Strong barrier properties of stratum corneum often limits the efficiency of drug delivery through skin. Several strategies were tried to improve permeation of drug through skin for local as well as ...systemic drug delivery. Incorporation of the drug within flexible liposomal vesicles has been one of the popular and well-studied approaches for delivering drug to deeper layers of the skin or even systemic circulation. Flexible/deformable/elastic liposomal systems such as invasomes, Transfersomes®, ethosomes, niosomes, etc. have demonstrated encouraging results in delivering small molecules and large proteins to the skin. It is necessary to recognize the promising concepts and analyze their potential, since a clear understanding of the drawbacks and advantages of these approaches will lead towards future development. In the current review we have attempted to give an overview of different liposomal drug carriers for transdermal drug delivery and their efficiency as drug delivery system through different in vivo and in vitro studies. Also, an overview of the studies which investigated the interactions between skin and vesicles, which have lead us to our current understanding of the skin penetration mechanisms of liposomal formulations is presented.
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Stratum corneum is the primary skin barrier to percutaneous absorption. Since 1980, topical liposomal formulations have been proposed and successfully employed for increasing the drug penetration ...through the skin. There is no clear consensus on the drug penetration mechanism from topically applied liposomes, despite a vast amount of research. One of the reasons for the ambiguity is that the interactions between the stratum corneum and liposomes are in nanoscale, which makes them difficult to probe. In this study, we employed tip-enhanced Raman scattering (TERS) to gain a better understanding of the interactions between the human stratum corneum and topically applied liposomal system called invasomes. TERS is capable of imaging at nanometer spatial resolution and can provide structural information at the nanometer scale. A sample preparation technique was developed and calibrated to enable TERS on complex stratum corneum samples. Invasomes prepared from a head deuterated phospholipid were employed to aid identification of topically applied liposomal phospholipid in the stratum corneum. Results presented in this study give for the first time a strong spectroscopic evidence along with high-resolution images to show intact invasome vesicles deep in the stratum corneum upon topical application.
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•Tip-enhanced Raman scattering (TERS) is proposed as a method to probe nanoscale invasome skin penetration.•Deuteration of lipids allows a clear distinction between cell membrane and vesicles in the skin.•Direct spectroscopic and topographic evidence of intact invasome migration into the stratum corneum is demonstrated.
Today, many of the newly developed pharmaceuticals and medical devices take advantage of nanotechnology and with a rising incidence of chronic diseases such as diabetes and cardiovascular disease, ...the number of patients afflicted globally with non-healing wounds is growing. This has created a requirement for improved therapies and wound care. However, converting the strategies applied in early research into new products is still challenging. Many of them fail to comply with the market requirements. This review discusses the legal and scientific challenges in the design of nanomedicines for wound healing. Are they lost in translation or is there a new generation of therapeutics in the pipeline?
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Purpose There are several endogenous and exogenous species in the gastrointestinal (GI) tract which can act as solubilizing agents and thereby affect drug dissolution. The purpose of this study is to ...understand food effects on drug dissolution and provide insight into their anticipated overall effect on absorption and bioavailability. Methods Dissolution kinetics of 15 drugs of variable logP, charge, and molecular weight were tested in simulated intestinal environment. The ability of a film-equilibrium-based model to predict the influence of a simulated intestinal environment on drug dissolution was examined. Results The most significant improvement in dissolution kinetics and solubility (up to 6-fold) was evident with highly hydrophobic compounds (logP > 4). Improvement in solubility did not always constitute improvement in dissolution kinetics on a relevant time scale. Comparison of simulation and experimental results indicates that a model considering micelle partitioning as a pseudo-equilibrium process can predict trends in the influence of food-related solubilizing agents on drug dissolution kinetics. Conclusions The significance of food-related solubilizing agents to drug dissolution is not always obvious, as it depends on multiple physicochemical parameters; however, simple modeling may provide insight into food effects on dissolution and, ultimately, overall absorption and bioavailability of compounds considered for oral formulation.
Nanomedicines - Tiny particles and big challenges Marques, Margareth R.C.; Choo, Qiuyi; Ashtikar, Mukul ...
Advanced drug delivery reviews,
November-December 2019, 2019 Nov - Dec, 2019-11-00, 20191101, Letnik:
151-152
Journal Article
Recenzirano
After decades of research, nanotechnology has been used in a broad array of biomedical products including medical devices, drug products, drug substances, and pharmaceutical-grade excipients. But ...like many great achievements in science, there is a fine balance between the risks and opportunities of this new technology. Some materials and surface structures in the nanosize range can exert unexpected toxicities and merit a more detailed safety assessment. Regulatory agencies such as the United States Food and Drug Administration or the European Medicines Agency have started dealing with the potential risks posed by nanomaterials. Considering that a thorough characterization is one of the key aspects of controlling such risks this review presents the regulatory background of nanosafety assessment and provides some practical advice on how to characterize nanomaterials and drug formulations. Further, the challenges of how to maintain and monitor pharmaceutical quality through a highly complex production processes will be discussed.
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Today, tacrolimus represents a cornerstone of immunosuppressive therapy for liver and kidney transplants and remains subject of preclinical and clinical investigations, aiming at the development of ...long-acting depot formulations for subcutaneous injection.
One major challenge arises from establishing in vitro-in vivo correlations due to the absence of meaningful in vitro methods predictive for the in vivo situation, together with a strong impact of multiple kinetic processes on the plasma concentration-time profile. In the present approach, two microsphere formulations were compared with regards to their in vitro release and degradation characteristics. A novel biorelevant medium provided the physiological ion and protein background. Release was measured using the dispersion releaser technology under accelerated conditions. A release of 100% of the drug from the carrier was achieved within 7 days. The capability of the in vitro performance assay was verified by the level A in vitro-in vivo correlation analysis. The contributions of in vitro drug release, drug degradation, diffusion rate and lymphatic transport to the absorption process were quantitatively investigated by means of a mechanistic modelling approach. The degradation rate, together with release and diffusion characteristics provides an estimate of the bioavailability and therefore can be a guide to future formulation development.
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•DR technology detects release and degradation of tacrolimus in biorelevant medium.•State-of-the-art computational framework to evaluate dialysis experiments.•Capability to predict the in vivo performance confirmed by IVIVC of two formulations.•Pharmacokinetic data obtained in relevant species (cynomolgus monkeys).•PBB model elucidates relevant influences on bioavailability in subcutaneous tissue.
Foscan®, a formulation comprising temoporfin dissolved in a mixture of ethanol and propylene glycol, has been approved in Europe for palliative photodynamic therapy of squamous cell carcinoma of the ...head and neck. During clinical and preclinical studies it was observed that considering the administration route, the drug presents a rather atypical plasma profile as plasma concentration peaks delayed. Possible explanations, as for example the formation of a drug depot or aggregation after intravenous administration, are discussed in current literature.
In the present study an advanced in silico model was developed and evaluated for the detailed description of Foscan® pharmacokinetics. Therefore, in vitro release data obtained from experiments with the dispersion releaser technology investigating dissolution pressures of various release media on the drug as well as in vivo data obtained from a clinical study were included into the in silico models. Furthermore, precipitation experiments were performed in presence of biorelevant media and precipitates were analyzed by nanoparticle tracking analysis. Size analysis and particle fraction were also incorporated in this model and a sensitivity analysis was performed. An optimal description of the in vivo situation based on in vitro release and particle characterization data was achieved, as demonstrated by an absolute average fold error of 1.21. This in vitro-in vivo correlation provides an explanation for the pharmacokinetics of Foscan® in humans.
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The present study compares three vesicular systems, cationic LeciPlex, invasomes, and conventional liposomes for their ability to deliver drugs deep into the skin. Skin penetration ...ability of the three vesicular systems was studied for two drugs namely idebenone (antioxidant/anticancer) and azelaic acid (antiacne). All systems showed sizes in nanometer range with small polydispersity indices. Vesicular systems were characterized by CryoTEM studies to understand the differences in morphology of the vesicular systems. Ex vivo human skin penetration studies suggested a pattern in penetration of drugs in different layers of the skin: LeciPlex showed higher penetration for idebenone whereas invasomes showed higher penetration of azelaic acid. Ex vivo study using a fluorescent dye (DiI) was performed to understand the differences in the penetration behavior of the three vesicular systems on excised human skin. In vitro cytotoxicity studies on B16F10 melanoma cell lines revealed, when loaded with idebenone, LeciPlex formulations had the superior activity followed by invasomes and liposomes. In vitro antimicrobial study of azelaic acid loaded systems on Propionibacterium acne revealed high antimicrobial activity for DDAB leciplex followed by almost equal activity for invasomes and CTAB LeciPlex followed by liposomes. Whereas antiacne efficacy study in rats for azelaic acid loaded systems, invasomes exhibited the best antiacne efficacy followed by liposomes and LeciPlex.
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The stratum corneum is a strong barrier that must be overcome to achieve successful transdermal delivery of a pharmaceutical agent. Many strategies have been developed to enhance the ...permeation through this barrier. Traditionally, drug penetration through the stratum corneum is evaluated by employing tape-stripping protocols and measuring the content of the analyte. Although effective, this method cannot provide a detailed information regarding the penetration pathways. To address this issue various microscopic techniques have been employed. Raman microscopy offers the advantage of label free imaging and provides spectral information regarding the chemical integrity of the drug as well as the tissue. In this paper we present a relatively simple method to obtain XZ-Raman profiles of human stratum corneum using confocal Raman microscopy on intact full thickness skin biopsies. The spectral datasets were analysed using a spectral unmixing algorithm. The spectral information obtained, highlights the different components of the tissue and the presence of drug. We present Raman images of untreated skin and diffusion patterns for deuterated water and beta-carotene after Franz-cell diffusion experiment.
Understanding the structure and the self-assembly process of cochleates has become increasingly necessary considering the advances of this drug delivery system towards the pharmaceutical industry. It ...is well known that the addition of cations like calcium to a dispersion of anionic lipids such as phosphatidylserines results in stable, multilamellar cochleates through a spontaneous assembly. In the current investigation we have studied the intermediate structures generated during this self-assembly of cochleates. To achieve this, we have varied the process temperature for altering the rate of cochleate formation. Our findings from electron microscopy studies showed the formation of ribbonlike structures, which with proceeding interaction associate to form lipid stacks, networks and eventually cochleates. We also observed that the variation in lipid acyl chains did not make a remarkable difference to the type of structure evolved during the formation of cochleates. More generally, our observations provide a new insight into the self-assembly process of cochleates based on which we have proposed a pathway for cochleate formation from phosphatidylserine and calcium. This knowledge could be employed in using cochleates for a variety of possible biomedical applications in the future.
