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.

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.

Recent advancements in liposome technology.

The liposomes have continued to be well-recognized as an important nano-sized drug delivery system with attractive properties, such a characteristic bilayer structure assembling the cellular membrane, easy-to-prepare and high bio-compatibility. Extensive effort has been devoted to the development of liposome-based drug delivery systems during the past few decades. Many drug candidates have been encapsulated in liposomes and investigated for reduced toxicity and extended duration of therapeutic effect. The liposomal encapsulation of hydrophilic and hydrophobic small molecule therapeutics as well as other large molecule biologics have been established among different academic and industrial research groups. To date, there has been an increasing number of FDA-approved liposomal-based therapeutics together with more and more undergoing clinical trials, which involve a wide range of applications in anticancer, antibacterial, and antiviral therapies. In order to meet the continuing demand for new drugs in clinics, more recent advancements have been investigated for optimizing liposomal-based drug delivery system with more reproducible preparation technique and a broadened application to novel modalities, including nucleic acid therapies, CRISPR/Cas9 therapies and immunotherapies. This review focuses on the recent liposome' preparation techniques, the excipients of liposomal formulations used in various novel studies and the routes of administration used to deliver liposomes to targeted areas of disease. It aims to update the research in liposomal delivery and highlights future nanotechnological approaches.

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.

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.

B'reshith.

The Hebrew word "b'reshith" (בְּרֵאשִׁית) means "in the beginning". It is the first word and title of the Book of Genesis, and it describes a process of creation. The four authors were present at the beginning of Langer labs, and the purpose of this essay is to convey the scientific and technological zeitgeist that existed in the late 1970s and early 1980s, when Bob Langer began his exceptionally creative work. While Langer labs has branched into many other areas, Bob's unique ability to recognize important problems and entice people to look beyond their own disciplines to solve them was evident from the start. We focus on the two areas of most interest to Bob at the time, namely controlled release of macromolecules from polymers, and removal of heparin in order to prevent uncontrolled bleeding during surgery.

Big data analysis of global advances in pharmaceutics and drug delivery 1980-2014.

This review provides a comprehensive perspective of the global research advances and frontiers in pharmaceutics from 1980 to 2014. Furthermore, a historical view and future prospects of drug delivery are discussed.

The History of Therapeutic Aerosols: A Chronological Review.

In 1956, Riker Laboratories, Inc., (now 3 M Drug Delivery Systems) introduced the first pressurized metered dose inhaler (MDI). In many respects, the introduction of the MDI marked the beginning of the modern pharmaceutical aerosol industry. The MDI 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 led to a surge in innovation that resulted in the diversification of inhaler technologies with significantly enhanced delivery efficiency, including modern MDIs, dry powder inhalers, and nebulizer systems. The innovative inhalers and drugs discovered by the pharmaceutical aerosol industry, particularly since 1956, have improved the quality of life of literally hundreds of millions of people. Yet, the delivery of therapeutic aerosols has a surprisingly rich history dating back more than 3500 years to ancient Egypt. The delivery of atropine and related compounds has been a crucial inhalation therapy throughout this period and the delivery of associated structural analogs remains an important therapy today. Over the centuries, discoveries from many cultures have advanced the delivery of therapeutic aerosols. For thousands of years, therapeutic aerosols were prepared by the patient or a physician with direct oversight of the patient using custom-made delivery systems. However, starting with the Industrial Revolution, advancements in manufacturing resulted in the bulk production of therapeutic aerosol delivery systems produced by people completely disconnected from contact with the patient. This trend continued and accelerated in the 20th century with the mass commercialization of modern pharmaceutical inhaler products. In this article, we will provide a summary of therapeutic aerosol delivery from ancient times to the present along with a look to the future. We hope that you will find this chronological summary intriguing and informative.

Pieter Cullis: an outstanding lipid biophysicist, drug delivery scientist, educator, and entrepreneur.

There are much said about Pieter Cullis in this special volume honoring him. He was the pioneer to study the role of hexagonal HII phase in membrane fusion and the one who applied this concept for the design of lipid nanoparticles. He was also the first to utilize remote loading techniques for the delivery of amphipathic bases. At the same time, he is a tremendous entrepreneur and an excellent mentor. He is, without doubt, an exceptional scientist and set us an excellent model to follow.

The Evolution of Pressurized Metered-Dose Inhalers from Early to Modern Devices.

Pressurized metered-dose inhalers (pMDIs) are sometimes viewed as old-fashioned and as having been superseded by dry powder inhalers (DPIs). Here, we review the technological advances that characterize modern pMDIs, and consider how they can influence the effectiveness of drug delivery for patients with asthma and chronic obstructive pulmonary disease. Compared with old chlorofluorocarbon (CFC)-based inhalers, many hydrofluoroalkane (HFA)-driven pMDIs have more favorable plume characteristics such as a reduced velocity and a higher fine particle fraction; together, these advances have resulted in the development of pMDIs with reduced oropharyngeal deposition and increased lung deposition. In addition, the plume from many HFA-pMDIs is warmer, which may facilitate their use by patients; moreover, devices are equipped with dose counters, which improves their reliability. As well as reviewing the technological advances of pMDIs, we also discuss the importance of individualizing inhaler therapies to each patient by accounting for their personal preferences and natural breathing patterns. Because pMDIs and DPIs differ considerably in their handling characteristics, matching the right inhaler to the right patient is key to ensuring effective therapy and good compliance. Finally, the majority of patients can be trained successfully in the correct use of their pMDI; training and regular monitoring of inhalation technique are essential prerequisites for effective therapy. While the 'ideal inhaler' may not exist, pMDIs are an effective device option suitable for many patients. pMDIs, together with other types of devices, offer opportunities for the effective individualization of treatments.

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.