reactive radicals. This activated species can cause destruction of targeted cells. Application of this process for treatment of microbial infections has been termed “photodynamic antimicrobial chemotherapy” (PACT). In the treatment of chronic wounds, the delivery of photosensitising agents is often impeded by the presence of a thick hyperkeratotic/necrotic tissue layer, reducing their therapeutic efficacy. Microneedles (MNs) are an emerging drug delivery technology that have been demonstrated to successfully penetrate the outer layers of the skin, whilst minimising damage to skin barrier function. Delivering photosensitising drugs using this platform has been demonstrated to have several advantages over conventional photodynamic therapy, such as, painless application, reduced erythema, enhanced cosmetic results and improved intradermal delivery. The aim of this study was to physically characterise dissolving MNs loaded with the photosensitising agent, methylene blue and assess their photodynamic antimicrobial activity. Dissolving MNs were fabricated from aqueous blends of Gantrez® AN-139 co-polymer containing varying loadings of methylene blue. A height reduction of 29.8% was observed for MNs prepared from blends containing 0.5% w/w methylene blue following application of a total force of 70.56 N/array. A previously validated insertion test was used to assess the effect of drug loading on MN insertion into a wound model. Staphylococcus aureus, Escherichia coli and Candida albicans biofilms were incubated with various methylene blue concentrations within the range delivered by MNs in vitro (0.1–2.5 mg/mL) and either irradiated at 635 nm using a Paterson Lamp or subjected to a dark period. Microbial susceptibility to PACT was determined by assessing the total viable count. Kill rates of >96%, were achieved for S. aureus and >99% for E. coli and C. albicans with the combination of PACT and methylene blue concentrations between 0.1 and 2.5 mg/mL. A reduction in the colony count was also observed when incorporating the photosensitiser without irradiation, this reduction was more notable in S. aureus and E. coli strains than in C. albicans. Full article
(This article belongs to the Special Issue Microneedle Patches: Developing Strategies for Delivery)
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Open AccessArticle
Solid Microneedles for Transdermal Delivery of Amantadine Hydrochloride and Pramipexole Dihydrochloride
Pharmaceutics 2015, 7(4), 379-396; https://doi.org/10.3390/pharmaceutics7040379
Received: 13 July 2015 / Revised: 9 September 2015 / Accepted: 16 September 2015 / Published: 28 September 2015
Cited by 16 | Viewed by 2401 | PDF Full-text (1103 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this project was to study the influence of microneedles on transdermal delivery of amantadine hydrochloride and pramipexole dihydrochloride across porcine ear skin in vitro. Microchannel visualization studies were carried out and characterization of the microchannel depth was performed using [...] Read more.
The aim of this project was to study the influence of microneedles on transdermal delivery of amantadine hydrochloride and pramipexole dihydrochloride across porcine ear skin in vitro. Microchannel visualization studies were carried out and characterization of the microchannel depth was performed using confocal laser scanning microscopy (CLSM) to demonstrate microchannel formation following microneedle roller application. We also report, for the first time, the use of TA.XT Plus Texture Analyzer to characterize burst force in pig skin for transdermal drug delivery experiments. This is the force required to rupture pig skin. The mean passive flux of amantadine hydrochloride, determined using a developed LC–MS/MS technique, was 22.38 ± 4.73 µg/cm2/h, while the mean flux following the use of a stainless steel microneedle roller was 49.04 ± 19.77 µg/cm2/h. The mean passive flux of pramipexole dihydrochloride was 134.83 ± 13.66 µg/cm2/h, while the flux following the use of a stainless steel microneedle roller was 134.04 ± 0.98 µg/cm2/h. For both drugs, the difference in flux values following the use of solid stainless steel microneedle roller was not statistically significantly (p > 0.05). Statistical analysis was carried out using the Mann–Whitney Rank sum test. Full article
(This article belongs to the Special Issue Microneedle Patches: Developing Strategies for Delivery)
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Open AccessArticle
Microneedles from Fishscale-Nanocellulose Blends Using Low Temperature Mechanical Press Method
Pharmaceutics 2015, 7(4), 363-378; https://doi.org/10.3390/pharmaceutics7040363
Received: 26 June 2015 / Revised: 10 September 2015 / Accepted: 14 September 2015 / Published: 24 September 2015
Cited by 6 | Viewed by 2470 | PDF Full-text (1894 KB) | HTML Full-text | XML Full-text
Abstract
Fish scale biopolymer blended with nanocellulose crystals is used for production of microneedles applying mechanical press microfabrication and the effect of nanocellulose on microfabrication, water absorption, moisture stability and mechanical properties of the microneedles is reported. The results show that microneedles produced from [...] Read more.
Fish scale biopolymer blended with nanocellulose crystals is used for production of microneedles applying mechanical press microfabrication and the effect of nanocellulose on microfabrication, water absorption, moisture stability and mechanical properties of the microneedles is reported. The results show that microneedles produced from the nanocellulose loaded fish scale biopolymer requires higher temperature for micromolding (80 ± 5 °C) than microneedles from only fish scale biopolymer, which were moldable at 50 ± 5 °C. The mechanical properties of the fish scale biopolymer-nanocellulose (FSBP-NC) films showed that the addition of nanocellulose (NC) resulted in lower elongation and higher tensile stress compared to fish scale biopolymer (FSBP) films. The nanocellulose also prevented dissolution of the needles and absorbed up to 300% and 234% its own weight in water (8% and 12% w/w NC/FSBP), whereas FSBP films dissolved completely within 1 min, Indicating that the FSBP-NC films can be used to produce microneedles with prolonged dissolution rate. FTIR spectrometry of the FSBP films was compared with the FSBP-NC films and the NC gels. The FTIR showed typical peaks for fish scale polymer and nanocellulose with evidence of interactions. SEM micrographs showed relatively good dispersion of NC in FSBP at both NC contents corresponding to 8% and 12% w/w NC/FSBP respectively. Full article
(This article belongs to the Special Issue Microneedle Patches: Developing Strategies for Delivery)
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Pharmaceutics EISSN 1999-4923 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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