Preclinical research for inhaled formulations is the stage in which inhaled formulations are comprehensively evaluated and validated prior to clinical trials. Key research can be conducted including drug characteristics evaluation, atomization performance evaluation, animal pharmacokinetics and toxicity studies, stability studies and toxicology evaluation. The goal of preclinical research on inhaled preparations is to fully understand the performance, safety and effectiveness of inhaled preparations, provide scientific basis for subsequent clinical trials, and ensure the quality and efficacy of inhaled preparations in clinical applications.
Currently, Medicilon can provide a complete safety evaluation of inhaled preparations (pharmacokinetics, toxicokinetics, safety pharmacology, toxicology, reproductive toxicology) and has accumulated a lot of experience in the development of inhalation preparations for many years. Before the test, a preliminary exploration of particle size, concentration, and aerosol generation will be conducted. During the experiment, aerosol concentration detection, temperature and humidity detection, oxygen/carbon dioxide detection and particle size detection were carried out regularly. There are also many detection points and high frequency during the experiment. The status of the animals is monitored in real time during the inhalation administration process. After the experiment, the animals will be subjected to detailed clinical observation, gross anatomy, and histopathological evaluation of various tissues of the respiratory system.
Previously, Xinyu Chen, the Leader of Medicilon Toxicology Research Department, was a guest in the Cloud Lecture Hall and explained the key points of preclinical research on inhaled preparations. Medicilon has compiled the questions and answers, hoping to help or reduce everyone’s worries about inhaled preparations.
Inhalation drug R&D platform
Medicilon is familiar with the development process and has extensive R&D experience of various inhalation formulations, especially in the field of DPI, nebulizer and nasal spray. The R&D team are fully integrated with the requirements of global policies, regulations and guidelines.
Q：What are the factors that may affect pulmonary particle absorption?
A：This issue is critical, and the influencing factors mainly include the following aspects: physiological and pathological conditions of the lungs, patient factors, physical and chemical properties of the drug, formulation factors, and delivery devices. Pathological conditions in the lungs, such as respiratory pathologies caused by respiratory infections, may alter the deposition pattern of inhaled therapeutic sprays. In chronic airway diseases (e.g., asthma, COPT) and fibrosis, focusing on the goblet cell to ciliated cell ratio, excessive mucus secretion may lead to airway obstruction and impair normal mucosal cell clearance. Second, patient factors such as the amount, frequency, and type of inhalation can influence the extent of drug deposition in the lungs. In addition, the physical and chemical properties of the drug, dosage form factors and delivery device also have an impact on pulmonary absorption.
Q：What are the specific details of the national standard OECD guiding principles?
A：The OECD issued the latest version of the inhalation toxicity testing guidelines in June 2018, which includes OECD 412 subacute 28-day inhalation toxicity testing and OECD 433 acute inhalation toxicity testing. These testing guidelines have been developed to take into account the increasing emergence of novel test subjects, such as bionanomaterials. Additionally, animal welfare and testing methods were revised to ensure their accuracy and reliability.
Q：What are the clinical pathology and histopathology research services?
A：In terms of detection indicators, they include lung function testing, conventional pathological staining, and some special staining to reflect specific pathological changes in the lungs. For example, the deposition of foreign matter in the lungs can be observed and may lead to phagocytosis or lysis by macrophages and the release of substances such as phospholipids, which bind to alveolar surfactant and other proteins in the alveolar fluid.
Q：Pharmaceutical quality research uses finished preparations, so should animal experiments use finished products or API?
A：We usually offer two options when it comes to using API or finished dosage form, but in most cases we prefer to provide finished dosage form. The finished preparation can maintain the consistency of the preparation in subsequent clinical trials, but if API is used, it needs to be formulated according to specific conditions; for example, dry powder API has fewer ingredients. However, we still recommend that the test substance be administered in the form of a finished product.
Q：The drug concentration-time curve after atomization in animals, how to sample it, and take blood from the tail vein?
A：Tail vein blood collection is generally done on rats and mice. When we conduct blood pressure concentration detection, PK (pharmacokinetics) or TK (toxicokinetics) studies, we usually choose to take jugular vein blood collection on mice or rats. Based on the previous data or exposure provided by the client, the corresponding time curve is set to collect blood in different time periods.
Q：What animal models are generally used?
A：Oronasal exposure feeds usually include large mice or guinea pigs. For large animals, corresponding experiments will be conducted on beagles, cynomolgus monkeys or rhesus monkeys. For research on biological drugs or chemical drugs, preliminary species screening is required to determine which animal to use. Medicilon can also conduct preliminary experiments on related animal screening to help confirm which species of animal model will be selected for the trial.
Q：Approximately how many doses of medicinal solution are needed for a mouse exposure tower experiment?
A：In the case of liquid administration, the dosage of mice is usually determined based on their breathing volume. Generally, at two liters per minute, if exposure is required for 30 minutes, up to 60 ml of liquid is required. This is the liquid dosage for the radio frequency flow generator only. For devices already in clinical use, such as PARI and Aerogen generators, the amount of drug used is relatively small. For example, PARI uses about 6 ml in ten minutes, while Aerogen uses less, about 4 ml in ten minutes is enough.
