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Biomaterials Jan 2021Transdermal drug delivery exhibited encouraging prospects, especially through superficial drug administration routes. However, only a few limited lipophilic drug... (Review)
Review
Transdermal drug delivery exhibited encouraging prospects, especially through superficial drug administration routes. However, only a few limited lipophilic drug molecules could cross the skin barrier, those are with low molecular weight and rational Log P value. Microneedles (MNs) can overcome these limitations to deliver numerous drugs into the dermal layer by piercing the outermost skin layer of the body. In the case of superficial cancer treatments, topical drug administration faces severely low transfer efficiency, and systemic treatments are always associated with side effects and premature drug degradation. MN-based systems have achieved excellent technical capabilities and been tested for pre-clinical chemotherapy, photothermal therapy, photodynamic therapy, and immunotherapy. In this review, we will focus on the features, progress, and opportunities of MNs in the anticancer drug delivery system. Then, we will discuss the strategies and advantages in these works and summarize challenges, perspectives, and translational potential for future applications.
Topics: Administration, Cutaneous; Antineoplastic Agents; Drug Delivery Systems; Microinjections; Needles; Pharmaceutical Preparations
PubMed: 32979655
DOI: 10.1016/j.biomaterials.2020.120410 -
Journal of Controlled Release :... Aug 2022Strategies that rely on oral mucosal administration have increased in the last decade and oromucosal products are paving the way to overcome specific challenges, namely... (Review)
Review
Strategies that rely on oral mucosal administration have increased in the last decade and oromucosal products are paving the way to overcome specific challenges, namely improving drug bioavailability when compared with the conventional oral route, due to a reduction of the hepatic first-pass metabolism and pre-systemic degradation. Overall, the advantages of these products make oromucosal route of administration attractive for the development of value-added medicines, which can address more properly the unmet medical needs of specific patients. Generally, such products have an easy and convenient administration since they do not require water for ingestion, which may be particularly relevant for geriatric and pediatric groups, or non-cooperative patients. Usually, the development of these products aims to provide a faster onset of action, critical for acute or emergency treatments. Although oriented to achieve better therapeutic outcomes, today's drug development is primarily focused on patient-centered care, meaning that patients' specific characteristics/needs are an important driving force behind product-development efforts. In accordance, pharmaceutical innovation can rely not only on new drug substances but also on re-formulation of already approved ones or alternative routes of administration, enhancing patient convenience, treatment efficacy and/or safety. Throughout this review, the oromucosal drug products, approved in the last decade, and a retrospective analysis of their critical quality attributes and specifications will be described. Furthermore, trends and opportunities of the latest technologies in this field, as well as the number of ongoing clinical studies, will be presented and discussed.
Topics: Administration, Mucosal; Administration, Oral; Aged; Biological Availability; Child; Humans; Pharmaceutical Preparations; Retrospective Studies
PubMed: 35660635
DOI: 10.1016/j.jconrel.2022.05.053 -
The AAPS Journal Aug 2022Oligonucleotide therapeutics (ONTs) are a diverse group of short synthetic nucleic acid-based molecules that exploit innovative intracellular molecular strategies to... (Review)
Review
Oligonucleotide therapeutics (ONTs) are a diverse group of short synthetic nucleic acid-based molecules that exploit innovative intracellular molecular strategies to create novel treatments for a variety of medical conditions. ONT molecules (~7-15 kDa) reside between traditional large and small molecules, and there has been debate regarding their immunogenicity risk. To date, 13 ON drugs have been approved, and as the field is relatively new, there are currently no specific regulatory guidelines to indicate how to develop, validate, and interpret the immunogenicity assays of ONTs. Some investigators do not test for immune responses to ONs while others test for antibodies (Abs) to components within the formulation, which may or may not include aspects of characterization such as domain mapping of ONT conjugates. Similar to other biopharmaceuticals, the immunogenic properties of ONTs could be influenced by sequence, route, dosage, target population, co-medications, etc. The current anti-drug antibody (ADA) data for different approved ONTs suggest that their administration poses a low immunogenicity risk without any significant impact on pharmacokinetics (PK), pharmacodynamics (PD), and safety; nevertheless, until the field matures with data from many more ON drugs, it remains prudent to assess immunogenicity. The emphasis of this article is to highlight how current ADA methodologies might be applied to the development of ONTs, discuss factors that may pose immunogenicity risks, and provide the authors' current position on immunogenicity assessment strategies for ONTs. We also discuss assay parameters that may be appropriate for the detection and characterization of ADAs, including the evaluation of neutralizing ADAs, ADA isotyping, Abs to dsDNA, and pre-existing ADA. Immunogenicity risk assessments (IRAs) and early interactions with regulators will inform how to proceed in late stage/pivotal studies.
Topics: Antibodies; Antibody Formation; Biological Products; Oligonucleotides; Pharmaceutical Preparations
PubMed: 36028587
DOI: 10.1208/s12248-022-00741-x -
Pharmaceutical Research May 2024Currently, the lengthy time needed to bring new drugs to market or to implement postapproval changes causes multiple problems, such as delaying patients access to new...
Currently, the lengthy time needed to bring new drugs to market or to implement postapproval changes causes multiple problems, such as delaying patients access to new lifesaving or life-enhancing medications and slowing the response to emergencies that require new treatments. However, new technologies are available that can help solve these problems. The January 2023 NIPTE pathfinding workshop on accelerating drug product development and approval included a session in which participants considered the current state of product formulation and process development, barriers to acceleration of the development timeline, and opportunities for overcoming these barriers using new technologies. The authors participated in this workshop, and in this article have shared their perspective of some of the ways forward, including advanced manufacturing techniques and adaptive development. In addition, there is a need for paradigm shifts in regulatory processes, increased pre-competitive collaboration, and a shared strategy among regulators, industry, and academia.
Topics: Humans; Drug Approval; Drug Development; Drug Industry; Technology, Pharmaceutical; Pharmaceutical Preparations; Chemistry, Pharmaceutical; Drug Compounding
PubMed: 38698195
DOI: 10.1007/s11095-024-03708-z -
Pharmaceutical Development and... Sep 2020Mucosa has now been recognized as a potential site for both local and systemic delivery of therapeutics. Mucoadhesive drug delivery systems with customizable release... (Review)
Review
Mucosa has now been recognized as a potential site for both local and systemic delivery of therapeutics. Mucoadhesive drug delivery systems with customizable release profiles have recently gained considerable interest among formulation scientists to improve clinical outcomes of drugs. This review summarizes the current development in the processing methods and polymers involved in mucoadhesive drug delivery systems. Mucoadhesive drug delivery systems are suitable for drugs that have a localized effect, undergo extensive pre-systemic metabolism, narrow absorption window, and narrow therapeutic index. Polymer characteristics like surface charge, hydrophilic surface groups, wettability, molecular weight, chain flexibility, molecular conformations, etc. are critical for assessing the extent of mucoadhesiveness and treatment response. The current review focuses on valuable principles, merits, drawbacks, and future outlooks of different mucoadhesive drug delivery systems.
Topics: Adhesiveness; Animals; Drug Administration Routes; Drug Compounding; Drug Delivery Systems; Forecasting; Humans; Mouth Mucosa; Pharmaceutical Preparations
PubMed: 32267180
DOI: 10.1080/10837450.2020.1753771 -
Journal of Pharmaceutical Sciences Feb 2023Regulatory authorities and the scientific community have identified the need to monitor the in vivo stability of therapeutic proteins (TPs). Due to the unique...
Regulatory authorities and the scientific community have identified the need to monitor the in vivo stability of therapeutic proteins (TPs). Due to the unique physiologic conditions in patients, the stability of TPs after administration can deviate largely from their stability under drug product (DP) conditions. TPs can degrade at substantial rates once immersed in the in vivo milieu. Changes in protein stability upon administration to patients are critical as they can have implications on patient safety and clinical effectiveness of DPs. Physiologic conditions are challenging to simulate and require dedicated in vitro models for specific routes of administration. Advancements of in vitro models enable to simulate the exposure to physiologic conditions prior to resource demanding pre-clinical and clinical studies. This enables to evaluate the in vivo stability and thus may allow to improve the safety/efficacy profile of DPs. While in vitro-in vivo correlations are challenging, benchmarking DP candidates enables to identify liabilities and optimize molecules. The in vivo stability should be an integral part of holistic stability assessments during early development. Such assessments can accelerate development timelines and lead to more stable DPs for patients.
Topics: Humans; Pharmaceutical Preparations; Protein Stability; Drug Stability
PubMed: 36202247
DOI: 10.1016/j.xphs.2022.09.032 -
Molecules (Basel, Switzerland) Jan 2023Central nervous system (CNS) disorders are a therapeutic area in drug discovery where demand for new treatments greatly exceeds approved treatment options. This is... (Review)
Review
Central nervous system (CNS) disorders are a therapeutic area in drug discovery where demand for new treatments greatly exceeds approved treatment options. This is complicated by the high failure rate in late-stage clinical trials, resulting in exorbitant costs associated with bringing new CNS drugs to market. Computer-aided drug design (CADD) techniques minimise the time and cost burdens associated with drug research and development by ensuring an advantageous starting point for pre-clinical and clinical assessments. The key elements of CADD are divided into ligand-based and structure-based methods. Ligand-based methods encompass techniques including pharmacophore modelling and quantitative structure activity relationships (QSARs), which use the relationship between biological activity and chemical structure to ascertain suitable lead molecules. In contrast, structure-based methods use information about the binding site architecture from an established protein structure to select suitable molecules for further investigation. In recent years, deep learning techniques have been applied in drug design and present an exciting addition to CADD workflows. Despite the difficulties associated with CNS drug discovery, advances towards new pharmaceutical treatments continue to be made, and CADD has supported these findings. This review explores various CADD techniques and discusses applications in CNS drug discovery from 2018 to November 2022.
Topics: Computer-Aided Design; Ligands; Drug Design; Psychotropic Drugs; Pharmaceutical Preparations
PubMed: 36770990
DOI: 10.3390/molecules28031324 -
Physical Review. E Jan 2022During the outbreak of a virus, perhaps the greatest concern is the future evolution of the epidemic: How many people will be infected and which regions will be affected...
During the outbreak of a virus, perhaps the greatest concern is the future evolution of the epidemic: How many people will be infected and which regions will be affected the most? The accurate prediction of an epidemic enables targeted disease countermeasures (e.g., allocating medical staff and quarantining). But when can we trust the prediction of an epidemic to be accurate? In this work we consider susceptible-infected-susceptible (SIS) and susceptible-infected-removed (SIR) epidemics on networks with time-invariant spreading parameters. (For time-varying spreading parameters, our results correspond to an optimistic scenario for the predictability of epidemics.) Our contribution is twofold. First, accurate long-term predictions of epidemics are possible only after the peak rate of new infections. Hence, before the peak, only short-term predictions are reliable. Second, we define an exponential growth metric, which quantifies the predictability of an epidemic. In particular, even without knowing the future evolution of the epidemic, the growth metric allows us to compare the predictability of an epidemic at different points in time. Our results are an important step towards understanding when and why epidemics can be predicted reliably.
PubMed: 35193247
DOI: 10.1103/PhysRevE.105.014302 -
Physical Review. E Apr 2023In competitive settings that entail several populations, individuals often engage in intra- and interpopulation interactions that determine their fitness and...
In competitive settings that entail several populations, individuals often engage in intra- and interpopulation interactions that determine their fitness and evolutionary success. With this simple motivation, we here study a multipopulation model where individuals engage in group interactions within their own population and in pairwise interactions with individuals from different populations. We use the evolutionary public goods game and the prisoner's dilemma game to describe these group and pairwise interactions, respectively. We also take into account asymmetry in the extent to which group and pairwise interactions determine the fitness of individuals. We find that interactions across multiple populations reveal new mechanisms through which the evolution of cooperation can be promoted, but this depends on the level of interaction asymmetry. If inter- and intrapopulation interactions are symmetric, the sole presence of multiple populations promotes the evolution of cooperation. Asymmetry in the interactions can further promote cooperation at the expense of the coexistence of the competing strategies. An in-depth analysis of the spatiotemporal dynamics reveals loop-dominated structures and pattern formation that can explain the various evolutionary outcomes. Thus, complex evolutionary interactions in multiple populations reveal an intricate interplay between cooperation and coexistence, and they also open up the path toward further explorations of multipopulation games and biodiversity.
Topics: Humans; Cooperative Behavior; Biological Evolution; Game Theory; Prisoner Dilemma
PubMed: 37198848
DOI: 10.1103/PhysRevE.107.044301 -
Journal of Pharmaceutical Sciences Sep 2021Therapeutic proteins are administered by injection or infusion. After administration, the physiologic environment in the desired body compartment - fluid or tissue - can... (Review)
Review
Therapeutic proteins are administered by injection or infusion. After administration, the physiologic environment in the desired body compartment - fluid or tissue - can impact protein stability and lead to changes in the safety and/or efficacy profile. For example, protein aggregation and fragmentation are critical quality attributes of the drug product and can occur after administration to patients. In this context, the in vivo stability of therapeutic proteins has gained increasing attention. However, in vivo protein aggregation and fragmentation are difficult to assess and have been rarely investigated. This mini-review summarizes analytical approaches to assess the stability of therapeutic proteins using simulated physiologic conditions. Furthermore, we discuss factors potentially causing in vivo protein aggregation, precipitation, and fragmentation in complex biological fluids. Different analytical approaches are evaluated with respect to their applicability and possible shortcomings when it comes to these degradation events in biological fluids. Tracking protein stability in biological fluids typically requires purifying or labeling the protein of interest to circumvent matrix interference of biological fluids. Improved analytical methods are strongly needed to gain knowledge on in vivo protein aggregation and fragmentation. In vitro models can support the selection of lead candidates and accelerate the pre-clinical development of therapeutic proteins.
Topics: Humans; Pharmaceutical Preparations; Protein Aggregates; Protein Stability; Proteins
PubMed: 33933436
DOI: 10.1016/j.xphs.2021.04.014