A once-a-week Parkinson’s injection could replace multiple daily pills, thanks to a new slow-release formulation developed by researchers. It promises easier treatment, fewer missed doses, and better symptom control.
The established best practice treatment for Parkinson’s disease is levodopa and carbidopa, taken together in a pill, three to five times a day. Levodopa replaces the dopamine that is lost due to the disease, and carbidopa ensures that levodopa is converted to dopamine in the brain, where it’s needed, and not in the bloodstream. But for people with swallowing difficulties, taking multiple daily doses can be especially challenging.
That’s why it’s significant that researchers from the Center for Pharmaceutical Innovation at the University of South Australia (UniSA) have developed a slow-release, injectable version of this drug combination that is given weekly.
“Levodopa is the gold-standard therapy for Parkinson’s, but its short life span means it must be taken several times a day,” said Professor Sanjay Garg, a pharmaceutical scientist and the study’s corresponding author. “Our goal was to create a formulation that simplifies treatment, improves patient compliance, and maintains consistent therapeutic levels of medication. This weekly injection could be a game-changer for Parkinson’s care.”
Something called the “on-off phenomenon” is an almost constant consequence of long-term levodopa treatment, experienced by people with Parkinson’s disease. “On” periods are times when the medication is working effectively, and symptoms are less noticeable. “Off” periods are when the medication’s effects have worn off, and symptoms return or get worse. This phenomenon is largely due to levodopa’s short half-life, which causes fluctuating levels of the drug in the bloodstream. It’s usually what necessitates an increase in the frequency of daily levodopa doses.
With this in mind, the researchers set about developing an injectable formulation of levodopa combined with carbidopa that would be slowly released over seven days. They created a liquid formulation using biodegradable polymers that solidifies into a depot (implant) when injected into muscle tissue, triggered by contact with body fluids.
They tested multiple batches with varying polymer ratios and found that the optimal formulation contained 26% PLGA (poly-lactic-co-glycolic acid) and 6% Eudragit L-100. PLGA is an FDA-approved, fast-degrading polymer used to control the drug’s release rate. Eudragit L-100 is a pH-sensitive polymer primarily used as a coating for controlled-release tablets. Because it dissolves at a pH above 6.0, the researchers considered it ideal for an intramuscular drug formulation, although the combination of both polymers to form an in-situ drug implant had not been reported before. The decided-upon formulation was low-viscosity and easily injectable; it solidified in the body.
Lab testing of the optimized formulation showed it released about 35% of levodopa and about 37% of carbidopa within the first 24 hours. Up to 92% levodopa and 81% carbidopa were released over seven days. Then they injected the drug into pig muscle to simulate the human body. The drug’s release in muscle tissue closely mirrored lab data, and implants showed over 80% degradation in seven days and complete degradation by day 13.
The force required to inject the drug through a standard 22-gauge needle – commonly used for intramuscular injections – was well within acceptable limits. Tests of cell viability showed moderate dose-dependent toxicity (cytotoxicity), in line with previous levodopa studies. Simulations of the predicted effect in humans suggested that the implant would maintain therapeutic blood levels of the medication for six days or more.
“The implications of this research are profound,” Garg said. “By reducing the frequency of dosing from multiple times a day to weekly injection is a major step forward in Parkinson’s therapy. We’re not just improving how the drug is delivered, we’re improving patients’ lives.”
In addition to eliminating the need for Parkinson’s patients to take multiple pills a day, which is a huge benefit for elderly patients or those with swallowing issues, a weekly injection would reduce the risk of missed doses and avoid the peaks and troughs in medication levels that contribute to the on-off phenomenon. For a patient comfort perspective, the injectable nature of the implantable treatment means that it is minimally invasive and does not require surgery.
The researchers have filed a patent for the long-acting injectable in Australia and are exploring commercialization opportunities. They hope to start clinical trials in the near future.
The study was published in the journal Drug Delivery and Translational Research.
Source: University of South Australia