In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clinical trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biologic. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clinical trials, with ~40% of trials listed in clinicaltrials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorganic and metallic particles in clinical trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clinical trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials (“theranostics”) and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what additional testing (e.g. safety and toxicity) is required before products become available.

Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date.

Nanomaterials hold promise as multifunctional diagnostic and therapeutic agents. However, the effective application of nanomaterials is hampered by limited understanding and control over their interactions with complex biological systems. When a nanomaterial enters a physiological environment, it rapidly adsorbs proteins forming what is known as the protein ‘corona’. The protein corona alters the size and interfacial composition of a nanomaterial, giving it a biological identity that is distinct from its synthetic identity. The biological identity determines the physiological response including signalling, kinetics, transport, accumulation, and toxicity. The structure and composition of the protein corona depends on the synthetic identity of the nanomaterial (size, shape, and composition), the nature of the physiological environment (blood, interstitial fluid, cell cytoplasm, etc.), and the duration of exposure. In this critical review, we discuss the formation of the protein corona, its structure and composition, and its influence on the physiological response. We also present an ‘adsorbome’ of 125 plasma proteins that are known to associate with nanomaterials. We further describe how the protein corona is related to the synthetic identity of a nanomaterial, and highlight efforts to control protein–nanomaterial interactions. We conclude by discussing gaps in the understanding of protein–nanomaterial interactions along with strategies to fill them (167 references).

Understanding and controlling the interaction of nanomaterials with proteins in a physiological environment

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications.

The protection and controlled release of bioactive compounds at the right time and the right place can be implemented by encapsulation. Nanoencapsulation remains to be the one of the most promising technologies having the feasibility to entrap bioactive compounds. Nanoencapsulation of bioactive compounds has versatile advantages for targeted site-specific delivery and efficient absorption through cells. However, researches in the application of nanotechnology in the food industry have been very limited and there are only a few review articles that explored the nanoencapsulation technology. This review focuses on the various nanoencapsulation techniques such as emulsification, coacervation, inclusion, complexation nanoprecipitation, emulsification–solvent evaporation, and supercritical fluid for food ingredients. Drying techniques such as spray drying and freeze drying for stabilization of nanoparticles are also discussed. Current state of knowledge, limitations of these techniques, and recent trends are also discussed. Finally, safety and regulatory issues in the nanoencapsulation of bioactive compounds are also highlighted.

Nanoencapsulation Techniques for Food Bioactive Components: A Review

Nanocrystals: Industrially feasible multifunctional formulation technology for poorly soluble actives

Introduction: Polyethylene glycol (PEG) is a polymer of choice in drug delivery systems. This USFDA-approved polymer is popular due to its tunable properties and well-established safety profile: prime requisites considered during the selection of any excipient in formulation development.Areas covered: The unique properties and applications of PEG have been discussed at length in the existing literature. However, a proper guidance on selection of PEG grade to cater to one’s purpose is lacking. This article provides preliminary guidelines to formulators on selection of appropriate PEG grade, typically based on its physico-chemical properties and role-based functional application in pharmaceuticals. It should be noted that the aim article is not to deep dive in each application area.Expert opinion: Guidance on PEG application and grade of choice is lacking in the available literature. The authors have discussed and provided guidance to formulators on the appropriate PEG grade selection for particular...

Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications

In 1990, the lipid nanoparticles were invented in the laboratories, the first patent filings took place in 1991. The lipid nanoparticles were developed as alternative to traditional carriers such as polymeric nanoparticles and liposomes. After 20 years of lipid nanoparticles, the present state of development is reviewed - academic progress but also the development state of pharmaceutical products for the benefit of patients. Meanwhile many research groups are active worldwide, their results are reviewed which cover many different administration routes: dermal and mucosal, oral, intravenous/ parenteral, pulmonary but also ocular. The lipid nanoparticles are also used for peptide/protein delivery, in gene therapy and various miscellaneous applications (e.g. vaccines). The questions of large scale production ability, accepted regulatory status of excipients, and - important for the public perception - lack of nanotoxicity are discussed, important pre-requisites for the use of each nanocarrier in products. Identical to the liposomes, the lipid nanoparticles entered first the cosmetic market, product examples are presented. Presently the pharmaceutical product development focuses on products for unmet needs and on niche products with lower development costs (e.g. ocular delivery), which can be realized also by smaller companies. A pharmaceutical perspective for the future is given, but also outlined the opportunities for non-pharmaceutical use, e.g. in nutraceuticals.

Ranjita Shegokar

Papers

Nanocrystals: Industrially feasible multifunctional formulation technology for poorly soluble actives

Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications

20 years of lipid nanoparticles (SLN and NLC): present state of development and industrial applications.

Lipid nanocarriers for dermal delivery of lutein: preparation, characterization, stability and performance.

Lutein nanocrystals as antioxidant formulation for oral and dermal delivery.