The development of new drugs can be divided into four main stages: (1) Drug Discovery, (2) Preclinical Studies, (3) Clinical Studies, and (4) New Drug Application (NDA). During the preclinical stage, studies on pharmacokinetics and toxicology are conducted. These studies involve animal subjects such as rats, mice, rabbits, and monkeys, necessitating the use of simple formulations (non-clinical formulations) for animal dosing. Early drug molecules, which were typically small and sufficiently soluble, could be handled with simple formulations. However, most contemporary drug molecules have poor solubility, rendering traditional formulations inadequate. Thus, the development of preclinical formulations (PCF) is required to meet the needs of preclinical research.
Primary Purposes of Early Preclinical Formulations
Early preclinical formulations are mainly used for pharmacology studies, pharmacokinetics studies, and general toxicology studies. Pharmacology investigates the interactions between drugs and the body and serves as a bridge between pharmacy, medicine, basic medical science, and clinical medicine. It includes the study of pharmacodynamics (PD) and pharmacokinetics (PK). PK focuses on the body's actions on the drug, including absorption, distribution, metabolism, and excretion (ADME), as well as the relationship between drug effects and blood concentration over time. PD examines the effects and mechanisms of drugs on the body. General toxicology studies the toxic effects of chemical substances within specific dose ranges over different exposure periods, including acute and chronic toxicity studies. The goals of the studies, the species of animals used, the routes of administration, the frequency and duration of dosing, and other factors all influence the strategies for developing early preclinical formulations.
Preclinical research primarily involves animals such as rats, mice, dogs, monkeys, rabbits, and pigs. The most commonly used are rats, mice, dogs, and monkeys. Animals are categorized by size into small animals (rats and mice) and large animals (dogs, monkeys, rabbits, and pigs). Small animals, like rats and mice, are used extensively for screening due to their small size, rapid breeding, and ease of modeling for efficacy studies. Large animals are required for preclinical studies to predict human pharmacokinetics, with dogs, monkeys, and rabbits being the most frequently used, particularly rats.
Dogs in Preclinical Research
Besides rats and mice, dogs, particularly Beagles, are commonly used in experiments. Adult Beagles typically weigh between 7-10 kg, have a docile temperament, keen sense of smell and hearing, and adapt well to different environments, making them easy to manage and train. Their small size facilitates experimental procedures and maintenance, and they exhibit stable and excellent genetic characteristics without hereditary neurological diseases, providing reproducible and consistent results in studies. Beagles are highly resilient, with strong resistance to diseases, making them ideal for experiments. Their organs function consistently, and their body temperature remains stable, ensuring reliable responses in experiments. Beagles reach sexual maturity relatively early (8-12 months), have a high litter size, and are non-aggressive, simplifying laboratory management. Their cheerful disposition remains intact even after multiple trials. These attributes make Beagles the most suitable experimental dogs recognized by the international medical and biological community. Common methods of administering drugs to experimental dogs include subcutaneous injection, intramuscular injection, intravenous injection, and oral gavage.
Monkeys in Preclinical Research
Monkeys are also widely used in preclinical research due to their close anatomical and genetic similarity to humans, unlike rodents such as mice and rabbits. Monkeys can be infected with almost all human diseases and viruses, making their use in preclinical trials more accurate. Commonly used experimental monkeys include the crab-eating macaque and the rhesus macaque. In the 1960s, human drug preclinical trials were conducted only on rats. A drug called thalidomide, intended to treat morning sickness in pregnant women, was approved after rat testing. However, it led to tragic consequences: over 10,000 newborns in more than 30 countries were born with phocomelia (severe limb malformations) due to thalidomide's side effects. This tragedy occurred because of the significant genetic differences between rats and humans. To prevent such tragedies, governments worldwide raised the standards for drug clinical trial approvals. The FDA now requires drugs or vaccines to be tested on both rodents (like rats or mice) and non-rodents (like dogs and monkeys) before entering clinical trials. Similarly, in China, all new drug developments must be backed by reliable conclusions from studies on non-human primates before proceeding to clinical research.
