Sustained-release capsules of Ofev (nintedanib), which is used to treat idiopathic pulmonary fibrosis (IPF), were better at reaching systemic circulation in the body than the current marketed formulation, according to a study.
Findings also suggested that the sustained-release formula of Ofev increased its absorption in the gut.
Electrospray technology uses electrostatic forces to produce micro- or nano-scale particles. This allows for improvements in delivering the medicine effectively and efficiently to the patient.
Boehringer Ingelheim’s Ofev is an approved treatment for IPF. It is marketed as a soft capsule with a reported low bioavailability — the proportion that reaches circulation and has an active effect — requiring higher treatment doses.
As a result, alternative formulations with higher bioavailability are needed to prolong Ofev’s therapeutic effects, improve patient compliance, lower the frequency of administration, and reduce side effects.
A team from China and the U.S. believed that a capsule that was able to delay or control the rate of Ofev’s release in the body might be the solution, with the aid of electrospray technology.
For this purpose, Ofev was prepared as a solid dispersion — formed by highly dispersed insoluble compounds in solid carrier materials — to improve its solubility. The carrier used was polyvinylpyrrolidone (PVP), a water-soluble polymer.
The researchers found that increasing the amounts of PVP and phospholipids — types of molecules that are the main components of cell membranes — led to faster Ofev release from the solid dispersion. They also optimized the electrospray parameters used by setting a liquid flow rate of 0.3 mL/h, a voltage of 21 kV, and 0.5 mm as the optimal needle inner diameter (leading to uniform and separated solid dispersions).
The team found that the accumulative release rate of the optimized Ofev solid dispersion was more than 60% in 30 minutes and 100% in one hour.
Sustained-release capsules were then prepared based on Ofev solid dispersion. Microcrystalline cellulose (MCC) was chosen as the diluent, given its superior sustained-release effect over starch and lactose.
The release rate of the new Ofev capsules was nearly 35% after two hours, 55% after six hours, 71% after eight hours, and 94% after 12 hours, with clear sustained release in vitro. The bioavailability and sustained release of the new formulation was then tested in rats.
Results showed that Ofev solid dispersion was absorbed in all intestinal segments of the animals, with no significant differences from in vitro. This means it “can effectively increase the absorption rate of the drug in each intestinal segment, which is conducive to improving the oral absorption,” the researchers wrote.
Furthermore, the time at which maximum concentration was achieved was three hours for the marketed soft capsule, two hours for solid dispersion, and six hours for the sustained-release capsules. The maximum concentration was 2.945 mg/mL for the soft capsule, 5.32 mg/mL for solid dispersion, and 3.75 mg/mL for the sustained-release capsules.
Importantly, the average bioavailability of the sustained release capsules was 162.55% relative to the soft capsule, and 104.89% relative to the solid dispersion.
“The results suggested superior bioavailability and a sustained-release effect from nintedanib [Ofev] sustained-release capsules, as compared to the reference (commercial nintedanib soft capsule),” the researchers concluded.