Evolution of nanomedicine formulations for targeted delivery and controlled release.

Nanotechnology research over the past several decades has been aimed primarily at improving the physicochemical properties of small molecules to produce druggable candidates as well as for tumor targeting of cytotoxic molecules. The recent focus on genomic medicine and the success of lipid nanoparticles for mRNA vaccines have provided additional impetus for the development of nanoparticle drug carriers for nucleic acid delivery, including siRNA, mRNA, DNA, and oligonucleotides, to create therapeutics that can modulate protein deregulation. Bioassays and characterizations, including trafficking assays, stability, and endosomal escape, are key to understanding the properties of these novel nanomedicine formats. We review historical nanomedicine platforms, characterization methodologies, challenges to their clinical translation, and key quality attributes for commercial translation with a view to their developability into a genomic medicine. New nanoparticle systems for immune targeting, as well as in vivo gene editing and in situ CAR therapy, are also highlighted as emerging areas.

Oral peptide delivery: Translational challenges due to physiological effects.

Oral delivery of peptide therapeutics as a convenient alternate to injections has been an area of research for the pharmaceutical scientific community for the last several decades. However, systemic delivery of therapeutic peptides via the oral route has been a daunting task due to the low pH denaturation of the peptides in the stomach, enzymatic instability, and poor transport across the tight junctions resulting in very low bioavailability. The low bioavailability is accompanied by large intra- and inter-subject variability leading to translational issues, preventing the development of successful peptide therapeutics. The inter-subject variability leads to large differences in pharmacologic responses in individuals and thus the dose required to produce therapeutic effect could vary between individuals making the development of drug product a very difficult task. A substantial amount of research has been (and continues to be) performed with a focus on getting acceptable absorption and reproducible results. Nonetheless, the high variability and low bioavailability during oral administration of peptides is still a work in progress and under-explored in a systematic way. While there are several review articles and scattered publications that discuss potential technologies for oral peptide delivery, a detailed look into the physiological challenges and absorption barriers which are a hindrance to successful clinical translation, is lacking. Herein, we have analyzed the physiological barriers within the gastrointestinal (GI) tract that are the root causes for the low bioavailability and high variability of oral delivery of peptides in humans. In particular, we have taken a detailed look at the key influencing factors such as the nature of various GI tract parameters, components of the GI tract that influences the uptake, site of absorption, pH of the gastric and intestinal compartments, food effect, and role of peptidases in affecting oral peptide absorption. Lack of in vitro - in vivo correlations and variability in animal models have also been highlighted as key impediments in understanding the challenges. The unique perspective presented herein for overcoming the physiological absorption barriers, will offer better developability approaches and will positively impact clinical translation of future oral peptide therapeutics. A deep understanding of these effects are vital, given the emergence of microbiome and oral biologic drug delivery that are fast emerging as the next wave of personalized patient centric therapies.

Design control considerations for biologic-device combination products.

Combination products are therapeutic and diagnostic medical products that combine drugs, devices, and/or biological products with one another. Historically, biologics development involved identifying efficacious doses administered to patients intravenously or perhaps by a syringe. Until fairly recently, there has been limited focus on developing an accompanying medical device, such as a prefilled syringe or auto-injector, to enable easy and more efficient delivery. For the last several years, and looking forward, where there may be little to distinguish biologics medicines with relatively similar efficacy profiles, the biotechnology market is beginning to differentiate products by patient-focused, biologic-device based combination products. As innovative as biologic-device combination products are, they can pose considerable development, regulatory, and commercialization challenges due to unique physicochemical properties and special clinical considerations (e.g., dosing volumes, frequency, co-medications, etc.) of the biologic medicine. A biologic-device combination product is a marriage between two partners with "cultural differences," so to speak. There are clear differences in the development, review, and commercialization processes of the biologic and the device. When these two cultures come together in a combination product, developers and reviewers must find ways to address the design controls and risk management processes of both the biologic and device, and knit them into a single entity with supporting product approval documentation. Moreover, digital medicine and connected health trends are pushing the boundaries of combination product development and regulations even further. Despite an admirable cooperation between industry and FDA in recent years, unique product configurations and design features have resulted in review challenges. These challenges have prompted agency reviewers to modernize consultation processes, while at the same time, promoting development of innovative, safe and effective combination products. It remains the manufacturer's responsibility to comply with the relevant requirements and regulations, and develop good business practices that clearly describe how these practices comply with FDA's final rule (21 CFR Part 4) and aligns with the company's already established quality system.

Engineered in-situ depot-forming hydrogels for intratumoral drug delivery.

Chemotherapy is the traditional treatment for intermediate and late stage cancers. The search for treatment options with minimal side effects has been ongoing for several years. Drug delivery technologies that result in minimal or no side effects with improved ease of use for the patients are receiving increased attention. Polymer drug conjugates and nanoparticles can potentially offset the volume of drug distribution while enhancing the accumulation of the active drug in tumors thereby reducing side effects. Additionally, development of localized drug delivery platforms is being investigated as another key approach to target tumors with minimal or no toxicity. Development of in-situ depot-forming gel systems for intratumoral delivery of immuno-oncology actives can enhance drug bioavailability to the tumor site and reduce systemic toxicity. This field of drug delivery is critical to develop given the advent of immunotherapy and the availability of novel biological molecules for treating solid tumors. This article reviews the advances in the field of engineered in-situ gelling platforms as a practical tool for local delivery of active oncolytic agents to tumor sites.