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Therapeutic Delivery Jul 2023The effectiveness of pharmaceutical drugs depends not only on their active components and manufacturing processes, but also on the role played by pharmaceutical... (Review)
Review
The effectiveness of pharmaceutical drugs depends not only on their active components and manufacturing processes, but also on the role played by pharmaceutical excipients. The traditional definition of excipients as inactive and cost-effective substances has evolved significantly. They are now recognized as essential elements of drug formulations, constituting 80-90% of the final product. The rapid advancements in delivery systems, along with scientific, regulatory, financial and technological developments in biopharmaceutics, have generated renewed interest in the use and functionality of excipients, especially in solid dosage forms. This review focuses on the categorization of excipients according to the International Pharmaceutical Excipient Council (IPEC) and the establishment of guidelines for evaluating the safety of a new proposed excipient.
Topics: Excipients; Chemistry, Pharmaceutical; Drug Compounding; Biopharmaceutics; Pharmaceutical Preparations
PubMed: 37464784
DOI: 10.4155/tde-2023-0026 -
Biotechnology Advances 2023Nucleic acid-based therapies such as messenger RNA have the potential to revolutionize modern medicine and enhance the performance of existing pharmaceuticals. The key... (Review)
Review
Nucleic acid-based therapies such as messenger RNA have the potential to revolutionize modern medicine and enhance the performance of existing pharmaceuticals. The key challenges of mRNA-based therapies are delivering the mRNA safely and effectively to the target tissues and cells and controlling its release from the delivery vehicle. Lipid nanoparticles (LNPs) have been widely studied as drug carriers and are considered to be state-of-the-art technology for nucleic acid delivery. In this review, we begin by presenting the advantages and mechanisms of action of mRNA therapeutics. Then we discuss the design of LNP platforms based on ionizable lipids and the applications of mRNA-LNP vaccines for prevention of infectious diseases and for treatment of cancer and various genetic diseases. Finally, we describe the challenges and future prospects of mRNA-LNP therapeutics.
Topics: Liposomes; Drug Carriers; Excipients; RNA, Messenger; Nanoparticles; RNA, Small Interfering
PubMed: 36933868
DOI: 10.1016/j.biotechadv.2023.108130 -
Nature Nanotechnology Mar 2024Inhaled delivery of mRNA has the potential to treat a wide variety of diseases. However, nebulized mRNA lipid nanoparticles (LNPs) face several unique challenges...
Inhaled delivery of mRNA has the potential to treat a wide variety of diseases. However, nebulized mRNA lipid nanoparticles (LNPs) face several unique challenges including stability during nebulization and penetration through both cellular and extracellular barriers. Here we develop a combinatorial approach addressing these barriers. First, we observe that LNP formulations can be stabilized to resist nebulization-induced aggregation by altering the nebulization buffer to increase the LNP charge during nebulization, and by the addition of a branched polymeric excipient. Next, we synthesize a combinatorial library of ionizable, degradable lipids using reductive amination, and evaluate their delivery potential using fully differentiated air-liquid interface cultured primary lung epithelial cells. The final combination of ionizable lipid, charge-stabilized formulation and stability-enhancing excipient yields a significant improvement in lung mRNA delivery over current state-of-the-art LNPs and polymeric nanoparticles.
Topics: Excipients; Cell Differentiation; Nanoparticles; Polymers; RNA, Messenger; RNA, Small Interfering
PubMed: 37985700
DOI: 10.1038/s41565-023-01548-3 -
Science Translational Medicine Sep 2023Tau pathogenesis is a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD). Although the events leading to initial tau misfolding and...
Tau pathogenesis is a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD). Although the events leading to initial tau misfolding and subsequent tau spreading in patient brains are largely unknown, traumatic brain injury (TBI) may be a risk factor for tau-mediated neurodegeneration. Using a repetitive TBI (rTBI) paradigm, we report that rTBI induced somatic accumulation of phosphorylated and misfolded tau, as well as neurodegeneration across multiple brain areas in 7-month-old tau transgenic PS19 mice but not wild-type (WT) mice. rTBI accelerated somatic tau pathology in younger PS19 mice and WT mice only after inoculation with tau preformed fibrils and AD brain-derived pathological tau (AD-tau), respectively, suggesting that tau seeds are needed for rTBI-induced somatic tau pathology. rTBI further disrupted axonal microtubules and induced punctate tau and TAR DNA binding protein 43 (TDP-43) pathology in the optic tracts of WT mice. These changes in the optic tract were associated with a decline of visual function. Treatment with a brain-penetrant microtubule-stabilizing molecule reduced rTBI-induced tau, TDP-43 pathogenesis, and neurodegeneration in the optic tract as well as visual dysfunction. Treatment with the microtubule stabilizer also alleviated rTBI-induced tau pathology in the cortices of AD-tau-inoculated WT mice. These results indicate that rTBI facilitates abnormal microtubule organization, pathological tau formation, and neurodegeneration and suggest microtubule stabilization as a potential therapeutic avenue for TBI-induced neurodegeneration.
Topics: Animals; Mice; Brain Injuries, Traumatic; Microtubules; DNA-Binding Proteins; Brain; Alzheimer Disease; Disease Models, Animal; Excipients; Mice, Transgenic
PubMed: 37703352
DOI: 10.1126/scitranslmed.abo6889 -
Journal of Pharmaceutical Sciences Jul 2023It has been nearly four decades since the first therapeutic monoclonal antibodies were approved and made available for widespread human use. Herein, US and EU approved... (Review)
Review
It has been nearly four decades since the first therapeutic monoclonal antibodies were approved and made available for widespread human use. Herein, US and EU approved antibody formulations are reviewed, and their nature and compositions are evaluated over time. From 1986 through Jan 2023, significant formulation trends have occurred and to represent this, 165 commercial antibody therapeutic formulations were binned into 5 different periods of time. Overall, we have observed the following: 1) The average formulation pH has decreased in recent years by over 0.5 units along with a decrease in variability that is largely driven by non-high concentration liquid in vial presentations for IV administration, 2) The use of certain excipients and buffers such as histidine, sucrose, metal chelators, arginine and methionine has become significantly more common, whereas formulations that contain phosphate, salt, no sugar or no surfactant have fallen out of favor, 3) Overall formulation space has increasingly become more homogenous and has converged in terms of formulation pH and excipient preferences regardless of formulation concentration, drug product presentation, and route of administration, 4) The average calculated isoelectric point (pI) has decreased 0.26 units, and 5) Overall, the average formulation pH and calculated pI for all commercial antibodies surveyed was 6.0 and 8.4, respectively. These trends and formulation convergence may be driven by multiple factors such as advancements in high-throughput computational and analytical technologies, the increased emphasis and understanding of certain developability attributes and formulation principles during lead selection and formulation development, and the adoption of low-risk development platform approaches.
Topics: Humans; Antibodies, Monoclonal; Isoelectric Point; Arginine; Excipients; Sucrose
PubMed: 37037341
DOI: 10.1016/j.xphs.2023.03.026 -
International Journal of Pharmaceutical... 2023Pharmaceutical excipients are substances formulated with an active ingredient in a medication. This article has provided a brief discussion on excipients, the...
Pharmaceutical excipients are substances formulated with an active ingredient in a medication. This article has provided a brief discussion on excipients, the purpose of excipients, the selection of appropriate excipients, the use of excipients in formulation development by compounding pharmacists/manufacturers, excipient examples and usage, the numerous incompatibilities that should be considered when choosing an excipient, and a list of adverse effects related to excipients.
Topics: Excipients; Drug Compounding
PubMed: 37816181
DOI: No ID Found -
International Journal of Pharmaceutical... 2023The impending updates to United States Pharmacopeia Chapter <797> and Chapter <795> specify that compounders must obtain active pharmaceutical ingredients and...
The impending updates to United States Pharmacopeia Chapter <797> and Chapter <795> specify that compounders must obtain active pharmaceutical ingredients and should obtain excipients from FDA-registered facilities. Additionally, the U.S. Food and Drug Administration cautions compounders to know their bulk active pharmaceutical ingredients and excipients suppliers. While the U.S. Food and Drug Administration expects 503B outsourcing facilities to qualify their critical suppliers, pharmacy boards and accrediting bodies are beginning to ask 503A compounders for their list of approved suppliers and how they qualify them. As such, pharmacies should become comfortable in qualifying suppliers as part of their quality assurance program. This article discusses how pharmacies can apply the elements of supplier qualification to their practice to ensure that critical supplies and services meet company specifications for quality and compliance.
Topics: United States; Excipients; United States Food and Drug Administration; Pharmacies; Pharmaceutical Services
PubMed: 38100663
DOI: No ID Found -
International Journal of Pharmaceutics May 2024Liposomes are widely used in the pharmaceutical industry as drug delivery systems to increase the efficacy and reduce the off-target toxicity of active pharmaceutical... (Review)
Review
Liposomes are widely used in the pharmaceutical industry as drug delivery systems to increase the efficacy and reduce the off-target toxicity of active pharmaceutical ingredients (APIs). The liposomes are more complex drug delivery systems than the traditional dosage forms, and phospholipids and cholesterol are the major structural excipients. These two excipients undergo hydrolysis and/or oxidation during liposome preparation and storage, resulting in lipids hydrolyzed products (LHPs) and cholesterol oxidation products (COPs) in the final liposomal formulations. These excipient-related impurities at elevated concentrations may affect liposome stability and exert biological functions. This review focuses on LHPs and COPs, two major categories of excipient-related impurities in the liposomal formulations, and discusses factors affecting their formation, and analytical methods to determine these excipient-related impurities.
Topics: Excipients; Liposomes; Drug Contamination; Cholesterol; Hydrolysis; Phospholipids; Oxidation-Reduction; Chemistry, Pharmaceutical; Drug Stability
PubMed: 38688429
DOI: 10.1016/j.ijpharm.2024.124164 -
International Journal of Molecular... Aug 2023Although antibodies remain the most widely used tool for biomedical research, antibody technology is not flawless. Innovative alternatives, such as Nanobody molecules,... (Review)
Review
Although antibodies remain the most widely used tool for biomedical research, antibody technology is not flawless. Innovative alternatives, such as Nanobody molecules, were developed to address the shortcomings of conventional antibodies. Nanobody molecules are antigen-binding variable-domain fragments derived from the heavy-chain-only antibodies of camelids (VHH) and combine the advantageous properties of small molecules and monoclonal antibodies. Nanobody molecules present a small size (~15 kDa, 4 nm long and 2.5 nm wide), high solubility, stability, specificity, and affinity, ease of cloning, and thermal and chemical resistance. Recombinant production in microorganisms is cost-effective, and VHH are also building blocks for multidomain constructs. These unique features led to numerous applications in fundamental research, diagnostics, and therapy. Nanobody molecules are employed as biomarker probes and, when fused to radioisotopes or fluorophores, represent ideal non-invasive in vivo imaging agents. They can be used as neutralizing agents, receptor-ligand antagonists, or in targeted vehicle-based drug therapy. As early as 2018, the first Nanobody, Cablivi (caplacizumab), a single-domain antibody (sdAb) drug developed by French pharmaceutical giant Sanofi for the treatment of adult patients with acquired thrombocytopenic purpura (aTTP), was launched. Nanobody compounds are ideal tools for further development in clinics for diagnostic and therapeutic purposes.
Topics: Antibodies, Monoclonal; Biomedical Research; Excipients; Fluorescent Dyes; Immunoglobulin Fab Fragments; Immunoglobulin Heavy Chains
PubMed: 37686035
DOI: 10.3390/ijms241713229 -
ACS Chemical Biology Sep 2023Carrier-protein-dependent metabolic pathways biosynthesize fatty acids, polyketides, and non-ribosomal peptides, producing metabolites with important pharmaceutical,...
Carrier-protein-dependent metabolic pathways biosynthesize fatty acids, polyketides, and non-ribosomal peptides, producing metabolites with important pharmaceutical, environmental, and industrial properties. Recent findings demonstrate that these pathways rely on selective communication mechanisms involving protein-protein interactions (PPIs) that guide enzyme reactivity and timing. While rational design of these PPIs could enable pathway design and modification, this goal remains a challenge due to the complex nature of protein interfaces. Computational methods offer an encouraging avenue, though many score functions fail to predict experimental observables, leading to low success rates. Here, we improve upon the Rosetta score function, leveraging experimental data through iterative rounds of computational prediction and mutagenesis, to design a hybrid fatty acid-non-ribosomal peptide initiation pathway. By increasing the weight of the electrostatic score term, the computational protocol proved to be more predictive, requiring fewer rounds of iteration to identify mutants with high in vitro activity. This allowed efficient design of new PPIs between a non-ribosomal peptide synthetase adenylation domain, PltF, and a fatty acid synthase acyl carrier protein, AcpP, as validated by activity and structural studies. This method provides a promising platform for customized pathway design, establishing a standard for carrier-protein-dependent pathway engineering through PPI optimization.
Topics: Carrier Proteins; Acyl Carrier Protein; Excipients; Fatty Acid Synthases; Fatty Acids; Metabolic Networks and Pathways
PubMed: 37671411
DOI: 10.1021/acschembio.3c00238