Using a novel drug-delivery approach, IIT Hyderabad researchers have made oral administration of the drug Amphotericin B for treating Kala-azar and fungal infection possible. The drug encapsulated in polymer nanofibres and made into tablets was released in a controlled and sustained manner for 10 days.
By encapsulating an antifungal drug in polymer nanofibres, researchers at the Indian Institute of Technology (IIT) Hyderabad have been able to achieve controlled and sustained release of the drug for up to 10 days. As a result, no fungal growth was seen up to seven days when the drug (Amphotericin B) was encapsulated in the polymer. The encapsulated drug can also be used for treating Kala-azar.
Most importantly, the antifungal activity against Candida albicans was observed when the encapsulated drug was compressed to form oral tablets. This would mean that oral administration of the drug might become possible if initial results achieved in the lab can be replicated in animal and human clinical trials. Currently, oral administration of the drug has major challenges — high toxicity, reduced bioavailability in the body due to poor solubility in water and high cost.
Researchers from IIT Hyderabad led by Prof. Chandra S. Sharma and Prof. Saptarshi Majumdar from the Department of Chemical Engineering produced nanofibres containing the drug by electrospinning the drug- gelatine polymer solution. The gelatine polymer is extremely water-loving (hydrophilic) and so is not stable. To increase the stability and allow the drug to be released in a controlled and sustained manner, the researchers used a commercially available crosslinker.
“The drug is found on the surface of the gelatine nanofibres but remains encapsulated when compressed into tablets,” says Prof. Majumdar.
“The cross-linked polymer matrix allows the drug to diffuse slowly when the polymer degrades. We have controlled the diffusion rate so it is released over a period of 10 days,” says Prof. Sharma. Only in vitro studies have been carried to test the stability of the tablet and controlled release. The results of the study were published in the journal Nano-Structures & Nano-Objects.
Since the main goal was to study if the drug can be administered orally, the researchers tested the stability of the tablet for eight hours at extremely acidic condition (1.5 pH). The stomach has acidic pH and the polymer should be stable for up to four hours. After eight hours at low pH, the tablets were kept for 10 days in an alkaline medium of 7.4 pH. “The tablets were stable for eight hours at low pH. The polymer matrix showed signatures of degradation after the sixth day but was stable for 10 days,” says Mrunalini K. Gaydhane from IIT Hyderabad and one of the first authors of the paper.
The researchers found that each day 10% of the drug was released from the polymer through diffusion. The drug was completely released from the polymer matrix at the end of the 10th day.
“We had used mice fibroblast cells for testing toxicity of the drug. There was negligible toxicity to cells even at the end of five days. In fact, the cells continued to multiply,” says Gaydhane.
Only 20 mg of the drug in 500 mg of polymer was used for making the table used for testing. “Our next target is to achieve the same drug release profile with dosages used for therapeutic purposes,” Prof. Sharma says.
The chemical crosslinker used in the study is highly toxic. In order to reduce toxicity, the researchers exposed the gelatine polymer to saturated vapour of the crosslinker for just six-eight minutes. In the conventional process, crosslinking takes 24 hours to complete. “Reducing the time taken to cross-link reduces toxicity. But we are now looking at increasing the stability of the polymer matrix without using any crosslinker,” Prof. Majumdar says.