Breaking Silos of Formulations in Preclinical, First-in-Human Trial, and Phase 3 Clinical Trial Stages

K. Olmstead
Nano PharmaSolutions, Inc.,
United States

Keywords: poorly soluble drugs, drug solubility, improved bioavailability, nanoformulation, nano-granulation, physical vapor deposition


Over 80% of small drug candidates are insoluble (BCS Class II or IV). Preclinical animal safety study formulations are often widely different than first-in-human formulations. Preclinical scientists often use strong solvent/surfactants to solubilize poorly soluble drug candidates to achieve a maximum exposure level in animals, however the same formulation may not be suitable for human clinical trials. For the first-in-human (FIH) Phase 1 clinical trial, minimal efforts are made for oral formulation development of these insoluble drugs, which makes the bioavailability sub-par, and also result in strong food-effect. Phase 1 clinical trials have a failure rate of approximately 40%, and improper formulation of insoluble drugs makes up a large portion of the failure rate. After FIH trial, major efforts are made to improve drug solubility using excipients/particle engineering. Per the FDA, changes in bioavailability between the FIH trials and Phase 2/3 trials require a bioequivalency tests. The silo effect seen in various stages of drug development programs can be avoided by using an enabled (solubility enhanced) formulations from the preclinical stages, and maintaining essentially the same formulation. Many pharmaceutical development scientists wish for an easily scalable formulation that does not require a large amount of drug nor development time. Sadly that option is not widely available today. Nano-granulation is a technology developed to address this need for a single formulation for all stages of development that and is very fast to develop for all small molecule drugs. By generating drug nanoparticles without using any additives, the resulting nano-granules are free of harsh chemicals or bulky excipients. Nanosized APIs can easily and quickly be compounded into oral gavage (for small animals), powder-in-capsule (for large animals and human), or tablets (for late-stage clinical supplies). Drug nanoparticles are generated by a physical vapor deposition (PVD) method that is widely used in industrial applications from aerospace to semiconductor industries. The development process is rapid, and it is easily scalable to multi-kilogram scales. Clinical supply manufacturing is also available through a contract manufacturing partnership. This non-chemical nanodrug delivery technology will break the silos and high failure rates of the fit-for-purpose drug delivery methods that have been used for decades.