Potentiality of Q3 characterization of nanosystem: Surrogate data for obtaining a biowaiver.

A tremendous increase in the entry of drug delivery systems (DDSs) based on nanotechnology has been observed as a result of the ability of pharmaceutical nanotechnology to overcome the various drawbacks related to the first generation DDS. The patent period of these proprietary branded drugs gives its manufacturers sole exclusivity of their product in the market. As the patent period of these products expire, the generic players will initiate their attempts to manufacture and bring generic versions of the reference listed drug product (RLD) into the market. The regulatory approval for a generic DDS based on nanotechnology requires proving the therapeutic equivalence of the generic product with that of the RLD via pharmacodynamics clinical endpoint study on healthy subjects or patients. These studies are extremely complex, expensive and time-consuming and may have uncertain outcomes. Furthermore, development, scale-up and manufacturing of generic versions of nanotechnology-based DDS involves complex steps and achieving an optimized formulation heavily depends on the process parameters during manufacturing. The information in this review addresses the said issues above and emphasizes on the possibility of using exhaustive in vitro characterization of the generic versions of nanotechnology-based DDSs in the current market to obtain a biowaiver. Various processes involved and their importance in obtaining an optimized formulation have been described to address the issue regarding manufacturing complexities.

1988-2018: Thirty years of drug smuggling at the nano scale. Challenges and opportunities of cell-penetrating peptides in biomedical research.

In 1988, two unrelated papers reported the discovery of peptide vectors with innate cell translocation properties, setting the ground for a new area of research that over the years has grown into considerable therapeutic potential. The vectors, named cell-penetrating peptides (CPPs), constitute a now large and diversified family, sharing the extraordinary ability to diffuse unaltered across cell membranes while ferrying diverse associated cargos. Such properties have made CPPs ideal tools for delivery of nucleic acids, proteins and other therapeutic/diagnostic molecules to cells and tissues via covalent conjugation or complexation. This year 2018 marks the 30th anniversary of a peptide research landmark opening new perspectives in drug delivery. Given its vastness, exhaustive coverage of the main features and accomplishments in the CPP field is virtually impossible. Hence this manuscript, after saluting the above 30th jubilee, focuses by necessity on the most recent contributions, providing a comprehensive list of recognized CPPs and their latest-reported applications over the last two years. In addition, it thoroughly reviews three areas of peptide vector research of particular interest to us, namely (i) efficient transport of low-bioavailability drugs into the brain; (ii) CPP-delivered disruptors of G protein-coupled receptor (GPCRs) heteromers related to several disorders, and (iii) CPP-mediated delivery of useful but poorly internalized drugs into parasites.

100 Years of Drug Delivery to the Lungs.

Inhalation therapy is one of the oldest approaches to the therapy of diseases of the respiratory tract. It is well recognised today that the most effective and safe means of treating the lungs is to deliver drugs directly to the airways. Surprisingly, the delivery of therapeutic aerosols has a rich history dating back more than 2,000 years to Ayurvedic medicine in India, but in many respects, the introduction of the first pressurised metered-dose inhaler (pMDI) in 1956 marked the beginning of the modern pharmaceutical aerosol industry. The pMDI was the first truly portable and convenient inhaler that effectively delivered drug to the lung and quickly gained widespread acceptance. Since 1956, the pharmaceutical aerosol industry has experienced dramatic growth. The signing of the Montreal Protocol in 1987 to reduce the use of CFCs as propellants for aerosols led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern pMDIs, dry powder inhalers and nebuliser systems. There is also great interest in tailoring particle size to deliver drugs to treat specific areas of the respiratory tract. One challenge that has been present since antiquity still exists, however, and that is ensuring that the patient has access to the medication and understands how to use it effectively. In this article, we will provide a summary of therapeutic aerosol delivery systems from ancient times to the present along with a look to the future.

Chemical materials and their regulation of the movement of molecules.

Materials chemistry has been fundamental to the enormous field that encompasses the delivery of molecules both to desired sites and/or at desired rates and durations. The field encompasses the delivery of molecules including fertilizers, pesticides, herbicides, food ingredients, fragrances and biopharmaceuticals. A personal perspective is provided on our early work in this field that has enabled the controlled release of ionic substances and macromolecules. Also discussed are new paradigms in creating biomaterials for human use, the non-invasive delivery of molecules through the skin and lungs, the development of intelligent delivery systems and extensions to nanomedicine. With the advent of potentially newer biopharmaceutics such as siRNA, mRNA and gene editing approaches and their use being limited by delivery, future research in this field may be more critical than ever before.

A Retrospective 30 Years After Discovery of the Enhanced Permeability and Retention Effect of Solid Tumors: Next-Generation Chemotherapeutics and Photodynamic Therapy--Problems, Solutions, and Prospects.

Solid tumor has unique vascular architecture, excessive production of vascular mediators, and extravasation of macromolecules from blood vessels into the tumor tissue interstitium. These features comprise the phenomenon named the EPR effect of solid tumors, described in 1986. Our investigations on the EPR revealed that many mediators, such as bradykinin, NO, and prostaglandins, are involved in the EPR effect, which is now believed to be the most important element for cancer-selective drug delivery. However, tumors in vivo manifest great diversity, and some demonstrate a poor EPR effect, for example, because of impaired vascular flow involving thrombosis, with poor drug delivery and therapeutic failure. Another important element of this effect is that it operates in metastatic cancers. Because few drugs are currently effective against metastases, the EPR effect offers a great advantage in nanomedicine therapy. The EPR effect can also be augmented two to three times via nitroglycerin, ACE inhibitors, and angiotensin II-induced hypertension. The delivery of nanomedicines to tumors can thereby be enhanced. In traditional PDT, most PSs had low MW and little tumor-selective accumulation. Our hydroxypropylmetacrylamide-polymer-conjugated-PS, zinc protoporphyrin (apparent MW >50 kDa) showed tumor-selective accumulation, as revealed by fluorescent imaging of autochthonous cancers. After one i.v. injection of polymeric PS followed by two or three xenon light irradiation/treatments, most tumors regressed. Thus, nanoprobes with the EPR effect seem to have remarkable effects. Enhancing the EPR effect by using vascular modulators will aid innovations in PDT for greater tumor-targeted drug delivery.

The History of Target-Controlled Infusion.

Target-controlled infusion (TCI) is a technique of infusing IV drugs to achieve a user-defined predicted ("target") drug concentration in a specific body compartment or tissue of interest. In this review, we describe the pharmacokinetic principles of TCI, the development of TCI systems, and technical and regulatory issues addressed in prototype development. We also describe the launch of the current clinically available systems.

History and present state of targeted intrathecal drug delivery.

Nearly 50 years ago, the seminal experiments of Melzack and Wall, culminating in the gate control theory, coupled with the discovery of endogenous opioid receptors, helped shape modern understandings of pain and provided interventionalists a potent therapeutic gateway to neuraxial analgesia. This paper emphasizes the historical antecedents, present state, and emerging future of the neuromodulatory technique of targeted intrathecal drug delivery (TIDD) for chronic pain. The strengths of TIDD are its customizability, reversibility, programmability, and low risk profile. Its benefits are evidenced by improved pain relief and quality of life and reduced demand for health-care resources.

Skin--'that unfakeable young surface'.

The 20- to 25-year period from the mid-1960s to the early 1990s represents, in many ways, a 'golden era' in the understanding of skin barrier function, percutaneous penetration and (trans)dermal drug delivery. From the ground-breaking mechanistic work of Scheuplein and Blank, and the 'gold standard' in vivo skin absorption experiments of Feldmann and Maibach, through the unravelling of the stratum corneum's structural and physicochemical characteristics that make it such an incredible feat of bioengineering, to the elegant biophysical and modelling studies of Potts, Francoeur and many others, the idea of administering drugs rationally to treat both local and systemic diseases was transformed from something close to the ravings of a lunatic to the reality of significant therapeutic and commercial success. This short article attempts to pick out some of the highlights along the way from the viewpoint of an interested observer and occasional participant in the 'action'. © 2013 S. Karger AG, Basel.

Brian Barry: innovative contributions to transdermal and topical drug delivery.

Brian Barry published over 300 research articles across topics ranging from colloid science, vasoconstriction and the importance of thermodynamics in dermal drug delivery to exploring the structure and organisation of the stratum corneum barrier lipids and numerous strategies for improving topical and transdermal drug delivery, including penetration enhancers, supersaturation, coacervation, eutectic formation and the use of varied liposomes. As research in the area blossomed in the early 1980s, Brian wrote the book that became essential reading for both new and established dermal delivery scientists, explaining the background mathematics and principles through to formulation design. Brian also worked with numerous scientists, as collaborators and students, who have themselves taken his rigorous approach to scientific investigation into their own research groups. This paper can only describe a small fraction of the many significant contributions that Brian made to the field during his 40-year academic career.

Analysing the skin barrier from down under.

Over the past 40 years the Australian contribution to the field of skin science has been led by Michael Roberts. One of his earliest papers on membrane permeation was published in Nature, setting the scene for his huge contribution to both the fundamental understanding of skin permeability and the application of that knowledge to improved clinical outcomes, new delivery technologies and minimizing toxicological risk. His work has been characterized by a mechanistic, mathematical approach to defining skin permeation. He defined the parameters important to skin permeation, established structure-penetration relationships and demonstrated the importance of maximum flux from a clinical and toxicological viewpoint. Through his systematic approach, Mike showed a parabolic relationship between maximum flux and lipophilicity, and established that this is driven mainly by variations in solubility of the solute in the stratum corneum. One of the significant strengths of Mike's work is the ability to express biological concepts in mathematical terms. He has developed mathematical models that enhance our understanding of epidermal, dermal, deep tissue permeation and follicular transport. Throughout his career Mike has been involved in pioneering new technologies both for analysing the skin barrier and influencing permeation across it. His fundamental work in the area of iontophoresis provided models that defined the parameters influencing its permeation enhancement. Mike's research has been translated into improved clinical outcomes, reduced toxicological risk and changes to the regulation of skin products. This article provides an insight into Mike Roberts and the Australian contribution to skin science.

Engineering approaches to transdermal drug delivery: a tribute to contributions of prof. Robert Langer.

Transdermal drug delivery continues to provide an advantageous route of drug administration over injections. While the number of drugs delivered by passive transdermal patches has increased over the years, no macromolecule is currently delivered by the transdermal route. Substantial research efforts have been dedicated by a large number of researchers representing varied disciplines including biology, chemistry, pharmaceutics and engineering to understand, model and overcome the skin's barrier properties. This article focuses on engineering contributions to the field of transdermal drug delivery. The article pays tribute to Prof. Robert Langer, who pioneered the engineering approach towards transdermal drug delivery. Over a period spanning nearly 25 years since his first publication in the field of transdermal drug delivery, Bob Langer has deeply impacted the field by quantitative analysis and innovative engineering. At the same time, he has inspired several generations of engineers by collaborations and mentorship. His scientific insights, innovative technologies, translational efforts and dedicated mentorship have transformed the field.

Happy birthday cell penetrating peptides: already 20 years.

The recent discovery of new potent therapeutic molecules that do not reach the clinic due to poor delivery and low bioavailability has made of delivery a keystone in therapeutic development. Several technologies have been designed to improve cellular uptake of therapeutic molecules, including cell-penetrating peptides (CPPs). CPPs were discovered 20 years ago based on the potency of several proteins to enter cells. So far numerous CPPs have been described which can be grouped into two major classes, the first requiring chemical linkage with the drug for cellular internalization, the second involving formation of stable, non-covalent complexes with cargos. Nowadays, CPPs constitute as a very promising tool for non-invasive cellular import of cargos and have been successfully applied for ex vivo and in vivo delivery of therapeutic molecules varying from small chemical molecules, nucleic acids, proteins, peptides, liposomes to particles. This short introduction will highlight the major breakthroughs in the CPP history, which have driven these delivery agents to the clinic.

Topical drug delivery: History, percutaneous absorption, and product development.

Topical products, widely used to manage skin conditions, have evolved from simple potions to sophisticated delivery systems. Their development has been facilitated by advances in percutaneous absorption and product design based on an increasingly mechanistic understanding of drug-product-skin interactions, associated experiments, and a quality-by-design framework. Topical drug delivery involves drug transport from a product on the skin to a local target site and then clearance by diffusion, metabolism, and the dermal circulation to the rest of the body and deeper tissues. Insights have been provided by Quantitative Structure Permeability Relationships (QSPR), molecular dynamics simulations, and dermal Physiologically Based PharmacoKinetics (PBPK). Currently, generic product equivalents of reference-listed products dominate the topical delivery market. There is an increasing regulatory interest in understanding topical product delivery behavior under 'in use' conditions and predicting in vivo response for population variations in skin barrier function and response using in silico and in vitro findings.

Nanotechnologies for the delivery of biologicals: Historical perspective and current landscape.

Biological macromolecule-based therapeutics irrupted in the pharmaceutical scene generating a great hope due to their outstanding specificity and potency. However, given their susceptibility to degradation and limited capacity to overcome biological barriers new delivery technologies had to be developed for them to reach their targets. This review aims at analyzing the historical seminal advances that shaped the development of the protein/peptide delivery field, along with the emerging technologies on the lead of the current landscape. Particularly, focus is made on technologies with a potential for transmucosal systemic delivery of protein/peptide drugs, followed by approaches for the delivery of antigens as new vaccination strategies, and formulations of biological drugs in oncology, with special emphasis on mAbs. Finally, a discussion of the key challenges the field is facing, along with an overview of prospective advances are provided.

Living with Insulin: The story of insulin from people with diabetes.

The history of insulin is rightly considered one of the most beautiful stories in medicine which goes even further than the extraordinary result of tens of millions of lives saved. Without a doubt, it constitutes a major achievement for medical science which, especially in the last 50 years, has led to an impressive acceleration in the succession of new treatment opportunities. We are going to describe the history of insulin therapy, the history we lived from two different angles as people living with type 1 diabetes, and obviously also as diabetologists, but as diabetologists with diabetes. Without a doubt, insulin and his story constitutes a major achievement for medical science which has led to an impressive acceleration in the succession of new treatment opportunities. Care opportunities that have not only allowed fundamental improvements in outcomes, but have also and above all impacted the quality of life of people with diabetes. Summarizing one hundred years of insulin is no simple endeavor. In our view, it would be easier, and probably more befitting, to focus on the last 50 years, namely the period we have lived closely and personally together with insulin. More to the point, these last 50 years have witnessed a dramatic acceleration of research and innovation. In our opinion, it is precisely the innovations in insulin therapy introduced from the last decades that fully justify the description of events in this incredible period as "the miracle of insulin". We'll describe how the most important innovations introduced in the last decades had impact on what we have nowadays, as patients and diabetologits: today, we can finally adapt insulin therapy to the patient's life or lifestyle, reversing what was the perception of patients until 20 years, when insulin was considered, by the most, as an obstacle, which seemed insurmountable to some, to a free and unconstrained life.

Translation of the Philadelphia chromosome into therapy for CML.

Throughout its history, chronic myeloid leukemia (CML) has set precedents for cancer research and therapy. These range from the identification of the first specific chromosomal abnormality associated with cancer to the development of imatinib as a specific, targeted therapy for the disease. The successful development of imatinib as a therapeutic agent for CML can be attributed directly to decades of scientific discoveries. These discoveries determined that the BCR-ABL tyrosine kinase is the critical pathogenetic event in CML and an ideal target for therapy. This was confirmed in clinical trials of imatinib, with imatinib significantly improving the long-term survival of patients with CML. Continuing in this tradition of scientific discoveries leading to improved therapies, the understanding of resistance to imatinib has rapidly led to strategies to circumvent resistance. Continued studies of hematologic malignancies will allow this paradigm of targeting molecular pathogenetic events to be applied to many additional hematologic cancers.

Bulk flow and diffusion revisited, and clinical applications.

The first Klatzo-Lecture pays homage to an exceptional academician, scientist and teacher. The author spent nearly 1 year in Klatzo's laboratory at the NHI in Bethesda, and the first part of results presented here originate directly from this collaboration. It was shown that following cortical injury, movement of edema fluid into the tissue occurs by bulk flow, and that the driving force is a small tissue pressure gradient. Resolution of edema fluid is achieved by clearance into the ventricular and subarachnoid CSF, is enhanced in the presence of pressure gradients and is supported by re-absorption into capillaries. Using appropriate techniques, the formation rate as well as clearance of edema into CSF and tissue resorption could be determined in human brain metastases and malignant gliomas. Three examples of clinical applications based on the discussed mechanisms are presented: a. Fluorescence-guided surgery of gliomas is based on the accumulation of 5-ALA in tumour cells; there being enzymatically converted to PP-IX, a compound with deep red fluorescence. This fluorescence is used for the more accurate surgical removal of gliomas. b. Radioimmunotherapy of gliomas uses an anti-tenascin antibody, coupled with a nuclide, administered postoperatively into the tumour cavity, from where it diffuses into tissue, couples to the receptor at the glioma cells. Then the isotope destroys the tumour cells. c. Convection-enhanced delivery is based on the interstitial infusion of an appropriate cytotoxic drug into the white matter at low pressure. Thus, the method employs bulk flow, distributes a drug in a larger tissue volume and eventually achieves drug concentrations greater than systemic levels. Experimental studies and clinical results are presented for all three clinical applications.I am very grateful to Z. Czernicki and the organizing group for being offered the great honour of presenting the first Igor Klatzo Lecture. In this report first previous results of bulk flow and diffusion in the development and resolution of brain edema will be revisited, then some recent examples will be shown as to how this knowledge of diffusion and bulk flow can be transferred into clinical applications.A great part of the work on bulk flow and diffusion was done during a stay in I. Klatzo's laboratory in Bethesda in 1973/1974 (Fig. 1). Since then a long collaboration developed with I. Klatzo and M. Spatz. Due to given limits, I will concentrate on the studies of our group. Unfortunately it will not be possible to mention all the important groups who have contributed by essential studies.