RESUMEN
Oligonucleotide drug products commercially approved in the US and the EU are reviewed. A total of 20 products that includes 1 aptamer, 12 antisense oligonucleotides (ASOs), 6 small interfering ribonucleic acids (siRNAs), and 1 mixture of single-stranded and double-stranded polydeoxyribonucleotides have been identified. A typical oligonucleotide formulation is composed of an oligonucleotide with buffering agent(s), pH adjusting agents, and a tonicity adjusting agent. All the products are presented as 2.1 - 200 mg/mL solutions at pH between 6 and 8.7. Majority of the products are approved for intravenous (IV) and subcutaneous (SC) routes, with two for intravitreal (IVT), two for intrathecal (IT), and one for intramuscular (IM) routes. The primary packaging includes vials and prefilled syringes (PFS). Products approved for IV and IT administration routes and requiring >1.5 mL dose volumes are supplied in vials, while those approved for SC, IM, and IVT and requiring ≤1.5 mL dose volume are supplied in PFS. Based on the compiled dataset, we propose a generalized starting point for an oligonucleotide formulation during early phase development for IV, SC, and IT administration routes. Overall, we believe this harmonized evaluation and understanding of various oligonucleotide drug product attributes will help derive platform generalizations and allows for accelerated early phase development for first-in-human studies.
Asunto(s)
Oligonucleótidos , Humanos , Oligonucleótidos/química , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/química , Aprobación de Drogas , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , Estados Unidos , Embalaje de Medicamentos/métodos , Química Farmacéutica/métodosRESUMEN
In 2003, Crommelin et al. published an article titled: "Shifting paradigms: biopharmaceuticals versus low molecular weight drugs" (https://doi.org/10.1016/S0378-5173(03)00376-4). In the present commentary, 16 years later, we discuss pharmaceutically relevant aspects of the evolution of biologics since then. First, we discuss the increasing repertoire of biologics, in particular, the rapidly growing monoclonal antibody family and the advent of advanced therapy medicinal products. Next, we discuss trends in formulation and characterization as well as summarize our current insights into immunogenicity of biologics. We spend a separate section on new product(ion) paradigms for biologics, such as cell-free production systems, production of advanced therapy medicinal products, and downscaled production approaches. Furthermore, we share our views on issues related to reaching the patient, including routes and techniques of administration, alternative development models for affordable biologics, biosimilars, and handling of biologics. In the concluding section, we outline outstanding issues and make some suggestions for resolving those.
Asunto(s)
Anticuerpos Monoclonales/química , Productos Biológicos/síntesis química , Biosimilares Farmacéuticos/síntesis química , Biotecnología/métodos , Química Farmacéutica/métodos , Anticuerpos Monoclonales/administración & dosificación , Productos Biológicos/administración & dosificación , Biosimilares Farmacéuticos/administración & dosificación , Biotecnología/tendencias , Química Farmacéutica/tendencias , Vías de Administración de Medicamentos , HumanosRESUMEN
Characterizing the in vivo biodistribution pattern and relative expression levels of oligonucleotide-based molecules such as mRNA, miRNA, siRNA, and anti-miRNAs in animal models, could be a helpful first-step in the successful development of therapeutic oligonucleotides. Here we describe a simple procedure called "Whole-Body Scanning PCR" (WBS-PCR), which combines the power of PCR with that of imaging. WBS-PCR relies on 384 well-defined extractions across a mouse whole-body section followed by a single dilution step which renders the lysates compatible with various qPCR-based assays. The in vivo biodistribution maps are generated by deconvoluting the qPCR data and converting it into a TissueView compatible image file which can be overlaid with an image of the whole-body section used for extractions. WBS-PCR is a flexible platform that can be adapted to other detection systems and thereby further expand the use of this technology.
Asunto(s)
Expresión Génica , Imagen Molecular/métodos , Oligonucleótidos/genética , Oligonucleótidos/metabolismo , Reacción en Cadena de la Polimerasa/métodos , Imagen de Cuerpo Entero/métodos , Animales , Crioultramicrotomía/métodos , Ratones , MicroARNs/genética , Modelos Animales , Oligonucleótidos/administración & dosificación , ARN Mensajero/genética , ARN Ribosómico 18S/genética , ARN Interferente Pequeño/genética , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Roedores , Distribución TisularRESUMEN
Use of antisense oligonucleotide probes (OP) for detection and genotyping of Shiga-like toxin producing Escherichia coli (SLTEC) was evaluated. Based on published deoxyribonucleic acid (DNA) sequences of the A subunits of Shiga-like toxin (SLT) I and II genes, three synthetic antisense OP were constructed (OP-1, -2 and -3). Their use for detection and genotyping of SLTEC was evaluated and the results were compared to those obtained using cloned toxin-gene probe fragments. Both the OP-1 and OP-2 hybridized with all 69 SLT-I and II producing strains. Furthermore, the OP-1 hybridized only with all 18 SLT-I-only producing strains, and the OP-2 hybridized only with all 48 SLT-II-only producing strains. OP-3, a pool of four OP, detected all SLTEC strains regardless of toxin genotype. None of the OP hybridized to any of the 91 SLT-negative strains. These results demonstrate the three OP to be unique reagents for SLTEC epidemiological studies.