AAPS Open最新文献

Glycopeptide antimicrobials are a class of naturally occurring or semi-synthetic glycosylated products that have shown antibacterial activity against gram-positive organisms by inhibiting cell-wall synthesis. In most cases, these drugs are prepared in dry powder (lyophilized) form due to chemical and physical instability in aqueous solution; however, from an economic and practical point of view, liquid formulations are preferred. Researchers have recently found ways to formulate some glycopeptide antibiotic therapeutic drugs in aqueous solution at refrigerated or room temperature. Chemical degradation can be significantly slowed by formulating them at a defined pH with specific buffers, avoiding oxygen reactive species, and minimizing solvent exposure. Sugars, amino acids, polyols, and surfactants can reduce physical degradation by restricting glycopeptide mobility and reducing solvent interaction. This review focuses on recent studies on glycopeptide antibiotic drug stability in aqueous solution. It is organized into three sections: (i) glycopeptide antibiotic instability due to chemical and physical degradation, (ii) strategies to improve glycopeptide antibiotic stability in aqueous solution, and (iii) a survey of glycopeptide antibiotic drugs currently available in the market and their stability based on published literature and patents. Antimicrobial resistance deaths are expected to increase by 2050, making heat-stable glycopeptides in aqueous solution an important treatment option for multidrug-resistant and extensively drug-resistant pathogens. In conclusion, it should be possible to formulate heat stable glycopeptide drugs in aqueous solution by understanding the degradation mechanisms of this class of therapeutic drugs in greater detail, making them easily accessible to developing countries with a lack of cold chains.

Resveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimer's disease), anti-cancer, and anti-aging activity in experimental models (Galiniak et al., Acta Biochim Pol 66:13-21, 2019). Unfortunately, this compound exhibits low bioavailability and solubility (Galiniak et al., Acta Biochim Pol 66:13-21, 2019), requiring large doses that can cause nausea and GI distress. JOTROL^TM is a micellar 10% resveratrol solubilization formulation that is thought to increase bioavailability of resveratrol via lymphatic system absorption. Jupiter Neurosciences (formerly Jupiter Orphan Therapeutics; "Jupiter") is pursuing the use of resveratrol in mucopolysaccharidosis type 1 (MPS 1), Friedreich's ataxia, and Alzheimer's disease/mild cognitive impairment. This paper describes a first in human study (FIH) to evaluate the bioavailability of resveratrol after ascending, single oral doses up to 700 mg resveratrol as JOTROL^TM. After a single 500 mg dose of JOTROL^TM, a Cmax of 455 ng/mL was observed, vs. 85 ng/mL Cmax after a 1 g encapsulated dose (Turner et al., Neurology 85:1383-91, 2015) and 1942 ng/mL after a 2.5 g micronized dose (Howells et al., Cancer Prev Res (Phila) 4:1419-1425, 2011). In this study, resveratrol exposures (AUCs and Cmax) increased with increasing doses. This increase appears to be higher than dose-proportional for AUC_0-t and Cmax. Resveratrol and its three major conjugates accounted for 40 to 55% of the dose in urine, consistent with a high extent of absorption, but < 1% of drug-related material was intact relative to key metabolites in plasma and urine. Studies in Alzheimer's patients and in MPS 1 are currently in development to test the effect this improved bioavailability has on those patient populations (Clintrials.gov, NCT04668274, 12/16/2020, https://clinicaltrials.gov/ct2/show/NCT04668274).

Supplementary information: The online version contains supplementary material available at 10.1186/s41120-022-00058-1.

The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Controls (CMC) Community hosted two virtual panel discussions focusing on several novel regulatory review pathways for innovative oncology products: Real-Time Oncology Review (RTOR), Project Orbis, and the Product Quality Assessment Aid (PQAAid). The panel sessions were held on August 27, 2021, for the discussion of RTOR, and January 21, 2022, for the discussion of Project Orbis and the PQAAid. Both panel sessions included representatives from the US Food and Drug Administration (FDA) and subject matter experts from the pharmaceutical and biotechnology industries, with the aim of facilitating knowledge sharing on CMC-specific advantages, challenges, eligibility criteria for participation, and operational modifications instituted through the utilization of these acceleration initiatives. Key topics included managing cross-regional regulatory CMC requirements, adapting to expedited development timelines, coordinating interactions between health authorities and industry, and potential opportunities for future improvement and expansion of these programs. As RTOR, Project Orbis, and PQAAid are relatively new initiatives, the experiences shared by the panel experts are valuable for providing deeper insight into these new regulatory pathways and processes.

The COVID-19 pandemic has led to increased usage of hand sanitizer products by the public to prevent the spread of COVID-19 and decrease the likelihood of acquiring the disease. The increase in demand has also led to an increase in the number of manufacturers. This work describes the FDA's Center for Drug Evaluation and Research (CDER) laboratories efforts to develop tests to assess the quality of hand sanitizer products containing ethanol or isopropanol as the primary active ingredient. The products were evaluated for the active ingredient content and determination of the 12 impurities listed in the FDA Hand Sanitizer Temporary Guidance, followed by a spike recovery assay performed to verify the test results. Extensive method development was conducted including an investigation into the stability of ethanol, isopropanol, and the 12 impurities. Stability and kinetic studies confirmed the instability of acetal in acidic liquid hand sanitizer products during spike recovery assay testing. The headspace GC-MS method was validated according to ICH Q2 (R1) guidelines and the spike recovery assay was validated using three concentrations of standards for the drug product. During method application, six liquid hand sanitizer products were tested and all were determined to have ethanol or isopropanol above 70% v/v. Two liquid hand sanitizer products were determined to contain acetaldehyde as an impurity above the FDA recommended safety levels.

Supplementary information: The online version contains supplementary material available at 10.1186/s41120-021-00049-8.